Significance of gut microbiota in alcoholic and non-alcoholic fatty liver diseases

Liver-gut communication is vital in fatty liver diseases,and gut microbes are the key regulators in maintaining liver homeostasis.Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology,which can contribute to fatty liver disease.In this review,we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology.We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.

Nutritional recommendations for patients with non-alcoholic fatty liver diseases

Fatty liver is the most common liver disease worldwide.Patients with fatty liver disease die primarily from cardiovascular disease and not from chronic liver diseases.Hyperglycemia and hyperinsulinemia induce lipogenesis,thereby increasing the hepatic pool of fatty acids.This pool is also increased by increased delivery of fatty acids through the diet or lipolysis in adipose tissue.Nutritional consultations and lifestyle modification are important in the treatment of non-alcoholic fatty liver disease(NAFLD).Among the dietary constituents,combination of vitamin D,vitamin E,and omega-3 fatty acids shows promise for the treatment of NAFLD.

Protection effect of trigonelline on liver of rats with non-alcoholic fatty liver diseases

Objective: To study the effect of trigonelline on the change of indicators of serum transaminase, lipoprotein and liver lipid of model rats with non-alcoholic fatty liver diseases and on the expression level of Bcl-2 and Bax proteins. Methods: A total of 45 SD rats were randomly divided into Fthe control group, model group and trigonelline intervention group. Rats in the control group were fed with the common diet, while rats in the model group and intervention group were fed with the high fat diet. 8 weeks later, the intervention group received the intragastric administration of trigonellin e(with the dosage of 40 mg/kg/d) for 8 weeks; while control group and model group received the intragastric administration of saline with the equal dosage. Blood was taken from the abdominal aorta of rats 8 weeks later, detecting the level of a series of indicators of ALT, AST, TG, TC, HDL-C and LDL-C in the serum. After the rats were sacrificed, detect the indicators of TG, TC, SOD and MDA in the liver tissue of rats, as well as the expression of Bcl-2 and Bax in the liver tissue. Results: Results of histopathologic examination showed that the damage degree of liver for rats in the trigonellineintervention group was smaller than the one in the model group, with significantly reduced hepatic steatosis and the partially visible hepatic lobule. The levels of ALT, AST, TC and LDL-C in the serum of rats in the trigonelline group were significantly reduced, while the change in the levels of TG and HDL-C was not significantly different. The levels of TG, TC and MDA in the liver tissues were significantly decreased, while the level of SOD significantly increased; the expression of Bcl-2 protein in the liver tissues of rats in the trigonelline intervention group was significantly increased, while the expression of Bax protein significantly decreased. Conclusions: The trigonelline contributes to the therapeutic effect of non-alcoholic fatty liver diseases. It can also increase the expression of Bcl-2 protein and decrease the expression of Bax protein in the liver tissues, which can protect the liver.

Inflammation and fibrosis in chronic liver diseases including nonalcoholic fatty liver disease and hepatitis C

At present chronic liver disease(CLD),the third commonest cause of premature death in the United Kingdom is detected late,when interventions are ineffective,resulting in considerable morbidity and mortality.Injury to the liver,the largest solid organ in the body,leads to a cascade of inflammatory events.Chronic inflammation leads to the activation of hepatic stellate cells that undergo transdifferentiation to become myofibroblasts,the main extra-cellular matrix producing cells in the liver;over time increased extra-cellular matrix production results in the formation of liver fibrosis.Although fibrogenesis may be viewed as having evolved as a“wound healing”process that preserves tissue integrity,sustained chronic fibrosis can become pathogenic culminating in CLD,cirrhosis and its associated complications.As the reference standard for detecting liver fibrosis,liver biopsy,is invasive and has an associated morbidity,the diagnostic assessment of CLD by non-invasive testing is attractive.Accordingly,in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice.Due to differing disease prevalence and treatment efficacy,disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection.To facilitate this,a review of the pathogenesis of both conditions is also conducted.Finally,the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed,including the current use of antifibrotic therapy.

Intestinal virome:An important research direction for alcoholic and nonalcoholic liver diseases

In recent years,the interaction between the gut microflora and liver diseases has attracted much attention.The intestinal microflora is composed of bacteria,archaea,fungi and viruses.There are few studies on the intestinal virome,and whether it has a causal relationship with bacterial changes in the gut is still unclear.However,it is undeniable that the intestinal virome is also a very important portion of the blueprint for the development of liver diseases and the diagnosis and therapeutic modalities in the future.

Antioxidant and anti-inflammatory agents in chronic liver diseases:Molecular mechanisms and therapy

Chronic liver disease(CLD)is a continuous process that causes a reduction of liver function lasting more than six months.CLD includes alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD),chronic viral infection,and autoimmune hepatitis,which can lead to liver fibrosis,cirrhosis,and cancer.Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD.Molecular signaling pathways such as AMPactivated protein kinase(AMPK),C-Jun N-terminal kinase,and peroxisome proliferator-activated receptors(PPARs)are implicated in the pathogenesis of CLD.Therefore,antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD,NAFLD,and hepatocellular carcinoma(HCC).In this review,we summarize some powerful products that can be potential applied in all the stages of CLD,from ALD/NAFLD to HCC.The selected agents such asβ-sitosterol,curcumin,genistein,and silymarin can regulate the activation of several important molecules,including AMPK,Farnesoid X receptor,nuclear factor erythroid 2-related factor-2,PPARs,phosphatidylinositol-3-kinase,and lysyl oxidase-like proteins.In addition,clinical trials are undergoing to evaluate their efficacy and safety.

New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases

Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.

COVID-19 and liver diseases,what we know so far

Coronavirus disease 2019(COVID-19)pneumonia outbreak started in December 2019.On March 12,2020,the World Health Organization(WHO)declared that the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)constitutes a pandemic,and as of May 2021,SARS-CoV-2 has infected over 167.3 million patients,including 3.4 million deaths,reported to WHO.In this review,we will focus on the relationship between SARS-CoV-2 infection and the liver.We will discuss how chronic liver diseases affect the COVID-19 disease course and outcomes.We will also discuss the SARS-CoV-2 effects on the liver,mechanisms of acute liver injury,and potential management plans.

Steatosis as a co-factor in chronic liver diseases

The finding of lipid accumulation in the liver, so-called hepatic steatosis or non-alcoholic fatty liver disease, is a common condition frequently found in healthy subjects. Its prevalence, in fact, has been estimated by magnetic resonance studies to be about 35% in the general population and 75% in obese persons. Nevertheless, its presence generates liver damage only in a small percentage of subjects not affected by other liver diseases. It should be defined as a "co-factor" capable of affecting severity and progression, and also therapeutic perspectives, of liver diseases to which it is associated. Herein we will evaluate the impact of hepatic steatosis and obesity on the most common liver diseases: chronic viral hepatitis C and B, and alcoholic liver disease.

Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease:From nomenclature to clinical outcomes

As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.

PTEN in liver diseases and cancer

The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt axis is a key signal transduction node that regulates crucial cellular functions, including insulin and other growth factors signaling, lipid and glucose metabolism, as well as cell survival and apoptosis. In this pathway, PTEN acts as a phosphoinositide phosphatase, which terminates PI3Kpropagated signaling by dephosphorylating PtdIns(3,4)P2 and PtdIns(3,4,5)P3. However, the role of PTEN does not appear to be restricted only to PI3K signaling antagonism, and new functions have been recently discovered for this protein. In addition to the well-established role of PTEN as a tumor suppressor, increasing evidence now suggests that a dysregulated PTEN expression and/or activity is also linked to the development of several hepatic pathologies. Dysregulated PTEN expression/activity is observed with obesity, insulin resistance, diabetes, hepatitis B virus/hepatitis C virus infections, and abusive alcohol consumption, whereas mutations/deletions have also been associated with the occurrence of hepatocellular carcinoma. Thus, it appears that alterations of PTEN expression and activity in hepatocytes are common and recurrent molecular events associated with liver disorders of various etiologies. These recent f indings suggest that PTEN might represent a potential common therapeutic target for a number of liver pathologies.

Extracellular vesicles in non-alcoholic and alcoholic fatty liver diseases

Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form of the disease,including as non-alcoholic steatohepatitis(NASH)and alcoholic steatohepatitis(ASH).In both instances central pathogenic events include hepatocyte death,liver inflammation,pathological angiogenesis,and fibrosis,followed by cirrhosis and cancer.Over the last few years,extracellular vesicles(EVs)have been identified as effective cell-to-cell communicators that contain a cell-and stressspecific cargo from the cell of origin and are capable of transferring this cargo to a target or acceptor cell.In this review,we focus on the growing evidence supporting a role for EVs in the pathophysiology of NASH and ASH as well as their potential roles as targets for novel biomarkers for these conditions.

Role of inflammatory response in liver diseases: Therapeutic strategies

Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus(HCV) infection, and sterile stressors(oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1β and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro-or antiapoptotic. Acute and chronic liver diseases are cytokinedriven diseases as several proinflammatory cytokines(IL-1α, IL-1β, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1β production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases.

Epidemiological and histopathological study of relevance of Guizhou Maotai liquor and liver diseases

AIM：To explore the relevance of Maotai liquor and liver diseases.METHODS:Epidemiological study was conducted on groups of subjects,each consisting of 3 subjects from the Maotai liquor roup consisting of 99 individuals and one from the non-alcoholic control group consisting of 33 individuals Liver biopsy was performed on 23 volunteere from Guizhou Maotai Distillery who had a constant and long history of drinking Maotai liquor.Experimental histopathological study was conducted as follows:Sixty male Wistar rate were divided into 3 groups randomly and fed with Maotai liquor,ordinary white wine,and physiological saline respectively for a period of 8and 12 weeks,The rats were sacrificed in batches,then serum ALT,AST,TBil,and AKP were measured.Rat livers were harvested to Measure the liver indexes GSH,and MDA.Histopathological examinations were also performed.Another eighty mice were randomly divided into 4 groups and fed with Maotai(at different dosages of 10ml.kg^-1 and 20ml.kg^-1),ethanol,and physiological saline.The animals were sacrificed after 4 weeks and serum ALT was determined ,Then the livers were harvested and liver indexes and MDA were measured.RESULTS:The incidence rate of hepatic symptoms splenomegaly,liver function impairment,reversal of Albumin/Globulin and increased diameter of portal verins in the Maotai liquor group were 1.0%(1/99),1.0%(1/99),1.0%(1/99),1.0%(1/99),9(9/99)and 9(0/99),0(0/99),0(0/99),0(0/99),0(0/99),respectively,There was no significant difference between the Maotai group[ and the non-alcoholic control group(P>0\05),Various degree of fatty infiltration of hepatocytes was found in the 23 volunteers receiving liver biopsy.but there was no obvious hepatic fibrosis or cirrhosis.A comparison was made between the Maotai liquor group and the ordinary white wine group,It was found that hepatic MAD in rats and mice,were 0.33±0.10and 0.49±0.23respectively in Maotai group and 0.61±0.22and 0.66±0.32inthe ordinary white wine group;MDA had an obvious decrease in the Maotai liquor group(P<0.05)hepatic GSH were 0.12mg.g^-1±0.06mg.g^-1 in rats of the Maotai liquor group and (0.08±0.02)mg.g^-1 in white wine group,it was obviously increased in the Maotai liquor group(P<0.05),Atfer the 20 rats had been fed with ordinary white wine for 8 Weeks consecutively,disarranged hepatocyte cords,fatty infiltration of hepatocytes,and fibrous septa of varying widths due to hepatic connective tissues proliferation were observed;after 12 weeks,the fibrous tissue proliferation continued and early cirrhosis appeared.COmpared with the ordinary whtite wine group fatty infiltration was observed in the 8-week and 12-week groups,but no necrosis or filbrosis or cirrhosis was found in the Maotai liquor group(P<0.05）。CONCLUSION:Maotai liquor may cause fatty liver but not hepatic fibrosis or cirrhosis,and it can strengthen lipid peroxidation in the liver。

Psoriasis,non-alcoholic fatty liver disease,and cardiovascular disease:Three different diseases on a unique background

Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease.

Gender specific medicine in liver diseases:a point of view

Gender medicine focuses on the patho-physiological,clinical,prevention and treatment differences in diseases that are equally represented in men and women.The purpose of gender medicine is to ensure that each individual man and woman receives the best treatment possible based on scientific evidence.The concept of"gender"includes not only the sexual characteristics of individuals but also physiological and psychological attributes of men and women,including risk factors,protective/aggravating effects of sexual hormones and variances linked to genetics and corporal structures that explain biological and physiological differences between men and women.It is very important to consider all the biological,physiological,functional,psychological,social and cultural characteristics to provide patients with individualized disease management.Herein,we critically analyze the literature regarding gender differences for diseases and acquired conditions of the most representative hepatic pathologies:primary biliary cirrhosis,autoimmune hepatitis,primary sclerosing cholangitis,non alcoholic fatty liver disease and alcoholic liver disease,and viral chronic hepatitis B and C.The last section addresses hemochromatosis,which is a prevalent iron overload disorder in the Caucasian population.This review aims to describe data from the literature concerning viral chronic hepatitis during pregnancy,management during pregnancy and delivery,and new effective drugs for the prevention of maternal infection transmission without significant adverse effects or complications.

A Cross Sectional Study on the Correlation between Waist Circumference and Fatty Liver on Ultrasonography among Non-Alcoholic Filipino Adults

Objectives: This study aimed to determine the correlation between waist circumference and fatty liver on ultrasonography among non-alcoholic Filipino adults. This will aid in detecting non-alcoholic fatty liver disease in its early course, hence improving our current therapeutic recommendations in preventing and managing the adverse health outcomes of NAFLD. Methods and Materials: A cross-sectional study with a total of 65 recruited participants. The data collected were age, sex, waist-circumference, co-morbidities with maintenance medications, history of alcohol intake with emphasis on the quantity and duration, and history of drug intake. Waist circumference was measured and recorded. The presence of NAFLD was determined through a review of the ultrasonography results of all subjects. The demographic profile and waist circumference of all subjects were described using descriptive statistics. The chi-square test was utilized to test the independence of the NAFLD and WC in the quartile. Pearson correlation was used to determine the linear relationship between the variables. Pearson correlation coefficient was statistically significant at p 0.05. Results: Among the subjects, 26 (42%) presented with fatty liver based on ultrasonography, 15 (58%) and 11 (42%), males and females, respectively. The mean waist circumference of 97.5 ± 12.43 was significantly related to the fatty liver with a p-value of 0.0001. Waist circumference showed a positive correlation with the frequency of fatty liver on ultrasonography with p-values of 0.000755 (r = 0.590083) and 3.04366E—05 (r = 0.659143523), in males and females, correspondingly. The overall correlation between waist circumference and fatty liver on ultrasonography is statistically significant with a p-value of 4.10503E—08 (r = 0.634737127). Conclusion: One measure used to assess central obesity is waist circumference. In addition, it can also be utilized to assess risk for NAFLD since they are strongly correlated as reported in this study. Waist circumference cut-off values for the Filipinos proposed in this study are the following: >88 cm and >95 cm, in males and females, respectively.

Treatment options for alcoholic and non-alcoholic fatty liver disease: A review

Alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are serious health problems worldwide.These two diseases have similar pathological spectra,ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma.Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver(simple steatosis),a small percentage develops progressive liver disease.Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available.The treatment for ALD remains as it was 50 years ago:abstinence,nutritional support and corticosteroids(or pentoxifylline as an alternative if steroids are contraindicated).As for NAFLD,the treatment modality is mainly directed toward weight loss and co-morbidity management.Therefore,new pathophysiology directed therapies are urgently needed.However,the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy.Hence,a combination therapy towards multiple targets would eventually be required.In this review,we delineate the treatment options in ALD and NAFLD,including various new targeted therapies that are currently under investigation.We hope that soon we will be having an effective multi-therapeutic regimen for each disease.

Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease

MicroRNAs(miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAsin alcoholic liver disease(ALD) and non-alcoholic fatty liver disease(NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34 a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.

Non-alcoholic fatty liver disease and thyroid dysfunction:A systematic review

Thyroid hormones are totally involved in the regulation of body weight, lipid metabolism, and insulin resistance. Therefore it is anticipated that thyroid hormones may have a role in the pathogenesis of non alcoholic fatty liver disease(NAFLD) and non alcoholic steatohepatitis(NASH). In this study, we reviewed the current literature on the association between thyroid dysfunction and NAFLD/NASH. A search for English language medical literature reporting an association between thyroid dysfunction and NAFLD/NASH in humans was conducted across PubMed, ISI Web of Science, and Scopus in August, 2013. Out of 140 studies initially identified through the search, 11 relevant articles were included in the final review. Thyroid dysfunctions in the form of overt or subclinical hypothyroidism are prevalent among patients with NAFLD/NASH. Hypothyroidism appears to be an independent risk factor for NAFLD/NASH in some studies; however, other newly published studies failed to find such anassociation. The results of the studies on the role of thyroid abnormalities in NAFLD/NASH are inconsistent, and further research is recommended to determine the relationship between hypothyroidism and NAFLD/NASH and the underlying mechanisms.