Elafibranor:A promising treatment for alcoholic liver disease,metabolic-associated fatty liver disease,and cholestatic liver disease

Liver diseases pose a significant threat to human health.Although effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes.This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease(ALD),as reported by Koizumi et al in the World Journal of Gastroenterology.We summarize the impact and mechanisms of Elafibranor on ALD,metabolic-associated fatty liver disease,and cholestatic liver disease based on current research.We also explore its potential as a dual agonist of PPARα/δ,which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis.Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.

Medical treatment of cholestatic liver diseases:From pathobiology to pharmacological targets

Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.

Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.

Cholestatic liver diseases:An era of emerging therapies

Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease. Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid (UDCA), the current standard treatment for cholestatic liver disease. Important novel treatment targets now also include nuclear receptors involved in bile acid (BA) homoeostasis like farnesoid X receptor and G proteincoupled receptors e.g., the G-protein-coupled BA receptor “transmembrane G coupled receptor 5”. Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA. In this review, we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.

Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation

Selective cyclooxygenase-2 （COX-2） inhibitors are widely used due to their efficacy and good safety profile. However, recent case reports have described varying degrees of liver injudes associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.

Fibrosing cholestatic hepatitis following cytotoxic chemotherapy for small-cell lung cancer

Fibrosing cholestatic hepatitis(FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver,renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy.FCH constitutes a well-described form of fulminant hepatitis having extensive fibrosis and severe cholestasis as its most characteristic pathological findings.Here,we report a case of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression.This is the first reported case in the literature of FCH after conventional chemotherapy for a solid tumor.In addition to a detailed report of the case,a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.

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.

Severe acute cholestatic hepatitis of unknown etiology successfully treated with the Chinese herbal medicine Inchinko-to (TJ-135)

Severe acute hepatitis of unknown etiology is difficult to treat and often progresses to subacute fulminant hepatitis or late-onset hepatic failure. A 45-year-old wellnourished, healthy man had progressive fatigue and his liver function tests showed severe liver dysfunction. The etiology of sever acute cholestatic hepatitis was unknown. The liver function tests normalized gradually, which excluded high persistent total bilirubin after starting on predonine. A liver biopsy showed chronic active hepatitis with mild f ibrosis (A2, F1). Oral Inchinko-to, a Chinese herbal medicine, at 7.5 g daily was prescribed. The treatment was effective with no adverse effects. We present a successfully treated case and discuss hepatoprotective and choleretic effects of Inchinko-to.

Altered Expression of Differential Genes in Thoracic Spinal Cord Involved in Experimental Cholestatic Itch Mouse Model

The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differential gene expression patterns were analyzed in the lower thoracic spinal cord involved in cholestatic pruritus after BDL operation using high-throughput RNA sequencing. At 21st day after BDL, the expression levels of ENSRNOG00000060523, ENSRNOG00000058405 and ENSRNOG00000055193 mRNA were significantly up-regulated, and those of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289, Gemin8, Serpina3n and Trim63 mRNA were significantly down-regulated in BDL group. The RNAseq data of selected mRNAs were validated by RT-qPCR. The expression levels of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289 and Serpina3n mRNA were significantly down-regulated in BDL group. This study suggested that cholestatic pruritus in experimental obstructive jaundice mouse model is related with in the changes of gene expression profiles in spinal cord.

Unique pattern of fibrosing cholestatic hepatitis after liver transplantation

To explore the pathological features and thedifferential diagnosis of recurrent HBV after livertransplantation.Methods: One case of liver transplantation for HBVcirrhosis was subjected to liver biopsises on time post-operatively.Results: 25 days after liver transplantation, serologicHBsAg, HBeAg and HBV-DNA of the patient becamenegative, but HBsAg was positive again on day 58 af-ter liver transplantation. Histopathological examina-tion showed balloon-like changes of hepatocytes withfragmental necrosis, fibrosis in the portal areas andaround the portal veins, cholestasis in some hepato-cytes and canaliculi, and positive HBsAg and HBcAgwith immunohistochemical staining. Clinically hepaticenzyme levels progressively increased, maintained forsome time, and decreased rapidly at last. Stubborn hy-poproteinemia was associated with the aggregation ofgeneral condition of the patient.Conclusions: Fibrosing cholestatic hepatitis (FCH) is aspecial type in recurrent infection of HBV after livertransplantation. It has a serious clinical process andspecific pathological changes different from those ofthe usual HBV.

Febrile cholestatic disease as an initial presentation of nodular lymphocyte-predominant Hodgkin lymphoma

Febrile cholestatic liver disease is an extremely unusual presentation of Hodgkin lymphoma(HL).The liver biopsy of a 40-year-old man with febrile episodes and cholestatic laboratory pattern disclosed an uncommon subtype of HL,a nodular lymphocyte-predominant HL(NLPHL).Liver involvement in the early stage of the usually indolent NLPHL's clinical course suggests an aggressiveness and unfavorable outcome.Emphasizing a liver biopsy early in the diagnostic algorithm enables accurate diagnosis and appropriate treatment.Although rare,HL should be considered in the differential diagnosis of cholestasis.

Cholestatic liver injury:A rare but fatal complication during and after COVID-19 infection

The 2019 coronavirus disease(COVID-19),resulting from the severe acute respiratory syndrome 2 virus,has transformed our globe and provided a new perspective on respiratory tract infections.However,COVID-19 would not be recognized as a condition restricted to only pneumonia.This narrative review was conducted by searching manuscripts in several databases,including PubMed/MEDLINE,Web of Science,and Reference Citation Analysis,from December 2019 to July 2022.Many studies have revealed a broad spectrum of potential systemic symptoms,including biliary complications.Although biliary injury has been observed in a very low proportion of COVID-19 patients,it is associated with increased mortalities and long-term morbidities.We identify a cholangiopathy condition in individuals during infection and after recovering from severe COVID-19,defined by a significant increase in serum alkaline phosphatase and signs of bile duct injury.Understanding the pathogeneses behind this condition would help us develop new techniques to prevent these complications.This review thoroughly discusses and summarizes the current information regarding COVID-19-associated cholangiopathy.In addition,the possible explanations for COVID-19-associated cholangiopathy are presented.Since the exact pathogenesis may not be concluded,this review could provide relevant information to encourage additional investigations shortly.

Chinese Expert Consensus for the Diagnosis and Treatmentof Cholestatic Liver Disease

Cholestatic liver disease (CLD) is a common problem in clinical practice with the main manifestation being cholestasis.Recently,there has been a steady increase in knowledge associated with the diagnosis and treatment of CLD.Therefore,the experts in China were organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases (Electronic Edition),Chinese Journal of Liver Diseases (Electronic Edition) and Infection International (Electronic Edition) to collect and analyze relevant research,ultimately resulting in the development of this work (Chinese Expert consensus for the diagnosis and treatment of CLDs,also abbreviated as consensus).

Mitochondria at the Crossroads of Cholestatic Liver Injury:Targeting Novel Therapeutic Avenues

Bile acids are byproducts of cholesterol metabolism in the liver and constitute the primary components of bile.Disruption of bile flow leads to cholestasis,characterized by the accumulation of hydrophobic bile acids in the liver and bloodstream.Such accumulation can exacerbate liver impairment.This review discussed recent developments in understanding how bile acids contribute to liver damage,including disturbances in mitochondrial function,endoplasmic reticulum stress,inflammation,and autophagy dysfunction.Mitochondria play a pivotal role in cholestatic liver injury by influencing hepatocyte apoptosis and inflammation.Recent findings linking bile acids to liver damage highlight new potential treatment targets for cholestatic liver injury.

Heritable Chronic Cholestatic Liver Diseases:A Review

Chronic cholestasis due to heritable causes is usually diagnosedin childhood.However,many cases can present andsurvive into adulthood.The time course varies considerablydepending on the underlying etiology.Laboratory data usuallyreveal elevated conjugated hyperbilirubinemia,alkalinephosphatase,and gamma-glutamyl transpeptidase.Patientsmay be asymptomatic;however,when present,the typicalsymptoms are pruritus,jaundice,fatigue,and alcoholicstools.The diagnostic methods and management requireddepend on the underlying etiology.The development of genome-wide associated studies has allowed the identificationof specific genetic mutations related to the pathophysiologyof cholestatic liver diseases.The aim of this review was tohighlight the genetics,clinical pathophysiology,presentation,diagnosis,and treatment of heritable etiologies of chroniccholestatic liver disease.

Progress in the Management of Patients with Cholestatic Liver Disease:Where Are We and Where Are We Going?

Cholestatic liver disease is a group of diseases in which bile acid accumulates in the liver for various reasons,resulting in abnormal liver biochemical indicators and histological damage.Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis,which will contribute to liver damage and progress to liver fibrosis and cirrhosis.Primary biliary cholangitis(PBC)and primary sclerosing cholangitis are the two most typical cholestatic liver diseases.Ursodeoxycholic acid is currently the first-line treatment for PBC,while obeticholic acid,budesonide and fibrates have also shown good potential in the treatment of PBC.There are currently no official drugs approved to treat primary sclerosing cholangitis,and the use of ursodeoxycholic acid may have certain clinical benefits.At present,progress has been made in new treatment directions for cholestatic liver disease,including fibroblast growth factor 19,cholestyramine,S-adenosyl-L-methionine,steroid drugs,farnesoid X receptor agonists,and more.Considerable progress has been made in the management of cholestatic liver disease but there are still many opportunities and challenges.In this review,we summarized the recommended guidelines for the management of cholestatic disease and the progress of new drug research and development,in order to provide an important reference for the clinical practice of cholestatic liver disease.

A Case of Severe Cholestatic Hepatitis Induced by a Novel Dual Agonist of Glucagon-like Peptide-1 and Glucosedependent Insulinotropic Polypeptide Receptors

Glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic polypeptide(GIP)receptor agonists are increasingly used in the management of type 2 diabetes mellitus and obesity due to their ability to stimulate insulin secretion,delay gastric emptying,and suppress appetite.The combination of GLP-1 and GIP agonists improves glycemic control and promotes weight loss.However,the introduction of these novel therapies has raised safety concerns,including the risk of cholestatic hepatitis.We report a case of a patient with obesity who was prescribed a GLP-1/GIP dual-receptor agonist as part of his treatment regimen.Importantly,both before the initiation of this therapy and during the course of treatment,the patient was not taking any other medications.Shortly after receiving four doses of the therapy,the patient developed symptoms of severe cholestatic hepatitis,including jaundice and elevated liver enzyme levels.During hospitalization,no alternative causes for the condition were identified,and a liver biopsy confirmed the diagnosis of druginduced cholestatic hepatitis.This is the first recorded case of cholestatic hepatitis induced by a GLP-1/GIP dual agonist,and it aimed to raise global awareness of this potential side effect.

Chuanxiong Rhizoma extracts prevent cholestatic liver injury by targeting H3K9ac-mediated and cholangiocyte-derived secretory protein PAI-1 and FN

Chuanxiong Rhizoma(CX,the dried rhizome of Ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies.Currently,little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells(HSCs).The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous,alkaloid,phenolic acid and phthalide extracts of CX(CX_(AE),CX_(AL),CX_(PA)and CX_(PHL))and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury.The active compounds of different CX extracts were identified by UPLC-MS/MS.A cholestatic liver injury mouse model induced by bile duct ligation(BDL),and transforming growth factor-β(TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes(HIBECs)and HSC cell line(LX-2 cells)were used for in vivo and in vitro studies.Histological and other biological techniques were also applied.The results indicated that CX_(AE),CX_(AL)and CX_(PHL)significantly reduced ductular reaction(DR)and improved liver fibrosis in the BDL mice.Meanwhile,both CX_(AE)and CX_(PHL)suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β.CX_(PHL)suppressed the transcription and transfer of plasminogen activator inhibitor-1(PAI-1)and fibronectin(FN)from the‘DR-like’cholangiocytes to activated HSCs.Mechanistically,the inhibition of PAI-1 and FN by CX_(PHL)was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3,followdd by the suppression of histone 3 lysine 9 acetylation(H3K9ac)-mediated transcription in cholangiocytes.In conclusion,CX_(PHL)exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts,and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.

The in vitro digestion fates of diacylglycerol under different intestinal conditions:a potential lipid source for lipid indigestion patients

The in vitro digestion models mimicking the gastrointestinal(GI)tract of general population and lipid indigestion patients(with lower levels of bile salts or pancreatic lipase)were selected to investigate whether diacylglycerols(DAGs)are potential good lipid sources for these patients.Linseed oil-based DAG(LD)and linseed oil(LT)were selected.LD-based emulsion((83.74±1.23)%)had higher lipolysis degree than LT-based emulsion((74.47±1.16)%)when monitoring the GI tract of normal population as previously reported.Indigestion conditions seriously decreased the digestive degree of LT-based emulsion((40.23±2.48)%-(66.50±3.70)%)while showed less influence on LD-based emulsion((64.18±2.41)%-(81.85±3.45)%).As opposed to LT-based emulsion,LD-based emulsion exhibited preference for releasing unsaturated fatty acids(especially oleic acid andα-linolenic acid)due to their different glycerolipid compositions.LD-based emulsion showed potential for providing lipids and nutrients(including essential fatty acids)for lipid indigestion patients.