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Guidelines emphasize screening high-risk patients for metabolic dysfunction-associated steatotic liver disease (MASLD) with a calculated FIB-4 score for therapy to reverse fibrosis. We aimed to determine whether FIB-4 can effectively screen and monitor changes in steatohepatitis (MASH). Data were retrieved from the NIDDK-CR R4R central repository, of the CRN/PIVENS (pioglitazone vs vitamin E vs placebo) trial of adult patients without diabetes mellitus and with MASLD. 220 patients with MASLD had alanine transaminase (ALT), aspartate aminotransferase (AST) and platelet count, to calculate FIB-4, and repeat liver biopsies for histological MASLD activity scores (NAS). Compared to NAS score of 2, Fib-4 was higher at NAS 5) (p = 0.03), and NAS score of 6 (p = 0.02). FIB-4 correlated with cellular ballooning (r = 0.309, p < 0.001). Levels of ALT (ANOVA, p = 0.016) and AST (ANOVA p = 0.0008) were associated with NAS. NAS improved with pioglitazone by 39 %, p < 0.001 and with vitamin E by 36 %, p < 0.001. Pioglitazone and vitamin E both improved histological sub-scores for steatosis, and inflammation, without statistical changes in fibrosis grade. Changes in FIB-4 correlated with changes in NAS (r = 0.237, p < 0.001). In this post hoc analysis, changes in FIB-4 were associated with changes of steatohepatitis. Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis. •FIB-4 is used in metabolic dysfunction-associated steatotic liver disease (MASLD) to screen for fibrosis.•A post hoc review of the NIDDK-CR R4R central repository of CRN/PIVENS trial evaluated FIB-4 in pre-fibrotic steatohepatitis.•Changes in FIB-4 correlated with changes in histological steatohepatitis.•Therapies with pioglitazone and Vitamin E improved inflammation by 37 %–35 % without changes in fibrosis.•Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis

Background/Aims: Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus. The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence.Methods: The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRIPDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH resolution index (achieving ≥–0.67).Results: Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (p<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH.Conclusions: These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.

A variety of dietary natural products have shown hepatoprotective effects. Increasing evidence has also demonstrated that gut microorganisms play an important role in the hepatoprotection contributed by natural products. Gut dysbiosis could increase permeability of the gut barrier, resulting in translocated bacteria and leaked gut-derived products, which can reach the liver through the portal vein and might lead to increased oxidative stress and inflammation, thereby threatening liver health. Targeting gut microbiota modulation represents a promising strategy for hepatoprotection. Many natural products could protect the liver from various injuries or mitigate hepatic disorders by reverting gut dysbiosis, improving intestinal permeability, altering the primary bile acid, and inhibiting hepatic fatty acid accumulation. The mechanisms underlying their beneficial effects also include reducing oxidative stress, suppressing inflammation, attenuating fibrosis, and decreasing apoptosis. This review discusses the hepatoprotective effects of dietary natural products via modulating the gut microbiota, mainly focusing on the mechanisms of action.

In this phase 2 trial involving adults with metabolic dysfunction–associated steatohepatitis and liver fibrosis, survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis.

The utility of Cytokeratin-18 fragment, namely CK18Asp396 (M30), for the diagnosis of non-alcoholic steatohepatitis (NASH) is currently uncertain. We aimed to provide further data in this area among multi-ethnic Asian subjects with NAFLD. The accuracy of M30 for detecting NASH was compared with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT) levels in consecutive adult subjects with biopsy-proven non-alcoholic fatty liver disease (NAFLD). Data for 93 NAFLD subjects (mean age 51.0 ± 11.1 years old and 51.6% males) and 20 healthy controls (mean age 50.2 ± 16.4 years old and 33.3% males) were analyzed. There were 39 NASH subjects (41.9%) and 54 non-NASH subjects (58.1%) among the NAFLD subjects. Plasma M30 (349 U/L vs. 162 U/L), and serum ALT (70 IU/L vs. 26 IU/L), AST (41 IU/L vs. 20 IU/L) and GGT (75 IU/L vs. 33 IU/L) were significantly higher in NAFLD subjects than in healthy controls. Serum ALT (86 IU/L vs. 61 IU/L), AST (58 IU/L vs. 34 IU/L) and GGT (97 IU/L vs. 56 IU/L) were significantly higher in NASH subjects compared to non-NASH subjects, but no significant difference was observed with plasma M30 (435 U/L vs. 331 U/L). The accuracy of plasma M30, and serum ALT, AST and GGT was good for predicting NAFLD (AUROC 0.91, 0.95, 0.87 and 0.85, respectively) but less so for NASH (AUROC 0.59, 0.64, 0.75 and 0.68, respectively). Serum ALT and AST, but not plasma M30 showed a significant trend with increasing grades of ballooning and lobular inflammation. The utility of M30 in the detection of NASH in clinical practice appears limited, in comparison to routine biochemical markers.

Saturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms. To investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans. Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction. General community. Men and women who are overweight or have obesity (n = 61). Muffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet. Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots. By design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat, or total body fat compared with PUFA. SFA consistently increased, whereas PUFA reduced circulating ceramides, changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction. SFA markedly induces liver fat and serum ceramides, whereas dietary PUFA prevents liver fat accumulation and reduces ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.

BackgroundThe benefit of ischemic postconditioning (IPostC) might be the throttled inflow following cold ischemia. The current study investigated advantage and mechanisms of IPostC in healthy and fatty rat livers.MethodsMale SD rats received a high-fat diet to induce fatty livers. Isolated liver perfusion was performed after 24 h ischemia at 4 °C as well as in vivo experiments after 90 min warm ischemia. The so-called follow-up perfusions served to investigate the hypothesis that medium from IPostC experiments is less harmful. Lactate dehydrogenase (LDH), transaminases, different cytokines, and gene expressions, respectively, were measured.ResultsFatty livers showed histologically mild inflammation and moderate to severe fat storage. IPostC reduced LDH and TXB2 in healthy and fatty livers and increased bile flow. LDH, TNF-α, and IL-6 levels in serum decreased after warm ischemia + IPostC. The gene expressions of Tnf, IL-6, Ccl2, and Ripk3 were downregulated in vivo after IPostC.ConclusionsIPostC showed protective effects after ischemia in situ and in vivo in healthy and fatty livers. Restricted cyclic inflow was an important mechanism and further suggested involvement of necroptosis. IPostC represents a promising and easy intervention to improve outcomes after transplantation.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).

Resmetirom is a selective agonist of THR-β. In adults with nonalcoholic steatohepatitis and fibrosis, daily resmetirom (80 mg or 100 mg) was superior to placebo with respect to NASH resolution and fibrosis improvement.

In this randomized trial comparing vitamin E, pioglitazone, and placebo in adults without diabetes who had nonalcoholic steatohepatitis, vitamin E therapy was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis than was placebo (43% vs. 19%). Significant benefits of pioglitazone over placebo were shown for some secondary outcomes but not for the primary outcome. In adults who had nonalcoholic steatohepatitis, vitamin E therapy was associated with a significantly higher rate of improvement than was placebo. Significant benefits of pioglitazone over placebo were shown for some secondary outcomes. Nonalcoholic steatohepatitis is a common liver disease that is characterized histologically by hepatic steatosis, lobular inflammation, and hepatocellular ballooning 1 , 2 ; it can progress to cirrhosis in up to 15% of patients. 3 , 4 There is currently no therapy that is of proven benefit for nonalcoholic steatohepatitis. The disease is closely associated with insulin resistance and features of the metabolic syndrome such as obesity, hypertriglyceridemia, and type 2 diabetes. 5 , 6 In addition to insulin resistance, oxidative stress has been implicated as a key factor contributing to hepatic injury in patients with nonalcoholic steatohepatitis. 6 , 7 Thus, both insulin resistance and oxidative stress . . .