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.

Insulin resistance and adipose tissue interactions as the cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis.

The relationship between metabolic derangements and fatty liver development are undeniable, since more than 75% of patients with type 2 diabetes mellitus present with fatty liver. There is also significant epidemiological association between insulin resistance (IR) and metabolic (dysfunction)-associated fatty liver disease (MAFLD). For little more than 2 years, the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups. While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed, the bottom line relies on the role of IR as an initiator and perpetuator of this disease. There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations, where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory element-binding protein-1c induced lipogenic enzyme stimulation; therefore, increased endogenous production of triglycerides. The same effect is achieved through impaired suppression of adipose tissue (AT) lipolysis in insulin-resistant states, increasing fatty acid influx into the liver. The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion, modifying fatty acid metabolism as well as IR in a variety of tissues, including skeletal muscle, AT, and the liver. The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

How far are we from an approved drug for nonalcoholic steatohepatitis?

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) previously known but still debatable, as nonalcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease and subsequent cirrhosis worldwide, accounting for around 30% of liver diseases. The change in its nomenclature has been brought about by the novel discoveries regarding its pathogenesis, in which metabolic dysfunction plays the most important role. It is widely known that for every disease, the treatment should always be targeted toward the underlying etiology and pathogenesis. AREAS COVERED: MAFLD/NAFLD pathogenesis is heterogeneous, and includes multiple gene polymorphisms, presence of insulin resistance, as well as concomitant diseases that contribute to the disease onset and progression. As a result of this, even though lifestyle modification (owing to metabolic abnormalities) is the first line of treatment, multiple drugs have been tested to target each of the known pathways leading to MAFLD/NAFLD and progression of steatohepatitis. We aim to review the most relevant information regarding previous and ongoing research and recommendations regarding treatment of MAFLD/NAFLD. EXPERT OPINION: Combination therapies associated to weight loss and exercise will be the optimal approach for these patients. It is important to evaluate each patient to select the specific combination according to patient characteristics.

Nonalcoholic Fatty Liver Disease in Latin America and Australia.

The epidemiologic and demographical features of nonalcoholic fatty liver disease (NAFLD) vary significantly across countries and continents. In this review, we analyze current data regarding prevalence of NAFLD in Latin America and Caribbean and Australia and review some peculiarities found in these regions. We stress the need of greater awareness of NAFLD and the development of cost-effective risk stratification strategies and clinical care pathways of the disease. Finally, we highlight the need of effective public health policies to control the main risk factors for NAFLD.

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.

Editorial: Treatment with Dual Incretin Receptor Agonists to Maintain Normal Glucose Levels May Also Maintain Normal Weight and Control Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD).

Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. MAFLD is associated with insulin resistance, type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Early diagnosis and management are vital to improving hepatic and cardiometabolic outcomes. Dietary change, weight loss, and structured exercise are the main treatment approaches for fatty liver disease. Since 2010, several investigational drug treatments failed to achieve regulatory approval due to mixed and unsatisfactory results. Although glucagon-like peptide 1 receptor agonists (GLP1-RAs) showed initial promise as therapeutic agents, metabolic liver damage can recur after monotherapy cessation. Dual incretin receptor agonists target the receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). Importantly, on May 13, 2022, the US Food and Drug Administration (FDA) approved tirzepatide as the first dual GLP-1 and GIP receptor agonist for the treatment of T2DM. Dual incretin receptor agonists induce weight loss and enhance hepatic lipid metabolism and systemic insulin sensitivity. Insulin resistance and hepatic steatosis are the main contributors to the development of MAFLD. Treatment with dual incretin analogs reduces hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels. The availability of dual incretin receptor agonists for patients with MAFLD may result in weight control, normalizing insulin sensitivity, and reducing or even reversing metabolic dysfunction and liver damage. This Editorial aims to provide an update and discuss how treatment with dual incretin receptor agonists may maintain normal glucose levels and weight and control MAFLD.

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.