Morphological aspects of small-duct cholangiopathies:A minireview

The biliary system consists of intrahepatic and extrahepatic bile ducts lined by biliary epithelial cells(cholangiocytes).Bile ducts and cholangiocytes are affected by a variety of disorders called cholangiopathies,which differ in aetiology,pathogenesis,and morphology.Classification of cholangiopathies is complex and reflects pathogenic mechanisms(immune-mediated,genetic,drug-and toxininduced,ischaemic,infectious,neoplastic),predominant morphological patterns of biliary injury(suppurative and non-suppurative cholangitis,cholangiopathy),and specific segments of the biliary tree affected by the disease process.While the involvement of large extrahepatic and intrahepatic bile ducts is typically visualised using radiology imaging,histopathological examination of liver tissue obtained by percutaneous liver biopsy still plays an important role in the diagnosis of cholangiopathies affecting the small intrahepatic bile ducts.To increase the diagnostic yield of a liver biopsy and determine the optimal therapeutic approach,the referring clinician is tasked with interpreting the results of histopathological examination.This requires knowledge and understanding of basic morphological patterns of hepatobiliary injury and an ability to correlate microscopic findings with results obtained by imaging and laboratory methods.This minireview describes the morphological aspects of small-duct cholangiopathies pertaining to the diagnostic process.

Functional roles of gut bacteria imbalance in cholangiopathies

Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver fibrosis.Bile duct epithelial cells,cholangiocytes,are a primary target for cholangiopathies.Ductular reaction is often observed in cholangiopathies and the proliferation of cholangiocytes is associated with ductular reaction and liver fibrogenesis.Accumulating evidence suggests that patients with chol-angiopathies have different gut bacterial profiles from healthy individuals,indicating the association between gut microbiota and cholangiopathies.Bile acids are produced by hepatocytes and modified by gut bacteria.Bile acids regulate cholangiocyte proliferation but effects vary depending on the type of bile acids.Recent studies suggest that therapies targeting gut bacteria,such as antibiotics administration and gut bacteria depletion or therapies using gut bacteria-associated bile acids,such as ursodeoxycholic acid(UDCA)administration,may be useful for treatments of cholangiopathies,although data are contro-versial depending on animal models or cohorts.This review summarizes current understandings of functional roles of gut bacterial imbalance and strategies for treatments of cholangiopathies targeting gut bacteria.

Diagnostic and therapeutic potentials of microRNAs in cholangiopathies

Cholangiopathies are a group of rare,devastating diseases that arise from damaged cholangiocytes,the cells that line the intra-and extra-hepatic bile ducts of the biliary epithelium.Cholangiopathies result in significant morbidity and mortality and are a major cause of liver transplantation.A better understanding of the underlying pathogenesis that influences cholangiocyte dysregulation and cholangiopathy progression is necessary,considering the dismal prognosis associated with these diseases.MicroRNAs are a class of small,non-coding RNAs that regulate post-transcriptional mRNA expression of specific genes.The role of microRNAs has expanded to include the initiation and development of many diseases,including cholangiopathies.Understanding microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these diseases.In this review,the authors primarily focus on studies published within the last five years that help determine the diagnostic and therapeutic potential of microRNAs in cholangiopathies.

Hepatic angiotensin-converting enzyme 2 expression in metabolic dysfunction-associated steatotic liver disease and in patients with fatal COVID-19

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD),characterised by hepatic lipid accumulation,causes inflammation and oxidative stress accompanied by cell damage and fibrosis.Liver injury(LI)is also frequently reported in patients hospitalised with coronavirus disease 2019(COVID-19),while preexisting MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy.Mechanisms of injury at the cellular level remain unclear,but it may be significant that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)which causes COVID-19,uses angiotensin-converting expression enzyme 2(ACE2),a key regulator of the‘anti-inflammatory’arm of the renin-angiotensin system,for viral attachment and host cell invasion.AIM To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19.METHODS ACE2 protein levels and localisation,and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum(isolated hepatocellular steatosis,metabolic dysfunction-associated steatohepatitis(MASH)+/-fibrosis,end-stage cirrhosis)and in post-mortem tissues from patients who had died with severe COVID-19,using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas,followed by quantification using machine learning-based image pixel classifiers.RESULTS ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes.Strikingly,ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis.ACE2 protein levels and histological fibrosis are not associated,but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum.Hepatic ACE2 levels are also increased in COVID-19 patients,especially those showing evidence of LI,but are not correlated with the presence of SARS-CoV-2 virus in the liver.However,there is a clear association between the hepatic lipid droplet content and the presence of the virus,suggesting a possible functional link.CONCLUSION Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI,while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication,accelerating MASLD progression and COVID-19-mediated liver damage.

Involvement of cholangiocyte proliferation in biliary fibrosis

Cholangiocytes are the epithelial cells that line the biliary tree.In the adult liver,they are a mitotically dormant cell population,unless ductular reaction is triggered by injury.The ability of cholangiocytes to proliferate is important in many different human pathological liver conditions that target this cell type,which are termed cholangiopathies(i.e.primary biliary cirrhosis,primary sclerosing cholangitis and biliary atresia).In our article,we provide background information on the morphological and functional heterogeneity of cholangiocytes,summarize what is currently known about their proliferative processes,and briefly describe the diseases that target these cells.In addition,we address recent findings that suggest cholangiocyte involvement in epithelial-to-mesenchymal transformation and liver fibrosis,and propose directions for future studies.

MicroRNAs in biliary diseases

Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with a broad variety of causes of different nature, which includes genetic, neoplastic, immune-associated, infectious, vascular, and drug-induced alterations, or being idiopathic. miRNAs, small non-coding endogenous RNAs that post-transcriptionally regulate gene expres sion, have been associated with pathophysiological processes in different organs and cell types, and are postulated as potential targets for diagnosis and therapy. In the current manuscript, knowledge regarding the role of miRNAs in the development and/or progression of cholangiopathies has been reviewed and the most relevant findings in this promising field of hepatology have been highlighted.

Ischemic cholangiopathy after livertransplantation

Orthotopic liver transplantation ( OLT) has evolved over the last forty years from an experimental endeavor to standard of care therapy for many patients with end stage hepatic disease. Many technical advances have contributed to the current success of OLT, but surgical complications, especially involving the biliary reconstruction, remain a morbid problem. Biliary complications after OLT include leaks and strictures. Strictures may be anastoinotic or intrahepatic and diffuse, as seen in cases of hepatic artery thrombosis. Current efforts to expand the limited donor pool include the use of non-heart beating donors. The organ procurement process in these donors entails an increased period of warm ischemia and results with non-heart beating donor grafts have been mixed. It is now appreciated that there is an increased incidence of subsequent diffuse biliary stricturing or ' ischemic cholangiopathy' in recipients of these organs. Animal models of this phenomenon and potential therapeutic strategies targeted at ischemic cholangiopathy are being developed with potential applicability to non-heart beating donation and will be the focus of this review.

Aetiology and risk factors of ischaemic cholangiopathy after liver transplantation

Liver transplantation (LT) is the best treatment for end-stage hepatic failure, with an excellent survival rates over the last decade. Biliary complications after LT pose a major challenge especially with the increasing number of procured organs after circulatory death. Ischaemic cholangiopathy (IC) is a set of disorders characterized by multiple diffuse strictures affecting the graft biliary system in the absence of hepatic artery thrombosis or stenosis. It commonly presents with cholestasis and cholangitis resulting in higher readmission rates, longer length of stay, repeated therapeutic interventions, and eventually re-transplantation with consequent effects on the patient’s quality of life and increased health care costs. The pathogenesis of IC is unclear and exhibits a higher prevalence with prolonged ischaemia time, donation after circulatory death (DCD), rejection, and cytomegalovirus infection. The majority of IC occurs within 12 mo after LT. Prolonged warm ischaemic times predispose to a profound injury with a subsequently higher prevalence of IC. Biliary complications and IC rates are between 16% and 29% in DCD grafts compared to between 3% and 17% in donation after brain death (DBD) grafts. The majority of ischaemic biliary lesions occur within 30 d in DCD compared to 90 d in DBD grafts following transplantation. However, there are many other risk factors for IC that should be considered. The benefits of DCD in expanding the donor pool are hindered by the higher incidence of IC with increased rates of re-transplantation. Careful donor selection and procurement might help to optimize the utilization of DCD grafts.

Epidemiology,determinants,and management of AIDS cholangiopathy:A review

Diseases of the liver and biliary tree have been described with significant frequency among patients with human immunodeficiency virus(HIV), and its advanced state, acquired immunodeficiency syndrome(AIDS). Through a variety of mechanisms, HIV/AIDS has been shown to affect the hepatic parenchyma and biliary tree, leading to liver inflammation and biliary strictures. One of the potential hepatobiliary complications of this viral infection is AIDS cholangiopathy, a syndrome of biliary obstruction and liver damage due to infection-related strictures of the biliary tract. AIDS cholangiopathy is highly associated with opportunistic infections and advanced immunosuppression in AIDS patients, and due to the increased availability of highly active antiretroviral therapy, is now primarily seen in instances of poor access to antiretroviral therapy and medication non-compliance. While current published literature describes well the clinical, biochemical, and endoscopic management of AIDS-related cholangiopathy, information on its epidemiology, natural history, and pathology are not as well defined. The objective of this review is to summarize the available literature on AIDS cholangiopathy, emphasizing its epidemiology, course of disease, and determinants, while also revealing an updated approach for its evaluation and management.

Vanishing bile duct syndrome in human immunodeficiency virus: Nevirapine hepatotoxicity revisited

Vanishing bile duct syndrome (VBDS) refers to a group of disorders characterized by prolonged cholestasis as a result of destruction and disappearance ofintrahepatic bile ducts. Multiple etiologies have been indentifi ed including infections, neoplastic disorders, autoimmune conditions and drugs. The natural history of this condition is variable and may involve resolution of cholestasis or progression with irreversible damage. VBDS is extremely rare in human immunodeficiency virus (HIV)-infected patients and anti-retroviral therapy has never been implicated as a cause. We encountered a young pregnant female with HIV and VBDS secondary to anti-retroviral therapy. Here, we report her clinical course and outcome.

Resected case of eosinophilic cholangiopathy presenting with secondary sclerosing cholangitis

Eosinophilic cholangiopathy is a rare condition characterized by eosinophilic infiltration of the biliary tract and causes sclerosing cholangitis. We report a patient with secondary sclerosing cholangitis with eosinophilic cholecystitis. A 46-year-old Japanese man was admitted to our hospital with jaundice. Computed tomography revealed dilatation of both the intrahepatic and extrahepatic bile ducts, diffuse thickening of the wall of the extrahepatic bile duct, and thickening of the gallbladder wall. Under the diagnosis of lower bile duct carcinoma, he underwent pyloruspreserving pancreatoduodenectomy and liver biopsy. On histopathological examination, conspicuous fibrosis was seen in the lower bile duct wall. In the gallbladder wall, marked eosinophilic infiltration was seen. Liver biopsy revealed mild portal fibrosis. He was diagnosed as definite eosinophilic cholecystitis with sclerosing cholangitis with unknown etiology. The possible etiology of sderosing cholangitis was consequent fibrosis from previous eosinophilic infiltration in the bile duct. The clinicopathological findings of our case and a literature review indicated that eosinophilic cholangiopathy could cause a condition mimicking primary sclerosing cholangitis （PSC）. Bile duct wall thickening in patients with eosinophilic cholangitis might be due to fibrosis of the bile duct wall. Eosinophilic cholangiopathy might be confused as PSC with eosinophilia.

Percutaneous transhepatic cholangiography vs endoscopic ultrasound-guided biliary drainage:A systematic review

BACKGROUND Percutaneous transhepatic cholangiography is a diagnostic and therapeutic procedure that involves inserting a needle into the biliary tree,followed by the immediate insertion of a catheter.Endoscopic ultrasound-guided biliary drainage(EUS-BD)is a novel technique that allows BD by echoendoscopy and fluoroscopy using a stent from the biliary tree to the gastrointestinal tract.AIM To compare the technical aspects and outcomes of percutaneous transhepatic BD(PTBD)and EUS-BD.METHODS Different databases,including PubMed,Embase,clinicaltrials.gov,the Cochrane library,Scopus,and Google Scholar,were searched according to the guidelines for Preferred Reporting Items for Systematic reviews and Meta-Analyses to obtain studies comparing PTBD and EUS-BD.RESULTS Among the six studies that fulfilled the inclusion criteria,PTBD patients underwent significantly more reinterventions(4.9 vs 1.3),experienced more postprocedural pain(4.1 vs 1.9),and experienced more late adverse events(53.8%vs 6.6%)than EUS-BD patients.There was a significant reduction in the total bilirubin levels in both the groups(16.4-3.3μmol/L and 17.2-3.8μmol/L for EUSBD and PTBD,respectively;P=0.002)at the 7-d follow-up.There were no significant differences observed in the complication rates between PTBD and EUSBD(3.3 vs 3.8).PTBD was associated with a higher adverse event rate than EUSBD in all the procedures,including reinterventions(80.4%vs 15.7%,respectively)and a higher index procedure(39.2%vs 18.2%,respectively).CONCLUSION The findings of this systematic review revealed that EUS-BD is linked with a higher rate of effective BD and a more manageable procedure-related adverse event profile than PTBD.These findings highlight the evidence for successful EUS-BD implementation.

COVID-19 related biliary injury:A review of recent literature

Since its emergence in 2019,it has become apparent that coronavirus 2019(COVID-19)infection can result in multi systemic involvement.In addition to pulmonary symptoms,hepatobiliary involvement has been widely reported.Extent of hepatic involvement ranges from minor elevation in liver function tests(LFTs)to significant hepatocellular or cholestatic injury.In majority of cases,resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection.However,severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation.Due to the timing of its presentation,this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy,and can result in devastating consequences for patients.COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury.Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase.Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis.Etiology of COVID-19 cholangiopathy is unclear.Several mechanisms have been proposed,including direct cholangiocyte injury,vascular compromise,and cytokine release syndromes.This review summarizes existing data on COVID-19 cholangiopathy,including reported cases in the literature,proposed pathophysiology,diagnostic testing,and long-term implications.

Sickle cell cholangiopathy:An endoscopic retrograde cholangiopancreatography evaluation

AIM:To evaluate the role of endoscopic retrograde cholangiopancreatography(ERCP) in patients with sickle cell disease(SCD) .METHODS:Two hundred and twenty four SCD patients with cholestatic jaundice(CJ) had ERCP.The indications for ERCP were based on clinical and biochemical evidence of CJ and ultrasound findings.RESULTS:Two hundred and forty ERCPs were performed.The indications for ERCP were:CJ only in 79,CJ and dilated bile ducts without stones in 103,and CJ and bile duct stones in 42.For those with CJ only,ERCP was normal in 42(53.2%) ,and 13(16.5%) had dilated bile ducts without an obstructive cause.In the remaining 22,there were bile duct stones with or without dilation.For those with CJ,dilated bile ducts and no stones,ERCP was normal in 17(16.5%) ,and 28(27.2%) had dilated bile ducts without an obstructive cause.In the remaining 58,there were bile ducts stones with or without dilation.For those with CJ and bile duct stones,ERCP was normal in two(4.8%) ,and 14(33.3%) had dilated bile ducts without an obstructive cause.In the remaining 26,there were bile duct stones with or without dilatation.CONCLUSION:Considering the high frequency of biliary sludge and bile duct stones in SCD,endoscopic sphincterotomy might prove helpful in these patients.

Secondary sclerosing cholangitis after critical COVID-19:Three case reports

BACKGROUND The global coronavirus disease 2019(COVID-19)pandemic has caused more than 5 million deaths.Multiorganic involvement is well described,including liver disease.In patients with critical COVID-19,a new entity called"post-COVID-19 cholangiopathy"has been described.CASE SUMMARY Here,we present three patients with severe COVID-19 that subsequently developed persistent cholestasis and chronic liver disease.All three patients required intensive care unit admission,mechanical ventilation,vasopressor support,and broad spectrum antibiotics due to secondary infections.Liver transplant protocol was started for two of the three patients.CONCLUSION Severe COVID-19 infection should be considered a potential risk factor for chronic liver disease and liver transplantation.

Donor preoperative oxygen delivery and post-extubation hypoxia impact donation after circulatory death hypoxic cholangiopathy

AIM: To evaluate donation after circulatory death (DCD) orthotopic liver transplant outcomes [hypoxic cholangiopathy (HC) and patient/graft survival] and donor risk-conditions.METHODS: From 2003-2013, 45 DCD donor transplants were performed. Predonation physiologic data from UNOS DonorNet included preoperative systolic and diastolic blood pressure, heart rate, pH, SpO2, PaO2, FiO2, and hemoglobin. Mean arterial blood pressure was computed from the systolic and diastolic blood pressures. Donor preoperative arterial O2 content was computed as [hemoglobin (gm/dL) × 1.37 (mL O2/gm) × SpO2%) + (0.003 × PaO2)]. The amount of preoperative donor red blood cell transfusions given and vasopressor use during the intensive care unit stay were documented. Donors who were transfused ≥ 1 unit of red-cells or received ≥ 2 vasopressors in the preoperative period were categorized as the red-cell/multi-pressor group. Following withdrawal of life support, donor ischemia time was computed as the number-of-minutes from onset of diastolic blood pressure < 60 mmHg until aortic cross clamping. Donor hypoxemia time was the number-of-minutes from onset of pulse oximetry < 80% until clamping. Donor hypoxia score was (ischemia time + hypoxemia time) ÷ donor preoperative hemoglobin.RESULTS: The 1, 3, and 5 year graft and patient survival rates were 83%, 77%, 60%; and 92%, 84%, and 72%, respectively. HC occurred in 49% with 16% requiring retransplant. HC occurred in donors with increased age (33.0 ± 10.6 years vs 25.6 ± 8.4 years, P = 0.014), less preoperative multiple vasopressors or red-cell transfusion (9.5% vs 54.6%, P = 0.002), lower preoperative hemoglobin (10.7 ± 2.2 gm/dL vs 12.3 ± 2.1 gm/dL, P = 0.017), lower preoperative arterial oxygen content (14.8 ± 2.8 mL O2/100 mL blood vs 16.8 ± 3.3 mL O2/100 mL blood, P = 0.049), greater hypoxia score >2.0 (69.6% vs 25.0%, P = 0.006), and increased preoperative mean arterial pressure (92.7 ± 16.2 mmHg vs 83.8 ± 18.5 mmHg, P = 0.10). HC was independently associated with age, multi-pressor/red-cell transfusion status, arterial oxygen content, hypoxia score, and mean arterial pressure (r2 = 0.6197). The transplantation rate was greater for the later period with more liberal donor selection [era 2 (7.1/year)], compared to our early experience [era 1 (2.5/year)]. HC occurred in 63.0% during era 2 and in 29.4% during era 1 (P = 0.03). Era 2 donors had longer times for extubation-to-asystole (14.4 ± 4.7 m vs 9.3 ± 4.5 m, P = 0.001), ischemia (13.9 ± 5.9 m vs 9.7 ± 5.6 m, P = 0.03), and hypoxemia (16.0 ± 5.1 m vs 11.1 ± 6.7 m, P = 0.013) and a higher hypoxia score > 2.0 rate (73.1% vs 28.6%, P = 0.006).CONCLUSION: Easily measured donor indices, including a hypoxia score, provide an objective measure of DCD liver transplantation risk for recipient HC. Donor selection criteria influence HC rates.

Acute and chronic hepatobiliary manifestations of sickle cell disease: A review

Sickle cell disease(SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as "sickle cell hepatopathy". This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process.

Role of biliary complications in chronic graft rejection after living donor liver transplantation

Postoperative biliary complications remain a substantial challenge after living donor liver transplantation,especially due to its heterogeneous clinical presentation.

Post-COVID-19 cholangiopathy:A systematic review

BACKGROUND The recent and still ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)entailed various long-term complications,including post-infectious cholangiopathy.AIM To identify the available studies concerning post-coronavirus disease 2019(COVID-19)cholangiopathy.METHODS An extensive bibliographical search was carried out in PubMed and in Cochrane Library to identify the articles(retrospective and prospective studies,cohort studies,case series and case reports)published between January 1,2020 and August 22,2022,using both MeSH terms and free-language keywords:cholangiopathy;COVID-19;post-COVID-19 cholangiopathy;SARS-CoV-2.RESULTS Thirteen studies fulfilled the inclusion criteria,which included 64 patients suffering from this condition.The patients were male in 82.8%of cases.Liver transplant was executed in 6 patients and scheduled in 7 patients,while 2 patients refused the surgical approach.Therefore in 23.4%of the cases,performing this procedure appeared to be necessary.CONCLUSION This review has revealed that generally the involvement of the liver in the course of SARS-CoV-2 infection is mild and transient,inducing cholestasis of cholangiocytes but can also be severe enough to cause organ failure in some cases.

Post-COVID-19 cholangiopathy:Current understanding and management options

Post-coronavirus disease 2019(COVID-19)cholangiopathy(PCC)is a rare but lifethreatening complication of COVID-19 infection.PCC typically presents when patients recovering from the contagion and manifests as cholestasis in patients with no history of pre-existing liver disease.The pathogenesis of PCC is little understood.Hepatic injury in PCC could be mediated by the predilection of severe acute respiratory syndrome coronavirus 2 for cholangiocytes.Though PCC shows some resemblance to secondary sclerosing cholangitis in critically ill patients,it is considered as a separate and unique entity in the literature.Various treatment options like ursodeoxycholic acid,steroids,plasmapheresis,and endoscopic retrograde cholangiopancreatography guided interventions have been tried but with limited success.We have noticed significant improvement in liver function with antiplatelet therapy in a couple of patients.PCC can progress to end-stage liver disease necessitating liver transplantation.In this article,we discuss the current knowledge of PCC focusing on its pathophysiology,clinical manifestations,and management strategies.