Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease

Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.

NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.

Demographic Profile and Clinical Spectrum of Alcoholic Liver Disease among Males in Pakistan

Introduction: Alcohol is the most common substance abused in western world. Males tend to have more severe liver disease because of heavy and regular drinking. Methods: Adult patients, 16 years of age and older, diagnosed with ALD within 1 year, were included in the study. Liver disease from other causes was excluded. Demographic profiles, clinical features, laboratory and endoscopic findings of the patients, Child-Turcotte-Pugh (CTP), Model End Stage Liver Disease (MELD) were recorded. Results: A total of 104 patients with ALD who met the inclusion criteria were enrolled in the study. The mean age of the patients enrolled in the study was 49.2 years (SD = 13.1). Most of the patients were in the 30-65 age group. The four most common clinical symptoms in patients were abdominal distension (n = 89, 85.6%), bilateral lower limb edema (n = 78, 75%), jaundice (n = 39, 37.5%) and anorexia (n = 41, 39.4%). Of 104 patients, 96 (92.3%) had cirrhosis, 9 (8.7%) had fatty liver and alcoholic hepatitis. Of 94 patients with ALD, 49(52.1%) had CTP grade C and 83 (88.3%) had MELD score ≥ 16. Conclusions: ALD was mainly observed in young patients. The most common clinical symptoms were abdominal distension, bilateral oedema of the lower limbs, jaundice and anorexia. Among patients with cirrhosis of the liver, the majority of patients were CTP class C and obtained a MELD score ≥16. Keywords: Alcoholic liver disease, clinical profile, demographic profile

Efficacy and Safety of a Fixed Combination of Glycyrrhizic Acid and Essential Phospholipids in Non-Alcoholic Fatty and Alcoholic Liver Disease: Results from Randomized Placebo-Controlled Trials

Background. Drug treatment of non-alcoholic fatty and alcoholic liver disease remains an urgent, unsolved problem. Due to the commonality of many pathogenetic mechanisms and predictors of progression, a universal approach to the search for a therapeutic agent can be considered. Aims pooled analysis of the results of two multicenter, randomized, double-blind, placebo-controlled studies of a fixed combination of glycyrrhizic acid and essential phospholipids in two dosage forms to study its efficacy and safety in non-alcoholic fatty and alcoholic liver disease, in the presence and absence of predictors of disease progression. Methods. The pooled analysis included 180 patients with non-alcoholic fatty liver disease (Gepard study) and 120 patients with alcoholic liver disease (Jaguar study). Patients of the main group received a fixed combination of 5.0 g intravenous jet 3 times a week for the first 2 weeks; then 2 capsules 3 times a day for the next 10 weeks. Patients in the control group received placebo according to the same scheme. The total duration of treatment was 12 weeks in the Gepard study (1 course of stepwise therapy) and 24 weeks in the Jaguar study (2 courses of stepwise therapy). A comparative analysis of the efficacy and safety of a fixed combination and a placebo was carried out, in the presence and absence of predictors of progression, separately for each nosology and in a mixed sample. Results. In patients with non-alcoholic fatty and alcoholic liver disease who received the fixed combination, in contrast to the placebo group, there was a statistically more significant decrease in the level of biochemical markers of inflammation alanine aminotransferase, aspartate aminotransferase, adiponectin, and the value of the AktiTest index. There was no negative trend in the NAFLD fibrosis score; more significant positive dynamics of FibroTest is shown. Predictors of disease progression hyperglycemia, hyperlipidemia, age did not have a negative impact on the results in the study group. The efficacy of the study drug was noted in patients with non-alcoholic fatty liver disease and normal body weight; data were obtained indicating its possible effectiveness with a high activity of the inflammatory process associated with alcoholic liver damage. The frequency of adverse events in the study and control groups was comparable. Conclusions. Based on a generalized analysis of the results of two studies, promising directions for the study and use of a fixed combination of glycyrrhizic acid and essential phospholipids were identified: non-alcoholic fatty liver disease without obesity, alcoholic steatohepatitis of high activity (as an adjuvant); steatohepatitis of non-alcoholic and alcoholic etiology, combined with hyperglycemia and hyperlipidemia.

Diagnostic and prognostic value of a diffusion-weighted image of the liver with magnetic resonance imaging in patients with alcoholic liver disease

The aim of the study was to assess the diagnostic and prognostic value of a diffusion-weighted image of the liver with magnetic resonance imaging in patients with alcoholic liver disease.Material and methods. A total of 113 patients with alcoholic liver disease (ALD) were examined. Among them, 65 (57.5%) are men and 48 (42.5%) are women. The mean age of patients is 46.3 ± 5.2 years. The structure of the instrumental algorithm for examining patients was presented: ultrasound of the abdominal cavity organs with clinical elastography – 98 (86.7%) patients, MRI of the liver with the mandatory inclusion of the DWI liver sequence in the protocol (n = 113). The b-factor values of 100/600/1000 were used for the liver DWI sequence. Liver biopsy was chosen as the reference method in 65 (57.5%) patients.Results. The patients were monitored for 12 months. At the first stage, the qualitative characteristics of the liver DWI sequence were assessed: no or there is a diffusion limitation. At the second stage, the quantitative indicators of the DWI sequence were assessed in the form of calculating the measured diffusion index and coefficient. In order to standardize the technique of liver DWI on MRI in patients with ALD, the results were compared with the data of clinical elastography (p < 0.01) and liver biopsy (p < 0.05). Upon admission and monitoring of patients (after 1, 3, 6, 9 months), a high correlation was found in the assessment of comparing the quantitative indicators of DWI with clinical elastography (r = 0.873) and an average correlation with biopsy data (r = 0.715).Conclusions. There was a high correlation between the limitation of liver diffusion on MRI and negative clinical and laboratory dynamics (r = 0.889) and in the absence of limitation of diffusion in the liver and positive clinical and laboratory dynamics (r = 0.885). DWI of the liver on MRI in patients with ALD has a high diagnostic and prognostic value in assessing abnormal abstinence regimen (AUROC = 0.903 (95% CI 0.871–0.911)). Diagnostic and prognostic significance of the developed criteria for DWI of the liver at MRI in patients with ABD at admission: for a qualitative assessment AUROC = 0.844 (95% CI 0.801–0.869), quantitative – AUROC = 0.908 (95% CI 0.875–0.911); with dynamic observation: for a qualitative assessment AUROC = 0.939 (95% CI 0.901–0.955), quantitative – AUROC = 0.919 (95% CI 0.871–0.931).