Non-alcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis (accumulation of fat in the liver to over 5% of its weight) in the absence of secondary causes of fat accumulation in the liver such as excessive alcohol use. NAFLD is divided into two types: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Therefore, in this clinical guideline, we sought to determine general and important policies for this disease and modify its managment approaches. We adapted this guideline for the management of NAFLD in Isfahan Province. This guideline was developed by clinical appraisal and review of the evidence, available clinical guidelines, and in consultation with members of the Isfahan Chamber of the Iranian Association of Gastroenterology and Hepatology. Biopsy is recommended as the most reliable method (gold standard) to diagnose steatohepatitis and fibrosis in patients with NAFLD. NAFLD fibrosis score (NFS) and fibrosis-4 (FIB-4) are recommended as the test with the highest predictive value for advanced fibrosis in patients with NAFLD compared to other serologic tests. Among the noninvasive methods used to assess liver fibrosis, transient elastography (TE) is preferable to other methods.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.

UNASSIGNED: Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease - NAFLD) is a chronic liver condition linked to obesity and metabolic syndrome. It affects one-third of people globally and, in some cases, can lead to metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis, NASH) and fibrosis. Weight loss is crucial for the treatment of MASLD, but diet and lifestyle modifications often fail.
UNASSIGNED: In recent years, endoscopic sleeve gastroplasty (ESG) has gained popularity as an effective and minimally invasive option for obesity treatment, with widespread use worldwide. We present a current overview of the most significant studies conducted on ESG for the management of obesity and MASLD. Our report includes data from published studies that have evaluated the impact of ESG on noninvasive hepatic parameters used to estimate steatosis and fibrosis. However, at present, there are no data available on liver histology.
UNASSIGNED: ESG has shown promising results in treating MASLD evaluated by noninvasive tests, but current data is limited to small, nonrandomized studies. More research is needed, particularly on the effects of ESG on histologically proven MASH. If future research confirms its efficacy, ESG may be incorporated into treatment guidelines in the future.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, making it the leading etiology of chronic liver diseases and a prime cause of liver-related mortality. MASLD can progress into steatohepatitis (termed MASH), fibrosis, cirrhosis, and ultimately cancer. MASLD is associated with increased risks of hepatocellular carcinoma (HCC) and also extrahepatic malignancies, which can develop in both cirrhotic and non-cirrhotic patients, emphasizing the importance of identifying patients with MASLD at risk of developing MASLD-associated malignancies. However, the optimal screening, diagnostic, and risk stratification strategies for patients with MASLD at risk of cancer are still under debate. Individuals with MASH-associated cirrhosis are recommended to undergo surveillance for HCC (e.g. by ultrasound and biomarkers) every six months. No specific screening approaches for MASLD-related malignancies in non-cirrhotic cases are established to date. The rapidly developing omics technologies, including genetics, metabolomics, and proteomics, show great potential for discovering non-invasive markers to fulfill this unmet need. This review provides an overview on the incidence and mortality of MASLD-associated malignancies, current strategies for HCC screening, surveillance and diagnosis in patients with MASLD, and the evolving role of omics technologies in the discovery of non-invasive markers for the prediction and risk stratification of MASLD-associated HCC.

The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) is a growing concern for the high incidence rate of hepatocellular carcinoma (HCC) globally. The progression of NAFLD to HCC is heterogeneous and non-linear, involving intermediate stages of non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. There is a high unmet clinical need for appropriate diagnostic, prognostic, and therapeutic options to tackle this emerging epidemic. Unfortunately, at present, there is no validated marker to identify the risk of developing HCC in patients suffering from NAFLD or NASH. Additionally, the current treatment protocols for HCC don\'t differentiate between viral infection or NAFLD-specific etiology of the HCC and have a limited success rate. The mammalian target of rapamycin complex 1 (mTORc1) is an important protein involved in many vital cellular processes like lipid metabolism, glucose homeostasis, and inflammation. These cellular processes are highly implicated in NAFLD and its progression to severe liver manifestations. Additionally, hyperactivation of mTORc1 is known to promote cell proliferation, which can contribute to the genesis and progression of tumors. Many mTORc1 inhibitors are being evaluated for different types of cancers under various phases of clinical trials. This paper deliberates on the strong pathological implication of the mTORc1 signaling pathway in NAFLD and its progression to NASH and HCC and advocates for a systematic investigation of known mTORc1 inhibitors in suitable pre-clinical models of HCC having NAFLD/NASH-specific etiology.

Amyloid beta (Aβ) plays a major role in the pathogenesis of Alzheimer\'s disease and, more recently, has been shown to protect against liver fibrosis. Therefore, we studied Aβ-42 levels and the expression of genes involved in the generation, degradation, and transport of Aβ proteins in liver samples from patients at different stages of metabolic dysfunction-associated liver disease (MASLD) and under steatotic conditions in vitro/in vivo. Amyloid precursor protein (APP), key Aβ-metabolizing proteins, and Aβ-42 were analyzed using RT-PCR, Western blotting, Luminex analysis in steatotic in vitro and fatty liver mouse models, and TaqMan qRT-PCR analysis in hepatic samples from patients with MASLD. Hepatocytes loaded with palmitic acid induced APP, presenilin, and neprilysin (NEP) expression, which was reversed by oleic acid. Increased APP and NEP, decreased BACE1, and unchanged Aβ-42 protein levels were found in the steatotic mouse liver compared to the normal liver. Aβ-42 concentrations were low in MASLD samples of patients with moderate to severe fibrosis compared to the livers of patients with mild or no MASLD. Consistent with the reduced Aβ-42 levels, the mRNA expression of proteins involved in APP degradation (ADAM9/10/17, BACE2) and Aβ-42 cleavage (MMP2/7/9, ACE) was increased. In the steatotic liver, the expression of APP- and Aβ-metabolizing proteins is increased, most likely related to oxidative stress, but does not affect hepatic Aβ-42 levels. Consistent with our previous findings, low Aβ-42 levels in patients with liver fibrosis appear to be caused by the reduced production and enhanced non-amyloidogenic processing of APP.

Metabolic-associated steatohepatitis liver disease (MASLD) currently impacts a quarter of the global population, and its incidence is expected to increase in the future. As a result, hepatocellular carcinoma associated with MASLD is also on the rise. Notably, this carcinoma does not always develop alongside liver cirrhosis, often leading to a more advanced stage at diagnosis. The challenge lies in accurately identifying patients who are at a higher risk to tailor screening processes effectively. Additionally, several therapeutic approaches are being explored to prevent hepatocellular carcinoma, although there are no universally accepted guidelines yet.

We assessed in vivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and β-hydroxybutyrate (β-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that in vivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased in vivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by ∼50% in the MASL group, which could be attributed in part to an ∼30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.

Characterized by hepatic lipid accumulation, non-alcoholic fatty liver disease (NAFLD) is a multifactorial metabolic disorder that could promote the progression of non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Benefiting from recent advances in omics technologies, such as high-throughput sequencing, voluminous profiling data in HCC-integrated molecular science into clinical medicine helped clinicians with rational guidance for treatments. In this review, we conclude the majority of publicly available omics data on the NAFLD-related disease spectrum and bring up new insights to inspire next-generation therapeutics against this increasingly prevalent disease spectrum in the post-genomic era.

Human genetic studies show that loss of function mutations in 17-Beta hydroxysteroid dehydrogenase (HSD17β13) are associated with protection from non-alcoholic steatohepatitis (NASH). As a result, therapies which reduce HSD17β13 are being pursued for the treatment of NASH. However, inconsistent effects on steatosis, inflammation and fibrosis pathogenesis have been reported in murine Hsd17b13 knockdown or knockout models. To clarify whether murine Hsd17b13 loss regulates liver damage and fibrosis, we characterized Hsd17b13 knockout mice subjected to pro-NASH diets or pro-inflammatory chemical-induced liver injury. There were no effects of Hsd17b13 loss on liver injury, inflammation, fibrosis or lipids after 28 weeks on the Gubra-Amylin NASH (GAN) diet or 12 weeks on a 45% choline deficient high fat diet (CDAHFD). However, AAV-mediated re-expression of murine Hsd17b13 in KO mice increased liver macrophage abundance in both sexes fed the 45% CDAHFD. In contrast, there was a modest reduction in liver fibrosis, but not lipids or inflammation within Hsd17b13 null female, but not male, mice after 12 weeks of a 60% CDAHFD compared to WT littermates. Fibrosis and the abundance of liver macrophages were increased in Hsd17b13 KO females upon adenoviral re-expression of mouse HSD17β13, but this was not reflected in inflammatory markers. Additionally, we found minimal differences in liver injury, lipids, or inflammatory and fibrotic markers 48 hours after acute CCl4 exposure. In summary, murine Hsd17b13 loss has modest diet- and sex-specific effects on liver fibrosis which contrasts with human genetic studies. This suggests a disconnect between the biological function of HSD17β13 in mice and humans.