Hepatic Fat Fraction Research Articles

Ambient air pollution exposure is associated with liver fat and stiffness in Latino youth with a more pronounced effect in those with PNPLA3 genotype and more advanced liver disease

BackgroundExposure to ambient air pollutants has emerged as a risk for metabolic-dysfunction associated steatotic liver disease (MASLD). ObjectivesWe sought to examine associations between short-term (prior month) and long-term (prior year) ambient air pollution exposure with hepatic fat fraction (HFF) and liver stiffness in Latino youth with obesity. A secondary aim was to investigate effect modification by patatin-like phospholipase domain-containing protein 3 (PNPLA3) genotype and liver disease severity. MethodsData was analyzed from 113 Latino youth (age 11–19) with obesity in Southern California. Individual exposure to particulate matter with aerodynamic diameter ≤ 2.5μm (PM2.5), ≤ 10μm (PM10), nitrogen dioxide (NO2), 8-hour maximum ozone (8hrMax-O3), 24-hr O3, and redox-weighted oxidative capacity (Oxwt) were estimated using residential address histories and United States Environmental Protection Agency air quality observations. HFF and liver stiffness were measured using magnetic resonance imaging. Linear models were used to determine associations between short-term and long-term exposure to air pollutants with HFF and liver stiffness. Modification by PNPLA3 and liver disease severity was then examined. ResultsShort-term exposure to 8hrMax-O3 was positively associated with HFF. Relationships between air pollution exposure and HFF were not impacted by PNPLA3 genotype or liver disease severity. Long-term exposure to 8hrMax-O3 and Oxwt were positively associated with liver stiffness. Associations between air pollution exposure and liver stiffness depended on PNPLA3 genotype, such that individuals with GG genotypes exhibited stronger, more positive relationships between short-term exposure to PM10, 8hrMax-O3, 24-hr O3, and Oxwt and liver stiffness than individuals with CC/CG genotypes. In addition, relationships between short-term exposure to NO2 and liver stiffness were stronger in those with severe liver disease. DiscussionAir pollution exposure may be a risk factor for liver disease among Latino youth with obesity, particularly in those with other preexisting risks for liver damage.

6819 Adult-Onset Craniopharyngioma Patients Are at High Risk for Hepatic and Metabolic Dysfunction in the First Year After Surgery

Abstract Disclosure: O. Cooper: None. V.S. Bonert: None. M. Noureddin: Advisory Board Member; Self; GlaxoSmithKline, Novo Nordisk, Merck, Takeda, Altimmune, BI, Northsea Therapeutics, Terns, 89BIO, Madrigal, Cytodyn, Corcept. Research Investigator; Self; Bristol-Myers Squibb, Akero, BI, GlaxoSmithKline, Allergan, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis Pharmaceuticals, Novo Nordisk, Shire, Takeda, Terns, Viking, Zudus, Gilead, Corcept. Stock Owner; Self; Rivus Pharma, CIMA, Cytodyn, ChronWell. M. Ader: None. M.O. Goodarzi: Advisory Board Member; Self; Nestle Health Science, Organon Laboratories. A.N. Mamelak: None. Background: Observational studies of adult-onset craniopharyngioma (AoCP) suggest that hepatic and metabolic dysfunction begin perioperatively, but rigorous evidence is lacking. We assessed prevalence of these sequelae in AoCP to better understand their long-term impact. Methods: The retrospective study included all patients with AoCP who underwent surgery at our center from 1993 to 2017. In the prospective study, newly diagnosed patients were assessed preoperatively and at 3 and 12 months postoperatively with MRI-PDFF/elastography, frequently sampled intravenous glucose tolerance test (FSIGT), and cardiometabolic biomarkers. The primary endpoint was hepatic fat fraction change from baseline. Secondary endpoints were changes in fibrosis, glucose/insulin metabolism, hypertension (HTN), and lipids. Data are summarized as median (IQR) or mean ± SD. Results: 35 patients were followed retrospectively for a mean of 116 months. After surgery, 73% had new-onset obesity. Mean BMI increased by 5.0 ± 5.8 kg/m2 and 40% progressed from overweight to obese. 43% had new-onset type 2 diabetes mellitus (T2DM) and 39% hyperlipidemia. In 16 patients with liver imaging, 11 had metabolic dysfunction-associated steatotic liver disease (MASLD), 5 metabolic dysfunction-associated steatohepatitis (MASH), and 4 cirrhosis. In the prospective study, data from 6 patients were analyzed, 4 for ≥12 months. Median age was 48.5 (40.5, 59); 50% were female. At baseline, 17% had HTN, 50% hyperlipidemia, 67% prediabetes, 50% obesity class 1, and 17% class 2. 40% had mild steatosis and none had fibrosis. Median A1C was 5.9% (5.3, 6.1). By 3 months postop, 83% had elevated liver enzymes and median hepatic fat fraction increased 213%, with steatosis in 67%. BMI increased by 4% (-1.8, 12.5); 1 patient remained normal weight, 1 progressed to overweight, 3 remained class 1 obesity and 1 class 2. By 12 months, 50% had elevated liver enzymes and all had steatosis, with fibrosis grade 3 in 1 patient. Median hepatic fat fraction increased 670% from baseline and 62% from month 3. 50% had T2DM and 50% prediabetes. Median A1C was 6.4% (5.9, 7.3). On FSIGT, disposition index decreased by 69% (-91, 50) and insulin sensitivity decreased by 51% (-70, 46). Median BMI was 30.8 kg/m2 (25.3, 37.1); 1 patient remained normal weight, 1 was overweight, 1 class 1 obesity, and 1 class 2. 50% had HTN and 50% had hyperlipidemia. Conclusion: By 10 years after surgery, most patients with AoCP have MASLD, with some progressing to MASH, fibrosis, and cirrhosis. T2DM, hyperlipidemia, and obesity are prevalent. In our small prospective cohort, by 1 year after surgery, all patients had developed MASLD, and BMI, blood pressure, and insulin and lipid profiles worsened. These results underscore the need for early interventions to halt progression of metabolic sequelae in patients with AoCP undergoing surgical resection and impede long-term comorbidity development. Presentation: 6/3/2024

B-063 Changes in nonalcoholic fatty liver disease and M2BPGi due to lifestyle intervention in primary healthcare

Abstract Background A healthy lifestyle is the most important method for managing nonalcoholic fatty liver disease (NAFLD). Mac-2-binding protein glycosylated isomer (M2BPGi) has been suggested as a biomarker for NAFLD. This study aimed to determine the efficacy of personalized lifestyle interventions on NAFLD remission. Methods This single-arm intervention study recruited participants with NAFLD who underwent health checkups at seven health-promotion centers in five South Korean cities. Fatty liver diagnosis was based on ultrasonography (US). The 109 individuals were recruited for personalized lifestyle interventions of hypocaloric diets and exercise. The participants attended the lifestyle intervention programs once per month for the first 3 months, and once every 3 months for the subsequent 6 months. And phone-based self-monitoring were also provided monthly during the 3-month follow-up period. The primary outcome was NAFLD remission at month 12 as measured on US and magnetic resonance elastography. The secondary outcomes were the changes in metabolic factors and M2BPGi. Results The 108 individuals (62 males and 46 females; age 51.1±12.4 years, mean±standard deviation) were finally analyzed after the 12month intervention. Body mass index, waist circumference (WC), blood pressure, blood lipids (total cholesterol, triglycerides, and HDL-C), and fasting blood sugar levels were improved relative to baseline (all P<0.05). Fatty liver at or above the moderate grade according to US was decreased at month 12 relative to baseline (67.6% vs 50.9%) (P=0.002). M2BPGi levels decreased during the 12-month study period (P<0.001). M2BPGi levels were moderately correlated with hepatic fat fraction by magnetic resonance imaging (r=0.33, P=0.05). WC (OR=0.82, 95% CI=0.67-1.00, P=0.05) and HDL-C (OR=1.17, 95% CI=1.03-1.32, P=0.014) were associated with remission of fatty liver in the multivariate analysis. Conclusions The personalized lifestyle intervention was effective in improving fatty liver and metabolic factors, but not hepatic stiffness, in NAFLD.

Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis

AimsTo compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). MethodsA database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. ResultsTwenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] −51.47; 95 % confidence interval [CI]: −68.25 to −34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD −47.08; 95 % CI: −58.83 to −35.34; SUCRA 75.5), GLP-1R agonists (MD −37.36; 95 % CI: −69.52 to −5.21; SUCRA 52.3) and THR-β agonists (MD −33.20; 95 % CI: −43.90 to −22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD −9.65; 95 % CI: −19.28 to −0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD −5.79; 95 % CI: −9.50 to −2.09; SUCRA 58.2), and GLP-1RAs (MD −5.58; 95 % CI: −15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. ConclusionThese results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Quantification of liver fat using non-invasive MRI-PDFF technique versus guided biopsy in potential liver donor

IntroductionSignificant hepatic steatosis affects the outcome of surgery when living donors are transplanted. The gold standard for diagnosing and evaluating hepatic steatosis is hepatic imaging-guided biopsy. Hepatic steatosis assessment using MR spectroscopy and the proton density fat fraction (MR-PDFF) method has produced positive findings.ObjectivesIs to compare the pre-operative assessment of liver fat quantification using MRI-PDFF methods, a non-invasive method, with histopathology.Subjects and methodsA 42 potential donors were then operated surgically for liver transplantation, consequently, were available for the assessment of the efficiency and sensitivity of the radiological findings MRI-PDFF procedures and imaging-guided liver biopsy. This radiological workup of these donors was done through a period of 7 months.ResultsIn many liver transplantations centers, liver imaging-guided biopsy histopathological examination is the gold standard. The study examined the MR proton density fat fraction modality, a recently developed test for hepatic steatosis measurement. The findings indicate 86.8% sensitivity, 50% specificity, 94.2% PDV, 28.5% NPV, 83.3% accuracy, and 0.684 AUC. On analyzing the fat percent, we found that the recorded fat percent using liver imaging-guided biopsy ranges between 1 and 10% with a median of 3. On the other hand, the recorded fat percent using MRI ranged between 2 and 15% with a median of 5.ConclusionThe non-invasive magnetic resonance hepatic proton density fat fraction approach using IDEAL sequence is a reliable and accurate means of quantitatively evaluating hepatic steatosis with excellent sensitivity, specificity, and accuracy.

The Impact of Bariatric Surgery on Coronary Microvascular Function Assessed Using Automated Quantitative Perfusion CMR

BackgroundCoronary microvascular function is impaired in patients with obesity, contributing to myocardial dysfunction and heart failure. Bariatric surgery decreases cardiovascular mortality and heart failure, but the mechanisms are unclear. ObjectivesThe authors studied the impact of bariatric surgery on coronary microvascular function in patients with obesity and its relationship with metabolic syndrome. MethodsFully automated quantitative perfusion cardiac magnetic resonance and metabolic markers were performed before and 6 months after bariatric surgery. ResultsCompared with age- and sex-matched healthy volunteers, 38 patients living with obesity had lower stress myocardial blood flow (MBF) (P = 0.001) and lower myocardial perfusion reserve (P < 0.001). A total of 27 participants underwent paired follow-up 6 months post-surgery. Metabolic abnormalities reduced significantly at follow-up including mean body mass index by 11 ± 3 kg/m2 (P < 0.001), glycated hemoglobin by 9 mmol/mol (Q1-Q3: 4-19 mmol/mol; P < 0.001), fasting insulin by 142 ± 131 pmol/L (P < 0.001), and hepatic fat fraction by 5.6% (Q1-Q3: 2.6%-15.0%; P < 0.001). Stress MBF increased by 0.28 mL/g/min (Q1-Q3: −0.02 to 0.75 mL/g/min; P = 0.003) and myocardial perfusion reserve by 0.13 (Q1-Q3: −0.25 to 1.10; P = 0.036). The increase in stress MBF was lower in those with preoperative type 2 diabetes mellitus (0.1 mL/g/min [Q1-Q3: −0.09 to 0.46 mL/g/min] vs 0.75 mL/g/min [Q1-Q3: 0.31-1.25 mL/g/min]; P = 0.002). Improvement in stress MBF was associated with reduction in fasting insulin (beta = −0.45 [95% CI: −0.05 to 0.90]; P = 0.03). ConclusionsCoronary microvascular function is impaired in patients with obesity, but can be improved significantly with bariatric surgery. Improvements in microvascular function are associated with improvements in insulin resistance but are attenuated in those with preoperative type 2 diabetes mellitus.

Correlation analysis of dynamic changes of abdominal fat during rapid weight loss after bariatric surgery: A prospective magnetic resonance imaging study

ObjectiveThe factors related to the changes in the liver and abdominal adipose tissue during the rapid weight loss after bariatric surgery remain uncertain. MethodsThis study included 44 participants who had undergone sleeve gastrectomy. The study aimed to analyze changes and correlations of body weight (BW), laboratory tests, and magnetic resonance imaging (MRI) indicators of the liver and abdominal adipose tissue conducted before and after bariatric surgery at 1, 3, and 6 months. ResultsFollowing a rapid weight loss within 6 months of surgery, there was a concurrent decrease in blood glucose, blood lipids, and fat content of the liver and abdomen and the changes showed a correlation. The change of BW (ΔBW) was positively correlated with the change of hepatic proton density fat fraction (ΔPDFF) in one and three months after surgery and was positively correlated with the change of abdominal visceral fat area (ΔAVFA) in six months after surgery, (P<0.05). In one month after surgery, ΔPDFF was positively correlated with the change of aspartate aminotransferase (ΔAST), change of alanine aminotransferase (ΔALT), and change of triglyceride glucose (ΔTYG) index (P<0.05). ΔPDFF was positively correlated with the change of hepatic native T1 values (P<0.001) and was moderately negatively correlated with the change of hepatic apparent diffusion coefficient (ΔADC) values in three months after surgery (P<0.05). ConclusionΔBW can serve as an indirect indicator for evaluating changes in liver fat fraction at 1 and 3 months after bariatric surgery and indicative of changes in visceral fat 6 months after surgery. ΔPDFF was positively correlated with ΔAST, ΔALT and ΔTYG index in 1 months after surgery.

The effect of vitamin E and docosahexaenoic acid ethyl ester on Metabolic Dysfunction-Associated steatotic Liver Disease (MASLD)-A randomised, double-blind, placebo-controlled, parallel-group clinical trial (PUVENAFLD).

We conducted a clinical trial to determine the efficacy of the combination of vitamin E and/or docosahexaenoic acid (DHA) versus placebo in reducing liver fat content after 6 months of intervention in adults with MASLD. Adults with MASLD were randomised to one of four treatment arms (vitamin E 1000 mg/daily + DHA 1.89 g/daily or combination arm, vitamin E 1000 mg alone, DHA 1.89 g alone or placebo) following a 2:1:1:2 randomisation. The primary objective was to determine the efficacy of DHA + vitamin E versus placebo in reducing hepatic fat fraction (%) relative to baseline after 6 months of intervention. Secondary objectives were to determine the effect of vitamin E or DHA alone versus placebo on reducing liver fat at 6 months. Our cohort consisted of 203 subjects with a mean age of 51 years, 53% female, 91% White, 59% Hispanic ethnicity. The combination of vitamin E + DHA had no effect on the primary endpoint of reducing hepatic steatosis as determined by MRI-PDFF (p = 0.98). Neither vitamin E alone (p = 0.91) nor DHA alone (p = 0.14) significantly reduced hepatic steatosis compared to placebo. However, the trial was not powered adequately for this analysis. Compared with placebo, no statistically significant differences were detected in the 3-month or 6-month levels for ALT (U/L) or AST (U/L) in all three intervention groups. The combination of DHA + vitamin E or either agent alone did not demonstrate efficacy on reducing liver fat or aminotransferases in the studied population.

Liver fibrosis and liver stiffness in patients with obesity and type 1 diabetes.

To compare hepatic stiffness and fat fraction in patients with obesity and type 1 diabetes (T1D) with type 2 diabetes (T2D) with a similar body mass index (BMI). In this prospective cross-sectional study, 90 participants with T1D (BMI 30.5 ± 4.5 kg/m2; diabetes duration 20.5 ± 9.8 years; HbA1c 8.2% ± 1.4%) and 69 with T2D (BMI: 30.8 ± 4.6 kg/m2; diabetes duration: 11.7 ± 7.8 years; HbA1c: 7.3% ± 1.4%) were included. Liver fat fraction and stiffness were examined by magnetic resonance imaging and elastography, respectively. Logistic regressions were used to evaluate associations with biomedical variables. The mean liver stiffness score in patients with obesity and T1D was 2.2 ± 0.5 kPa, while in T2D it was 2.6 ± 0.8 kPa (P < .001). The liver fat fraction in patients with obesity and T1D was 3.7% ± 6.3%, and in T2D it was 10.6% ± 7.9% (P < .001). Metabolic dysfunction-associated steatotic liver disease (MASLD) was present in 13.3% of patients with T1D and in 69.6% of patients with T2D, whereas fibrosis was suggested in 7.8% of patients with T1D and in 27.5% of patients with T2D. Liver stiffness was four times higher in patients with T2D compared with those with T1D (odds ratio = 5.4, 95% confidence interval: 2.1-13.6, P < .001). Aspartate transaminase (AST), alanine transaminase, gamma-glutamyl transferase (GGT), triglycerides and the android-to-gynoid ratio were associated with elevated fat fraction in both cohorts. AST and GGT were associated with elevated liver stiffness in both cohorts. Patients with obesity and T1D had lower liver fat and liver stiffness compared with those patients with T2D, despite similar levels of BMI, a longer duration of diabetes and worse glycaemic control.

Associations between adrenal gland volume and adipose tissue compartments – a whole body MRI study

BackgroundObesity is associated with alterations in the hypothalamic–pituitary–adrenal (HPA) axis. Effects of glucocorticoids on adipose tissues appear to depend on the specific adipose depot, in which they take place. In this study, we aimed to investigate the role of MRI-based adrenal gland volume as an imaging marker in association with different adipose tissue compartments.MethodsThe study cohort derives from the population-based research platform KORA (Cooperative Health Research in the Augsburg Region, Germany) MRI sub-study, a cross-sectional sub-study investigating the interactions between subclinical metabolic changes and cardiovascular disease in a study sample of 400 participants. Originally, eligible subjects underwent a whole-body MRI. MRI-based segmentations were performed manually and semi-automatically for adrenal gland volume, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), epi- and pericardial fat and renal sinus fat. Hepatic and pancreatic lipid content were measured as pancreatic proton density fraction (PDFF) and MR-spectroscopic hepatic fat fraction (HFF). Multivariable linear regression analyses were performed.ResultsA number of 307 participants (56.2 ± 9.1 years, 60.3% male, 14.3% with type 2 diabetes (T2DM), 30.6% with obesity, 34.2% with hypertension) were included. In multivariable analyses, strong positive associations between adrenal gland volume and VAT, total adipose tissue (TAT) as well as HFF persisted after extensive step-wise adjustment for possible metabolic confounders (VAT: beta = 0.31, 95%-CI [0.71, 0.81], p < 0.001; TAT: beta = 0.14, 95%-CI [0.06, 0.23], p < 0.001; HFF: beta = 1.17, 95%-CI [1.04, 1.31], p = 0.009). In contrast, associations between adrenal gland volume and SAT were attenuated in multivariate analysis after adjusting for BMI. Associations between pancreatic PDFF, epi- and pericardial fat and renal sinus fat were mediated to a great extent by VAT (pancreatic PDFF: 72%, epicardial adipose tissue: 100%, pericardial adipose tissue: 100%, renal sinus fat: 81.5%).ConclusionOur results found MRI-based adrenal gland volume as a possible imaging biomarker of unfavorable adipose tissue distribution, irrespective of metabolic risk factors. Thus, adrenal gland volume may serve as a potential MRI-based biomarker of metabolic changes and contributes to an individual characterization of metabolic states and individual risk stratification. Future studies should elucidate in a longitudinal study design, if and how HPA axis activation may trigger unfavorable adipose tissue distribution and whether and to which extent this is involved in the pathogenesis of manifest metabolic syndrome.

Efficacy and safety of tesamorelin in people with HIV on integrase inhibitors.

Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy. We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily vs. identical placebo among participants on INSTI-based regimens at baseline. In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms. Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: -25 [-93, -2] vs. 14 [3, 41] cm 2 , P = 0.001), hepatic fat (-4.2% [-12.3%, -2.7%] vs. -0.5% [-3.9%, 2.7%], P = 0.01), and trunk-to-appendicular fat ratio (-0.1 [-0.3, 0.0] vs. 0.0 [-0.1, 0.1], P = 0.03). Tesamorelin was well tolerated with a similar frequency of adverse events, including hyperglycemia, between groups. The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control.

Bariatric intervention improves metabolic dysfunction-associated steatohepatitis in patients with obesity: A systematic review and meta-analysis.

Bariatric intervention has been reported to be an effective way to improve metabolic dysfunction-associated steatotic liver disease (MASLD) in obese individuals. The current systemic review aimed to assess the changes in MRI-determined hepatic proton density fat fraction (MRI-PDFF) and nonalcoholic fatty liver disease activity score (NAS) after bariatric surgery or intragastric balloon/gastric banding in MASLD patients with obesity. We searched various databases including PubMed, OVID Medline, EMBASE, and Cochrane Library. Primary outcomes were the changes in intrahepatic fat on MRI-PDFF and histologic features of metabolic dysfunction-associated steatohepatitis (MASH). Thirty studies with a total of 3,134 patients were selected for meta-analysis. Bariatric intervention significantly reduced BMI (ratio of means, 0.79) and showed 72% reduction of intrahepatic fat on MRI-PDFF at 6 months after bariatric intervention (ratio of means, 0.28). Eight studies revealed that NAS was reduced by 60% at 3-6 months compared to baseline, 40% at 12-24 months, and 50% at 36-60 months. Nineteen studies revealed that the proportion of patients with steatosis decreased by 44% at 3-6 months, 37% at 12-24 months, and 29% at 36-60 months; lobular inflammation by 36% at 12-24 months and 51% at 36-60 months; ballooning degeneration by 38% at 12-24 months; significant fibrosis (≥F2) by 18% at 12-24 months and by 17% at 36-60 months after intervention. Bariatric intervention significantly improved MRI-PDFF and histologic features of MASH in patients with obesity. Bariatric intervention might be the effective alternative treatment option for patients with MASLD who do not respond to lifestyle modification or medical treatment.

Safety and efficacy of resmetirom in the treatment of patients with non-alcoholic steatohepatitis and liver fibrosis: a systematic review and meta-analysis.

Non-alcoholic fatty liver disease (NAFLD), spanning from non-alcoholic steatohepatitis (NASH) to liver fibrosis, poses a global health challenge amid rising obesity and metabolic syndrome rates. Effective pharmacological treatments for NASH and liver fibrosis are limited. This study systematically reviews and meta-analyzes the safety and efficacy of resmetirom, a selective thyroid hormone receptor-β agonist, in NASH and liver fibrosis treatment. By analyzing data from clinical trials, we aim to offer evidence-based recommendations for resmetirom's use in managing these conditions and identify avenues for future research. Electronic databases (PubMed, Scopus, Science Direct, Google Scholar, ClinicalTrials.gov, and Cochrane CENTRAL) were systematically searched, supplemented by manual screening of relevant sources. Only English-language randomized controlled trials were included. Data extraction, risk of bias assessment, pooled analyses, and meta-regression were performed. Three randomized controlled trials involving 2231 participants were analyzed. Resmetirom demonstrated significant reductions in hepatic fat fraction [standardized mean difference (SMD) -4.61, 95% CI -6.77 to -2.44, P < 0.0001], NASH resolution without worsening fibrosis [risk ratio (RR) 2.51, 95% CI 1.74-3.64, P = 0.00001), and liver fibrosis improvement (RR 2.31, 95% CI 1.20-4.44, P = 0.01). Secondary outcomes showed significant improvements in lipid profiles, liver enzymes, and NASH biomarkers with resmetirom treatment. Meta-regression revealed associations between covariates and primary outcomes. Resmetirom exhibits promising efficacy in reducing hepatic fat, improving NASH resolution, and ameliorating liver fibrosis with a favorable safety profile. Further research is warranted to validate findings and optimize therapeutic strategies for NASH and liver fibrosis management.

Obesity, liver steatosis and metabolic syndrome: The hidden enemies in transfusion-dependent thalassaemia.

In their paper, the authors quantified liver iron concentration (LIC) and hepatic steatosis (HS) using MRI-T2* technology in transfusion-dependent thalassaemia (TDT) patients and healthy controls and found that the prevalence of HS among patients with TDT was 36.4%. In comparison with healthy controls, the hepatic fat fraction (FF) was significantly higher in the TDT population (p = 0.013). Active hepatitis C virus infection, body mass index (BMI) and LIC were independent predictors of HS. An inverse correlation between hepatic FF and high-density lipoprotein cholesterol (p = 0.042) and a significant association of high glycaemia level (p = 0.037) with higher hepatic FF and a significant relationship (p = 0.026) between HS and higher BMI (though in a 'lean' group of patients) in TDT patients indicated that 'metabolic syndrome' was present in this subset with TDT. The impact of metabolic syndrome on TDT, including cardiac disease unrelated to iron overload, needs further study. Commentary on: Ricchi etal. Liver steatosis in patients with transfusion-dependent thalassaemia. Br J Haematol 2024;204:2458-2467.

Metabolic-Associated Fatty Liver Disease is Characterized by a Post-Oral Glucose Load Hyperinsulinemia in Individuals with Mild Metabolic Alterations.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remains unclear. We compared the glucose metabolism, insulin resistance, insulin secretion and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a BMI between 25-40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3h 75g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic ß-cell function. Fifty percents of participants had MAFLD. Median age (IQR) (57 (45-65) vs 57 (44-63) years) and gender (60% vs 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (p <0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity and first phase pancreatic β cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (p <0.02). Amongst individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance, while exhibiting lower first phase β-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede type 2 diabetes.

Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Noncirrhotic MASH With Fibrosis

Background and aimsCotadutide, a peptide co-agonist at the glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors has demonstrated robust improvements in body weight, glycemia, and hepatic fat fraction (HFF) in patients living with obesity and type 2 diabetes mellitus. MethodsIn PROXYMO, a 19-week randomized double-blind placebo-controlled trial, the safety and efficacy of cotadutide (600 μg, 300 μg) or placebo were evaluated in 74 participants with biopsy-proven non-cirrhotic MASH with fibrosis. Analyses were performed using intent-to-treat and modified intent-to-treat population data. ResultsDose- and time-dependent improvements in HFF, alanine (ALT) and aspartate aminotransferase (AST), markers of liver health, and metabolic parameters were observed with significant improvements after 19 weeks with 600 μg ([LS] mean difference vs placebo [95%CI] for absolute HFF: -5.0% [-8.5,-1.5]; ALT: -23.5 U/L [-47.1,-1.8]; AST: -16.8 U/L [-33.0,-0.8]). Incidences of any grade treatment-emergent adverse events (TEAE) were 91.7%, 76.9% and 37.5% with cotadutide 600 μg, 300 μg, and placebo respectively. The majority were gastrointestinal (GI), mild to moderate in severity and generally consistent with other incretins at this stage of development. TEAE leading to treatment discontinuation were 16.7%, 7.7% and 4.2% with cotadutide 600 μg, 300 μg, and placebo respectively. ConclusionPROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven non-cirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH.

Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Influence of Gadoxetate disodium to the hepatic proton density fat fraction quantified with the Dixon sequences in a rabbit model

ObjectiveTo study the impact of Gx on quantification of hepatic fat contents under metabolic dysfunction-associated steatotic liver disease (MASLD) imaged on VIBE Dixon in hepatobiliary specific phase.MethodsForty-two rabbits were randomly divided into control group (n = 10) and high-fat diet group (n = 32). Imaging was performed before enhancement (Pre-Gx) and at the 13th (Post-Gx13) and 17th (Post-Gx17) min after Gx enhancement with 2E- and 6E-VIBE Dixon to determine hepatic proton density fat fractions (PDFF). PDFFs were compared with vacuole percentage (VP) measured under histopathology.Results33 animals were evaluated and including control group (n = 11) and MASLD group (n = 22). Pre-Gx, Post-Gx13, Post-Gx17 PDFFs under 6E-VIBE Dixon had strong correlations with VPs (r2 = 0.8208—0.8536). PDFFs under 2E-VIBE Dixon were reduced significantly (P < 0.001) after enhancement (r2 = 0.7991/0.8014) compared with that before enhancement (r2 = 0.7643). There was no significant difference between PDFFs of Post-Gx13 and Post-Gx17 (P = 0.123) for which the highest consistency being found with 6E-VIBE Dixon before enhancement (r2 = 0.8536). The signal intensity of the precontrast compared with the postcontrast, water image under 2E-VIBE Dixon increased significantly (P < 0.001), fat image showed no significant difference (P = 0.754).Conclusion2E- and 6E-VIBE Dixon can obtain accurate PDFFs in the hepatobiliary specific phase from 13 to 17th min after Gx enhancement. On 2E-VIBE Dixon (FA = 10°), effective minimization of T1 Bias by the Gx administration markedly improved the accuracy of the hepatic PDFF quantification.Graphical abstract

Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study

Background & AimsIn phase 2 studies, efruxifermin, an Fc–FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis (NASH), now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. MethodsCohort D was a double-blind, placebo-controlled phase 2b study in adults with T2D and MASH with fibrosis (F1–F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. ResultsAdults (N=31) with T2D and MASH fibrosis (F1–F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (N=21) or placebo (N=10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well tolerated. The most frequent efruxifermin-related adverse events were mild–moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P<.0001 vs placebo) compared to a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA–mediated weight loss. ConclusionsThe tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. Clinicaltrials.gov no. NCT05039450

Changes in nonalcoholic fatty liver disease and M2BPGi due to lifestyle intervention in primary healthcare.

A healthy lifestyle is the most important method for managing nonalcoholic fatty liver disease (NAFLD). Mac-2-binding protein glycosylated isomer (M2BPGi) has been suggested as a biomarker for NAFLD. This study aimed to determine the efficacy of personalized lifestyle interventions on NAFLD remission. This single-arm intervention study recruited participants with NAFLD who underwent health checkups at seven health-promotion centers in five South Korean cities. Fatty liver diagnosis was based on ultrasonography (US). The 109 individuals were recruited for personalized lifestyle interventions of hypocaloric diets and exercise. The participants attended the lifestyle intervention programs once per month for the first 3 months, and once every 3 months for the subsequent 6 months. In addition to sessions through center visits, phone-based intervention and self-monitoring at 4-, 5-, 7-, and 8-month were provided during the 9-month intervention period. And phone-based self-monitoring were also provided monthly during the 3-month follow-up period. The primary outcome was NAFLD remission at month 12 as measured on US and magnetic resonance elastography. The secondary outcomes were the changes in metabolic factors and M2BPGi. The 108 individuals (62 males and 46 females; age 51.1±12.4 years, mean±standard deviation) were finally analyzed after the 12month intervention. Body mass index, waist circumference (WC), blood pressure, blood lipids (total cholesterol, triglycerides, and HDL-C), and fasting blood sugar levels were improved relative to baseline (all P<0.05). Fatty liver at or above the moderate grade according to US was decreased at month 12 relative to baseline (67.6% vs 50.9%) (P = 0.002). M2BPGi levels decreased during the 12-month study period (P<0.001). M2BPGi levels were moderately correlated with hepatic fat fraction by magnetic resonance imaging (r = 0.33, P = 0.05). WC (OR = 0.82, 95% CI = 0.67-1.00, P = 0.05) and HDL-C (OR = 1.17, 95% CI = 1.03-1.32, P = 0.014) were associated with remission of fatty liver in the multivariate analysis. The personalized lifestyle intervention was effective in improving fatty liver and metabolic factors, but not hepatic stiffness, in NAFLD. ICTRP, cris.nih.go.kr (KCT0006380).