Molecular Mechanisms Involved in MAFLD in Cholecystectomized Patients: A Cohort Study.

Gallstone disease and metabolic dysfunction-associated fatty liver disease (MAFLD) share numerous common risk factors and progression determinants in that they both manifest as organ-specific consequences of metabolic dysfunction. Nevertheless, the precise molecular mechanisms underlying fibrosis development in cholecystectomized MAFLD patients remain inadequately defined. This study aimed to investigate the involvement of farnesoid X receptor 1 (FXR1) and fibroblast growth factor receptor 4 (FGFR4) in the progression of fibrosis in cholecystectomized MAFLD patients. A meticulously characterized cohort of 12 patients diagnosed with MAFLD, who had undergone liver biopsies during programmed cholecystectomies, participated in this study. All enrolled patients underwent a follow-up regimen at 1, 3, and 6 months post-cholecystectomy, during which metabolic biochemical markers were assessed, along with elastography, which served as indirect indicators of fibrosis. Additionally, the hepatic expression levels of FGFR4 and FXR1 were quantified using quantitative polymerase chain reaction (qPCR). Our findings revealed a robust correlation between hepatic FGFR4 expression and various histological features, including the steatosis degree (r = 0.779, p = 0.023), ballooning degeneration (r = 0.764, p = 0.027), interphase inflammation (r = 0.756, p = 0.030), and steatosis activity score (SAS) (r = 0.779, p = 0.023). Conversely, hepatic FXR1 expression did not exhibit any significant correlations with these histological features. In conclusion, our study highlights a substantial correlation between FGFR4 expression and histological liver damage, emphasizing its potential role in lipid and glucose metabolism. These findings suggest that FGFR4 may play a crucial role in the progression of fibrosis in cholecystectomized MAFLD patients. Further research is warranted to elucidate the exact mechanisms through which FGFR4 influences metabolic dysfunction and fibrosis in this patient population.

Screening for MAFLD: who, when and how?

Metabolic-associated fatty liver disease (MAFLD) is a highly prevalent disease with increasing prevalence worldwide. Currently, no universal screening methods have been standardized, even when this disease poses a major health burden. MAFLD as a spectrum of diseases can range from simple steatosis, and steatohepatitis to fibrosis and hepatocellular carcinoma. Its extra-hepatic manifestations are vast and include cardiovascular diseases, extra-hepatic malignancies, cognitive and respiratory alterations. Given its extensive damage targets as well as its high prevalence, timely identification of the high-risk population presenting metabolic dysfunction should undergo universal non-invasive screening methods, which can be carried out through blood tests, easy and effective imaging techniques, such as ultrasound, score calculation and general clinical information brought together from primary patient-physician contact.

Identification of Hepatic Dendritic Cells in Liver Biopsies Showing Steatosis in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Associated with Obesity.

BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the term used for hepatic steatosis in patients who are overweight or obese, have type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation. The prevalence of MAFLD among morbidly obese subjects is 65-93%. Hepatic dendritic cells (hDCs) are antigen-presenting cells that induce T cell-mediated immunity. MAFLD pathogenesis involves numerous immune cell-mediated inflammatory processes, while the particular role of hDCs is yet to be well defined. This study aimed to identify hDCs in liver biopsies from 128 patients with MAFLD associated with obesity. MATERIAL AND METHODS In this cross-sectional study, 128 liver biopsies from 128 patients with MAFLD (diagnosed as presence of hepatic steatosis, plus T2DM, metabolic dysregulation or overweight/obesity) were collected and assessed for CD11c⁺ immunoreactivity degree (CD11c as dendritic cell biomarker), through antigen retrieval, reaction with CD11c antibodies (primary), and marking with diaminobenzidine chromogen. RESULTS Among the 128 patients with MAFLD, 64 (50%) had MAFLD and fibrosis and 72 (56.2%) positively expressed hDCs (CD11c⁺). Among morbidly obese patients, 49 (64.5%) positively expressed hDCs (CD11c⁺) in liver tissue; from patients with obesity grade I- grade II (GI-II), 18 (54.5%) positively expressed hDCs (CD11c⁺) in liver tissue; and from non-obese patients with MAFLD, 5 (26.3%) positively expressed hDCs (CD11c⁺) in liver tissue. CONCLUSIONS hDC expression increases significantly in morbidly obese patients with MAFLD compared with non-obese patients, independent of the degree of fibrosis, suggesting the role of adaptive changes within hDCs in the perpetuation of inflammatory insults in chronic liver diseases.

Detangling the interrelations between MAFLD, insulin resistance, and key hormones.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has increasingly become a significant and highly prevalent cause of chronic liver disease, displaying a wide array of risk factors and pathophysiologic mechanisms of which only a few have so far been clearly elucidated. A bidirectional interaction between hormonal discrepancies and metabolic-related disorders, including obesity, type 2 diabetes mellitus (T2DM), and polycystic ovarian syndrome (PCOS) has been described. Since the change in nomenclature from non-alcoholic fatty liver disease (NAFLD) to MAFLD is based on the clear impact of metabolic elements on the disease, the reciprocal interactions of hormones such as insulin, adipokines (leptin and adiponectin), and estrogens have strongly pointed to the intrinsic links that lead to the heterogeneous epidemiology, clinical presentations, and risk factors involved in MAFLD in different populations. The objective of this work is twofold. Firstly, there is a brief discussion regarding the change in nomenclature as well as epidemiology, risk factors, and pathophysiologic mechanisms other than hormonal effects, which include nutrition and the gut microbiome, as well as genetic and epigenetic influences. Secondly, we review the basis of the most important hormonal factors involved in the development and progression of MAFLD that act both independently and in an interrelated manner.

Editorial: Acute Hepatitis of Unknown Origin in Children. Is Autoimmunity at Play?

A recent global outbreak of cases of acute hepatitis of unknown origin in children has raised health alerts. Increasing numbers of cases are being reported in most countries, mainly in the United Kingdom (UK). Although the cause remains unknown, several viruses have been isolated from affected children, including adenovirus, severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), Epstein-Barr virus (EBV), and rhinovirus. Notably, the cause is not from common hepatitis viruses, as serology for hepatitis viruses A, B, C, D, and E has been negative. Current causal hypotheses include possible infection with a new adenovirus variant that affects immunocompetent children, a new pediatric manifestation of COVID-19, or coinfection with enteric adenovirus type F41. This Editorial aims to present current hypotheses regarding the etiology of acute hepatitis of unknown origin in children, including the role of autoimmune hepatitis secondary to viral infection.