Dynamic changes and clinical value of lipocalin 2 in liver diseases caused by microbial infections

Lipocalin 2(LCN2)plays a pivotal role in iron metabolism,particularly in the context of microbial infection resistance(e.g.,viruses,bacteria,parasites,etc.).LCN2 combats microbial infection by directly assisting the body in competing with microorganisms for iron,inducing immune cells to secrete various cytokines to enhance systemic immune responses,or recruiting neutrophils to infectious sites.The liver serves as the primary organ for LCN2 secretion during microbial infections.This review encapsulates recent advances in dynamic changes,clinical values,and the effects of LCN2 in infectious liver diseases caused by various microbial microorganisms.

Ferritinophagy: A new idea for liver diseases regulated by ferroptosis

Background:The discovery of regulatory cell death has led to a breakthrough in the therapeutic field.Various forms of cell death,such as necrosis,apoptosis,pyroptosis,autophagy,and ferroptosis,play an important role in the development of liver diseases.In general,more than one form of cell death pathways is responsible for the disease state.Therefore,it is particularly important to study the regulation and interaction of various cell death forms in liver diseases.Data sources:We performed a PubMed search up to November 2022 with the following keywords:ferritinophagy,ferroptosis,and liver disease.We also used terms such as signal path,inducer,and inhibitor to supplement the query results.Results:This review summarized the basic characteristics of ferritinophagy and ferroptosis and the regulation of ferroptosis by ferritinophagy and reviewed the key targets and treatment strategies of ferroptosis in different liver diseases.Conclusions:Ferritinophagy is a potential therapeutic target in ferroptosis-related liver diseases.

Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases

Nonalcoholic fatty liver disease(NAFLD)is a global health concern associated with significant morbidity and mortality.NAFLD is a spectrum of diseases originating from simple steatosis,progressing through nonalcoholic steatohepatitis(NASH),fibrosis,and cirrhosis that may lead to hepatocellular carcinoma(HCC).The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflam-matory cytokines expression leading to inflammation,oxidative stress,and mitochondrial dysfunction de-noted as“two-hit hypothesis”,advancing with a“third hit”of insufficient hepatocyte proliferation,lead-ing to the increase in hepatic progenitor cells contributing to fibrosis and HCC.Wnt/β-catenin signaling is responsible for normal liver development,regeneration,hepatic metabolic zonation,ammonia and drug detoxification,hepatobiliary development,etc.,maintaining the overall liver homeostasis.The key regula-tors of canonical Wnt signaling such as LRP6,Wnt1,Wnt3a,β-catenin,GSK-3β,and APC are abnormally regulated in NAFLD.Many experimental studies have shown the aberrated Wnt/β-catenin signaling dur-ing the NAFLD progression and NASH to hepatic fibrosis and HCC.Therefore,in this review,we have em-phasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.

Bone loss in chronic liver diseases:Could healthy liver be a requirement for good bone health?

Given that the liver is involved in many metabolic mechanisms,it is not surprising that chronic liver disease(CLD)could have numerous complications.Secondary osteoporosis and increased bone fragility are frequently overlooked complications in CLD patients.Previous studies implied that up to one-third of these individuals meet diagnostic criteria for osteopenia or osteoporosis.Recent publications indicated that CLD-induced bone fragility depends on the etiology,duration,and stage of liver disease.Therefore,the increased fracture risk in CLD patients puts a severe socioeconomic burden on the health system and urgently requires more effective prevention,diagnosis,and treatment measures.The pathogenesis of CLD-induced bone loss is multifactorial and still insufficiently understood,especially considering the relative impact of increased bone resorption and reduced bone formation in these individuals.It is essential to note that inconsistent findings regarding bone mineral density measurement were previously reported in these individuals.Bone mineral density is widely used as the“golden standard”in the clinical assessment of bone fragility although it is not adequate to predict individual fracture risk.Therefore,microscale bone alterations(bone microstructure,mechanical properties,and cellular indices)were analyzed in CLD individuals.These studies further support the thesis that bone strength could be compromised in CLD individuals,implying that an individualized approach to fracture risk assessment and subsequent therapy is necessary for CLD patients.However,more well-designed studies are required to solve the bone fragility puzzle in CLD patients.

Autoimmune liver diseases and SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),causing coronavirus disease 2019(COVID-19),can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry.Here we summarise the current knowledge about autoimmune liver diseases(AILDs)and SARS-CoV-2,focusing on:(1)The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs;(2)the role of SARS-CoV-2 in inducing liver damage and triggering AILDs;and(3)the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver.Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine.Although SARSCoV-2 infection can lead to the development of several autoimmune diseases,few reports correlate it to the appearance of de novo manifestation of immunemediated liver diseases such as autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)or AIH/PBC overlap syndrome.Different case series of an AIHlike syndrome with a good prognosis after SARS-CoV-2 vaccination have been described.Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established,these reports suggest that this association could be more than coincidental.

Albumin-bilirubin score in non-malignant liver diseases should be properly validated

The albumin-bilirubin(ALBI)score to assess the risk of decompensation in patients with initially compensated cirrhosis may improve their prognostic evaluation.This letter critically evaluates the research,which utilizes the ALBI score to forecast decompensation in cirrhosis patients over a three-year period.This score was initially developed to assess liver function in hepatocellular carcinoma,its prognostic utility for non-malignant liver diseases has now been explored,recognizing decompensation as a pivotal event that significantly affects patient’s survival.Some concerns regarding the methodology of this research may be raised,particularly the exclusive use of radiological diagnosis,potentially including patients without definite cirrhosis and thus skewing the decompensation risk assessment.The reported predominance of variceal bleeding as a decompensating event conflicts with established literature,that often reports ascites as the initial decompensation manifestation.The letter highlights the absence of details on esophageal varices and their management,which could introduce bias in evaluating the ALBI score's predictive power.Furthermore,the letter points out the small sample size of patients with high-risk ALBI grades,potentially compromising the score's validity in this context.We suggest prospective future research to investigate the dynamic changes in the ALBI score over time to reinforce the validity of the ALBI score as a predictor of decompensation in non-malignant liver disease.

Diagnostic role of transient elastography in patients with autoimmune liver diseases:A systematic review and meta-analysis

BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease.The diagnostic value of transient elastography for autoimmune liver diseases(AILDs)is worth studying.AIM To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD.METHODS The PubMed,Cochrane Library and EMBASE databases were searched.Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs[autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC)]were included.The summary area under the receiver operating characteristic curve(AUROC),diagnostic odds ratio,sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis.RESULTS A total of 60 articles were included in this study,and the number of patients with AIH,PBC and PSC was 1594,3126 and 501,respectively.The summary AUROC of transient elastography in the diagnosis of significant fibrosis,advanced fibrosis and cirrhosis in patients with AIH were 0.84,0.88 and 0.90,respectively,while those in patients with PBC were 0.93,0.93 and 0.91,respectively.The AUROC of cirrhosis for patients with PSC was 0.95.However,other noninvasive indices(aspartate aminotransferase to platelet ratio index,aspartate aminotransferase/alanine aminotransferase ratio,fibrosis-4 index)had corresponding AUROCs less than 0.80.CONCLUSION Transient elastography exerts better diagnostic accuracy in AILD patients,especially in PBC patients.The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.

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.

Collagen matrix scaffolds:Future perspectives for the management of chronic liver diseases

Approximately 1.5 billion chronic liver disease(CLD)cases have been estimated worldwide,encompassing a wide range of liver damage severities.Moreover,liver disease causes approximately 1.75 million deaths per year.CLD is typically characterized by the silent and progressive deterioration of liver parenchyma due to an incessant inflammatory process,cell death,over deposition of extracellular matrix proteins,and dysregulated regeneration.Overall,these processes impair the correct function of this vital organ.Cirrhosis and liver cancer are the main complications of CLD,which accounts for 3.5%of all deaths worldwide.Liver transplantation is the optimal therapeutic option for advanced liver damage.The liver is one of the most common organs transplanted;however,only 10%of liver transplants are successful.In this context,regenerative medicine has made significant progress in the design of biomaterials,such as collagen matrix scaffolds,to address the limitations of organ transplantation(e.g.,low donation rates and biocompatibility).Thus,it remains crucial to continue with experimental and clinical studies to validate the use of collagen matrix scaffolds in liver disease.

Global burden of cirrhosis and other chronic liver diseases due to nonalcoholic fatty liver disease,1990-2019

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)has become the leading cause of cirrhosis and other chronic liver diseases(COCLDs).AIM To conduct a comprehensive and comparable updated analysis of the global,regional,and national burden of COCLDs due to NAFLD in 204 countries and territories from 1990 and 2019 by age,sex,and sociodemographic index.METHODS Data on COCLDs due to NAFLD were collected from the Global Burden of Diseases,Injuries,and Risk Factors Study 2019.Numbers and age-standardized prevalence,death,and disability-adjusted life years(DALYs)were estimated through a systematic analysis of modelled data from the Global Burden of Diseases,Injuries,and Risk Factors Study 2019.The estimated annual percentage change was used to determine the burden trend.RESULTS In 2019,the global age-standardized prevalence rate of COCLDs due to NAFLD was 15022.90 per 100000 population[95%uncertainty interval(UI):13493.19-16764.24],which increased by 24.51%(22.63%to 26.08%)from 1990,with an estimated annual percentage change of 0.78(95%confidence interval:0.74-0.82).In the same year,however,the age-standardized death rate and age-standardized DALYs per 100000 population were 1.66(95%UI:1.20-2.17)and 43.69(95%UI:31.28-58.38),respectively.North Africa and the Middle East had the highest prevalence rates of COCLDs due to NAFLD.The death rate increased with age up to the 95+age group for both sexes.Males had higher numbers of prevalence,death rate,and DALYs than females across all age groups before the 65-69 age group.The sociodemographic index was negatively correlated with the age-standardized DALYs.CONCLUSION Globally,the age-standardized prevalence rate has increased during the past three decades.However,the agestandardized death rate and age-standardized DALYs decreased.There is geographical variation in the burden of COCLDs due to NAFLD.It is strongly recommended to improve the data quality of COCLDs due to NAFLD across all countries and regions to facilitate better monitoring of the burden of COCLDs due to NAFLD.

Shifting perspectives in liver diseases after kidney transplantation

Liver diseases after kidney transplantation range from mild biochemical abnormalities to severe hepatitis or cirrhosis.The causes are diverse and mainly associated with hepatotropic viruses,drug toxicity and metabolic disorders.Over the past decade,the aetiology of liver disease in kidney recipients has changed significantly.These relates to the use of direct-acting antiviral agents against hepatitis C virus,the increasing availability of vaccination against hepatitis B and a better understanding of drug-induced hepatotoxicity.In addition,the emergence of the severe acute respiratory syndrome coronavirus 2 pandemic has brought new challenges to kidney recipients.This review aims to provide healthcare professionals with a comprehensive understanding of recent advances in the management of liver complications in kidney recipients and to enable them to make informed decisions regarding the risks and impact of liver disease in this population.

Hypoxia,angiogenesis and liver fibrogenesis in the progression of chronic liver diseases

Angiogenesis is a dynamic,hypoxia-stimulated and growth factor-dependent process,and is currently referred to as the formation of new vessels from preexisting blood vessels.Experimental and clinical studies have unequivocally reported that hepatic angiogenesis,irrespective of aetiology,occurs in conditions of chronic liver diseases(CLDs) characterized by perpetuation of cell injury and death,inflammatory response and progressive fibrogenesis.Angiogenesis and related changes in liver vascular architecture,that in turn concur to increase vascular resistance and portal hypertension and to decrease parenchymal perfusion,have been proposed to favour fibrogenic progression of the disease towards the end-point of cirrhosis.Moreover,hepatic angiogenesis has also been proposed to modulate the genesis of portal-systemic shunts and increase splanchnic blood flow,thus potentially affecting complications of cirrhosis.Hepatic angiogenesis is also crucial for the growth and progression of hepatocellular carcinoma.Recent literature has identified a number of cellular and molecular mechanisms governing the cross-talk between angiogenesis and fibrogenesis,with a specifi c emphasis on the crucial role of hypoxic conditions and hepatic stellate cells,particularly when activated to the myofibroblast-like pro-fibrogenic.Experimental anti-angiogenic therapy has been proven to be effective in limiting the progression of CLDs in animal models.From a clinical point of view,anti-angiogenic therapy is currently emerging as a new pharmacologic intervention in patients with advanced fibrosis and cirrhosis.

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.

New insight of vitamin D in chronic liver diseases

BACKGROUND： Vitamin D is a fat-soluble sterol derivative that is predominantly synthesized in the liver and has multiple functions. The accumulative data showed that the clinical manifestations and prognosis of chronic liver diseases are associated with serum vitamin D levels. DATA SOURCES： A PubMed and Google Scholar search using terms： ＂vitamin D＂, ＂25 （OH）D＂, ＂liver disease＂, ＂viral hepatitis＂, ＂non-alcoholic fatty liver disease＂, ＂liver fibrosis＂, ＂cirrhosis＂, ＂hepatocellular carcinoma＂ and ＂autoimmune liver disease＂ was performed, and relevant articles published in English between January 2000 and March 2014 were reviewed. Fulb text publications relevant to the field were selected and relevant articles from reference lists were also included. RESULTS： The insufficiency or deficiency of vitamin D is common in various kinds of chronic liver diseases including viral hepatitis B and C. Serum 25-hydroxyvitamin D and vitamin D receptors are possibly interrelated with the incidence, treatment and prognosis of diseases. Though the evidence of vitamin D supplementation in viral hepatitis and associated liver diseases is still limited, there is great potential to apply this adjuvant therapy to improve the treatments. CONCLUSIONS： Although the exact role and mechanisms of vitamin D have not been fully elucidated in chronic liver diseases, it is potentially beneficial in the treatment of chronic liver diseases. Further mechanistic studies are needed to validate its clinical application.

Role of bile acids in liver diseases mediated by the gut microbiome

The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites.The interaction between the gut microbiome and bile acids is bidirectional.The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes.Similarly,bile acids also shape the composition of the gut microbiome by modulating the host’s natural antibacterial defense and the intestinal immune system.The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases,especially liver diseases.As essential mediators of the gut-liver crosstalk,bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1.Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases.We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle.

Progress of intravoxel incoherent motion diffusion-weighted imaging in liver diseases

Traditional magnetic resonance(MR)diffusion-weighted imaging(DWI)uses a single exponential model to obtain the apparent diffusion coefficient to quantitatively reflect the diffusion motion of water molecules in living tissues,but it is affected by blood perfusion.Intravoxel incoherent motion(IVIM)-DWI utilizes a double-exponential model to obtain information on pure water molecule diffusion and microcirculatory perfusion-related diffusion,which compensates for the insufficiency of traditional DWI.In recent years,research on the application of IVIM-DWI in the diagnosis and treatment of hepatic diseases has gradually increased and has achieved considerable progress.This study mainly reviews the basic principles of IVIM-DWI and related research progress in the diagnosis and treatment of hepatic diseases.

Critical role of estrogen in the progression of chronic liver diseases

Background:Estrogens regulate sexual function and also have a significant role in various pathophysiological processes.Estrogens have a non-reproductive role as the modulators of the immune system,growth,neuronal function,and metabolism.Estrogen receptors are expressed in the liver and their impaired expression and function are implicated with obesity and liver associated metabolic dysfunctions.The purpose of the current review is to discuss the disparity role of estrogens on several forms of liver diseases.Data sources:A comprehensive search in PubMed and EMBASE was conducted using the keywords“estrogens and liver diseases”,“estradiol and liver diseases”,“hormones and liver diseases”,“endocrine function in liver diseases”,and“female hormones in liver diseases”.Relevant papers published before September 30,2019 were included.Results:The present review confirms the imperative role of estrogen in various forms of chronic liver diseases.Estrogens play a key role in maintaining homeostasis and make the liver less susceptible to several forms of chronic liver diseases in healthy premenopausal individuals.In contrast,clinical studies also showed increased estrogen levels with chronic liver diseases.Conclusions:Several studies reported the protective role of estrogens in chronic liver diseases and this has been widely accepted and confirmed in experimental studies using ovariectomized rat models.However,in a few clinical studies,increased estrogen levels are also implicated in chronic liver diseases.Therefore,further studies are warranted at molecular level to explore the role of estrogen in various forms of chronic liver diseases.

Clinical implications,diagnosis,and management of diabetes in patients with chronic liver diseases

Diabetes mellitus(DM)negatively affects the development and progression of chronic liver diseases(CLD)of various etiologies.Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality,the occurrence of hepatic decompensation,and the development of hepatocellular carcinoma(HCC).Unfortunately,early diagnosis and optimal treatment of DM can be challenging,due to the lack of established clinical guidelines as well as the medical complexity of this patient population.We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population.We reviewed the epidemiological and pathophysiological associations between DM and CLD,the impact of insulin resistance on the progression and manifestations of CLD,the pathogenesis of hepatogenic diabetes,as well as the practical challenges in diagnosis and monitoring of DM in this patient population.We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes.Finally,we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.

The advances of traditional Chinese medicine in the treatment of liver diseases in 2019

Background:Currently,the treatment of liver diseases remains an unsolved problem due to its complicated etiology and pathogenesis.Traditional Chinese medicine(TCM)has been used for liver disease treatment for thousands of years.Disease treatment using TCM compounds conforms to the concept of“holism”,which coincides with the complicated pathogenic mechanisms of liver diseases.However,the mechanisms have not been clearly explained due to the complex components and multi-targets,which is a big obstacle TCM’s popularity and application.In recent years,studying the mechanisms and identifying the novel ingredients in herbal medicines are becoming a hot spot for many researchers.Therefore,we obtained literature in PubMed and summarized the progress of TCM’s active ingredients and formulas in treating various liver diseases in 2019.Based on the literature,flavonoids,polysaccharides,saponins,and alkaloids,as well as Chinese medicine formulas,such as Ba-Bao pill and Yin-Chen-Hao decoction,have attracted much attention.In addition,we also focused on the application of new omics analysis techniques,such as metabolomics,network pharmacology,and other omics analyses in the study of TCM formulas.

Osteosarcopenia in autoimmune cholestatic liver diseases:Causes,management,and challenges

Primary biliary cholangitis and primary sclerosing cholangitis(PSC)are the most common cholestatic liver diseases(CLD)in adults and are both characterized by an immune pathogenesis.While primary biliary cholangitis is a model autoimmune disease,with over 90%of patients presenting very specific autoantibodies against mitochondrial antigens,PSC is considered an immune mediated disease.Osteoporosis is the most common bone disease in CLD,resulting in frequent fractures and leading to significant morbidity.Further,sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients.The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected.Although timely diagnosis,prevention,and management of osteosarcopenia are crucial to limit the consequences,there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD.International guidelines recommend screening for bone disease at the time of diagnosis of CLD.However,the optimal monitoring strategies and treatments have not been defined yet and vary among centers.We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD,and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.