Nonalcoholic fatty liver disease (NAFLD) is increasingly concerning due to its rising prevalence. It encompasses conditions from simple steatosis to severe nonalcoholic steatohepatitis (NASH), posing risks such as fibrosis, cirrhosis, or hepatocellular carcinoma if untreated. This systematic review and meta-analysis aims to assess aldafermin, an FGF19 analog, for efficacy and safety in NASH patients.

Eligible studies were identified by searching PubMed, Cochrane Library, and Google Scholar, resulting in 1115 studies. Three RCTs were included. The risk of bias was assessed using the Cochrane Risk of Bias tool, and data synthesis utilized Review Manager software. The certainty of evidence was evaluated with the GRADE approach.

In the 3 mg dose group, aldafermin significantly improved various parameters. The ELF score decreased notably (pooled MD: -0.46, 95% CI: -0.64 to -0.28; P<0.00001). Additionally, fibrosis improvement without NASH worsening showed a pooled MD of 8.15 (95% CI: -3.62 to 19.93; P<0.17), and fibrosis improvement with NASH resolution displayed a pooled MD of 10.16 (95% CI: 1.68-18.64; P=0.02). Furthermore, significant reductions were noted in absolute AST levels (pooled MD: -13.40, 95% CI: -18.66 to -8.14; P<0.00001) and absolute ALT levels (pooled MD: -19.92, 95% CI: -27.08 to -12.75; P<0.00001), suggesting improved liver function.

The meta-analysis indicates that aldafermin, particularly, the 3 mg dose, shows significant efficacy in improving liver histology and biochemical markers in NASH patients compared to placebo, along with a satisfactory safety profile.

Non-alcoholic steatohepatitis (NASH) is a severe medical illness that has few available therapeutic options. Resmetirom, a liver-targeting agonist of the thyroid hormone receptor (THR), has recently been licenced by the FDA. We assess the effectiveness and safety of resmetirom in patients with NASH.

PubMed, SCOPUS and Cochrane Central were searched till March 2024 to find potential articles. Outcomes assessed included MRI-proton density fat fraction (MRI-PDFF), Fat Reduction, and NASH Resolution Without Fibrosis, changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), low-density lipoprotein (LDL), and triglyceride (TG) levels, along with diarrhoea, nausea, urinary tract infection (UTI), and headache. Subgroup analysis was performed between outcomes before and after 6 months. Outcomes were analyzed with a random-effects model and results presented as mean difference (MD) for continuous outcomes and odds ratios (OR) for safety analysis, along with their 95% confidence intervals. A risk of bias assessment was performed using Cochrane Risk of Bias tool.

Four randomized controlled trials (RCTs) were included in our analysis. Resmetirom shown a substantial improvement in MRI-PDFF with a MD of -19.23 (P<0.00001). Additionally, it resulted in a 30% reduction in fat (OR: 3.54, P=0.004) and resolution of NASH without fibrosis (OR: 2.41, P=0.04). There was no notable enhancement observed in AST levels, with a mean difference of -0.87 and a P value of 0.73. The usage of resmetirom resulted in significant improvement in ALT levels (MD: -4.36, P value: 0.32), GGT levels (MD: -17.87, P value: <0.00001), TG levels (MD: -23.48, P value: <0.00001), LDL levels (mean difference: -12.80, P value: <0.00001), and rT3 levels (MD: -2.08, P value: <0.00001). The use of Resmetirom was associated with a higher likelihood of experiencing diarrhoea (OR: 2.07, P<0.0001) and nausea (OR: 1.81, P=0.0003). However, there was no significant difference observed in the occurrence of UTI (OR: 1.04, P=0.85) or headaches (OR: 0.79, P=0.48).

Resmetirom demonstrates efficacy in enhancing MRI-PDFF score, diminishing adipose tissue, resolving NASH without fibrosis, reducing GGT, TG, LDL, reverse triiodothyronine (rT3) levels in NASH patients. Nevertheless, there is also an observed heightened susceptibility to experiencing diarrhoea and nausea. Additional trials are necessary to further examine the efficacy and safety of this medication.

Non-alcoholic steatohepatitis (NASH) is an advanced subtype of non-alcoholic fatty liver disease (NAFLD). NASH prevalence is increasing exponentially and carries a high risk for disease progression, cirrhosis, and liver-related mortality. Aldafermin, a fibroblast growth factor 19 (FGF19) analog, is one of the evolving therapeutic agents with the potential to regulate multiple pathways involved in the pathogenesis of NASH. We aimed to investigate the efficacy and safety of aldafermin in patients with NASH.

PubMed, Scopus, Cochrane Library, and Web of Science were searched till November 2023 to identify eligible randomized controlled trials (RCTs). Continuous data were pooled as mean difference (MD), while dichotomous data were pooled as risk ratios (RR) with a 95 % confidence interval. A subgroup meta-analysis was conducted to evaluate the efficacy of the two doses (1 mg and 3 mg) of aldafermin.

Four RCTs with a total of 491 patients were included. Aldafermin showed a dose-dependent improvement in the ≥30 % reduction in the liver fat content (RR: 2.16, 95 % CI [1.41 to 3.32]) and (RR: 5.00, 95 % CI [1.34 to 18.64]), alanine aminotransferase levels (MD: -19.79, 95 % CI [-30.28 to -9.3]) and (MD: -21.91, 95 % CI [-29.62 to -14.21]), aspartate aminotransferase levels (MD: -11.79, 95 % CI [-18.06 to -5.51]) and (MD: -13.9, 95 % CI [-18.59 to -9.21]), and enhanced liver fibrosis score (ELF) (MD: -0.13, 95 % CI [-0.29 to 0.02]) and (MD: -0.33, 95 % CI [-0.50 to -0.17]), in the 1 mg and 3 mg subgroups respectively. No significant differences were detected in the aldafermin group regarding histologic endpoints, lipid profile, metabolic parameters, and overall adverse effects, except for the increased occurrence of diarrhea in the aldafermin 3 mg subgroup.

Aldafermin is a promising well-tolerated therapeutic agent for NASH with evidence supporting its ability to reduce liver fat content, fibrosis serum biomarkers, and liver enzymes. However, its effectiveness in improving histologic fibrosis, while showing numerical trends, still lacks statistical significance. Larger and longer NASH trials are warranted to enhance the robustness of the evidence.

The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.

Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP-1RA) and thiazolidinedione (TZD) can improve nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). However, comprehensive research comparing the effects of GLP-1RA and TZD is limited. Thus, this study aimed to compare the effects of GLP-1RA and TZD on NAFLD or NASH through a network meta-analysis.

The PubMed, Embase, Web of Science, and Scopus databases were searched for randomized controlled trials (RCTs) that explored the efficacy of GLP-1RAs or TZDs in adult patients with NAFLD or NASH. The outcomes were liver biopsy-based (NAFLD activity score [NAS], fibrosis stage, and NASH resolution), noninvasive technique-based (liver fat content on proton magnetic resonance spectroscopy [1H-MRS] and controlled attenuation parameter [CAP]), biological, and anthropometric indicators. A random effects model was used to calculate the mean difference (MD) and relative risk with 95% confidence interval (CI).

Twenty-five RCTs with 2,237 overweight or obese patients were included. GLP-1RA was significantly superior in reducing liver fat content evaluated using 1H-MRS (MD -2.42, 95% CI -3.84 to -1.00), body mass index (MD -1.60, 95% CI -2.41 to -0.80), and waist circumference (MD -4.89, 95% CI -8.17 to -1.61) than TZD. In liver biopsy-based evaluation and liver fat content assessment using CAP, GLP-1RA tended to surpass TZD, albeit not significantly. Sensitivity analysis showed consistent results with the main results.

Compared with TZD, GLP-1RA had better effects on liver fat content, body mass index, and waist circumference in overweight or obese patients with NAFLD or NASH.

The metabolic syndrome as a consequence of the obesity pandemic resulted in a substantial increase in the prevalence of metabolic-associated fatty live disease (MAFLD) and type 2 diabetes mellitus (T2DM). Because of the similarity in pathobiology shared between T2DM and MAFLD, both disorders coexist in many patients and may potentiate the disease-related outcomes with rapid progression and increased complications of the individual diseases. In fact, awareness about this coexistence and the risk of complications are often overlooked by both hepatologists and diabetologists. Management of these individual disorders in a patient should be addressed wholistically using an appropriate multidisciplinary team approach involving both the specialists and, when necessary, liaising with dieticians and surgeons. This comprehensive review is to compile the current evidence from a diabetologist's perspective on MAFLD and T2DM and to suggest optimal management strategies.

Fibrosis impacts long-term outcomes among patients with nonalcoholic fatty liver disease (NAFLD). Due to well-documented flaws associated with liver biopsy, there has been a recent emphasis on prioritizing noninvasive testing over liver biopsy for the assessment of fibrosis.

A comprehensive systematic review and frequentist random effects network meta-analysis was performed among randomized controlled trials reporting pharmacologic intervention in NAFLD. The primary endpoint was the absolute change in liver stiffness measurement (LSM) via elastography. Secondary endpoints included changes in noninvasive serologic tests including APRI, fibrosis-4 index, NAFLD fibrosis score, enhanced liver fibrosis (ELF) and FibroTest (FibroSure in the USA).

Forty-five randomized controlled trials enrolling 6932 patients were identified for this network meta-analysis. Across the primary endpoint, firsocostat, semaglutide, montelukast, cilofexor plus firsocostat, obeticholic acid and diacerein (change in LSM via vibration controlled transient elastography), in addition to lubiprostone and pemafibrate (change in LSM via magnetic resonance elastography) were found to be the most effective and statistically significant treatment interventions. Similarly, the following interventions were determined to be most effective as compared to placebo among secondary endpoints: saroglitazar, lubiprostone, and obeticholic acid (change in APRI); saroglitazar, semaglutide, firsocostat and cilofexor plus firsocostat (change in ELF); obeticholic acid and belapectin [change in FibroTest/FibroSure].

This is the first systematic review and network meta-analysis reporting pharmacologic efficacy in the progression of fibrosis based on noninvasive testing among patients with NAFLD. Semaglutide, obeticholic acid, firsocostat, cilofexor plus firsocostat and lubiprostone were found to be the most effective treatments based on their consistent efficacy reproduced across multiple endpoints, both via elastography and noninvasive blood tests.