Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD

The pathogenesis of metabolic-associated fatty liver disease (MAFLD) is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility. The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction, endoplasmic reticular stress, and over production of reactive oxygen species (ROS). Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy, oxidative phosphorylation, and mitochondrial biogenesis. In excess, ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis. ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death. In select cases, the use of anti-oxidants and ROS scavengers have been shown to diminish the pro-apoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD. Thyroid hormone receptor β (THRβ) agonists and nuclear peroxisome proliferation-activated receptor (PPAR) family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD. Unfortunately, the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD. Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell transcriptome-based projects underway, there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets

Advances and Emerging Therapies in the Treatment of Non-alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH) now represents one of the most prevalent forms of cirrhosis and hepatocellular carcinoma. A number of treatment agents have undergone assessment in humans following promising results in animal models. Currently, about 50 therapeutic agents are in various stages of development. Recently, however, there have been a number of exciting and positive developments in this landscape, although there are inherent challenges ahead. In this article, we review the aetiological and pathological basis of NASH progression and describe putative targets for current therapies. We also discuss some of the likely future directions and difficulties around this complex and challenging disease paradigm

Guideline Review:EASL Clinical Practice Guidelines: Drug-Induced Liver Injury (DILI)

The European Association for the Study of the Liver has produced extensive guidelines for the investigation and management of drug-induced liver injury. Here, we provide a commentary and overview of some of the principle disease investigations and management that arise from these guideline recommendations

New Horizons in Hepatitis B and C in the Older Adult

Hepatitis C (HCV) and hepatitis B (HBV), are blood-borne viruses that can cause acute hepatitis; but are clinically relevant because chronic infection is associated with development of cirrhosis and hepatocellular carcinoma. Both these viruses are becoming more common in the older population, due to the ageing of generations exposed to the risk factors associated with infection; intravenous drug use, multiple sexual partners and men who have sex with men. This review will cover the natural history and epidemiology of these infections as well as the revolution in drug therapy that now allows cure of HCV infection and complete control of HBV infection.</p

Cohort Study:Apparent Redundancy of Fibrosis Assessment in Young Persons with HCV; Development of Realistic Approaches to Break the Paradigm

Introduction and Objectives: Hepatitis C Virus (HCV) is a blood-borne, hepatotropic RNA virus causing both acute and chronic infection. Chronic HCV infection predisposes individuals to liver fibrosis, cirrhosis and hepatocellular carcinoma. Staging of fibrosis prior to treatment to determine either treatment choice or required follow up, is standard practice. However, this often acts as a barrier to treatment initiation. We sought to validate the hypothesis that those individuals; mono-infected with HCV, ≤35 years of age; with no additional hepatic insult were unlikely to have significant fibrosis. Methods: We performed a retrospective analysis of a Hepatitis C Virus database; with collation of relevant basic demographics including age, sex and baseline Transient Elastography measurements pre-treatment. Additionally, we compared the reliability of biochemical fibrosis scores with corresponding transient elastography scores. Results: Our results support the hypothesis that those individuals with chronic HCV ≤35 years old, with no additional risk for fibrogenesis did not have significant liver fibrosis within our cohort. Conclusion: Patients ≤35 years old likely do not necessitate fibrosis assessment prior to Direct Acting Antiviral (DAA) treatment in the absence of other significant risk factors for fibrosis. Given the emerging evidence that DAA treatment results in a significant decrease in all-cause mortality and hepatocellular carcinoma development, treatment of those with chronic HCV represents a global priority

Integrating social nutrition principles into the treatment of steatotic liver disease

Current treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) focuses on adjusting patients’ lifestyles, including promoting weight loss and physical activity. Here, we suggest adopting a holistic preventive hepatology approach encompassing social nutrition, social prescribing and broader societal changes to facilitate individuals’ engagement with behavioural modifications

In situ H(2)S passivation of In(0.53)Ga(0.47)As/InP metal-oxide-semiconductor capacitors with atomic-layer deposited HfO(2) gate dielectric

We have studied an in situ passivation of In(0.53)Ga(0.47)As, based on H(2)S exposure (50-350 degrees C) following metal organic vapor phase epitaxy growth, prior to atomic layer deposition of HfO(2) using Hf[N(CH(3))(2)](4) and H(2)O precursors. X-ray photoelectron spectroscopy revealed the suppression of As oxide formation in air exposed InGaAs surfaces for all H(2)S exposure temperatures. Transmission electron microscopy analysis demonstrates a reduction of the interface oxide between the In(0.53)Ga(0.47)As epitaxial layer and the amorphous HfO(2) resulting from the in situ H(2)S passivation. The capacitance-voltage and current-voltage behavior of Pd/HfO(2)/In(0.53)Ga(0.47)As/InP structures demonstrates that the electrical characteristics of samples exposed to 50 degrees C H(2)S at the end of the metal-organic vapor-phase epitaxy In(0.53)Ga(0.47)As growth are comparable to those obtained using an ex situ aqueous (NH(4))(2)S passivation. (c) 2008 American Institute of Physics. (DOI: 10.1063/1.2829586