MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model

BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options.Recombinant adeno-associated virus(rAAV)provides a promising platform for gene therapy on such kinds of diseases.A microRNA(miRNA)let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated.AIM To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8(rAAV8)on a xenobiotic-induced mouse model of sclerosing cholangitis.METHODS A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine(DDC)feeding for 2 wk or 6 wk.A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding.Upon sacrifice,the liver and the serum were collected from each mouse.The hepatobiliary injuries,hepatic inflammation and fibrosis were evaluated.The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.RESULTS rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk.The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers,and prevent the proliferation of cholangiocytes and biliary fibrosis.Furthermore,inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1,which consequently inhibit of NF-κB-mediated hepatic inflammation.CONCLUSION Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis,which provides a possible clinical translation of PSC of human.

Autoimmune hepatitis and primary sclerosing cholangitis after direct-acting antiviral treatment for hepatitis C virus:A case report

BACKGROUND Chronic hepatitis C virus(HCV)infection is a major global health concern that leads to liver fibrosis,cirrhosis,and cancer.Regimens containing direct-acting antivirals(DAAs)have become the mainstay of HCV treatment,achieving a high sustained virological response(SVR)with minimal adverse events.CASE SUMMARY A 74-year-old woman with chronic HCV infection was treated with the DAAs ledipasvir,and sofosbuvir for 12 wk and achieved SVR.Twenty-four weeks after treatment completion,the liver enzyme and serum IgG levels increased,and antinuclear antibody became positive without HCV viremia,suggesting the development of autoimmune hepatitis(AIH).After liver biopsy indicated AIH,a definite AIH diagnosis was made and prednisolone was initiated.The treatment was effective,and the liver enzyme and serum IgG levels normalized.However,multiple strictures of the intrahepatic and extrahepatic bile ducts with dilatation of the peripheral bile ducts appeared on magnetic resonance cholangiopancreatography after 3 years of achieving SVR,which were consistent with primary sclerosing cholangitis.CONCLUSION The potential risk of developing autoimmune liver diseases after DAA treatment should be considered.

IgG4-related sclerosing cholangitis associated with essential thrombocythemia:A case report

BACKGROUND The complexity of immunoglobulin G4(IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear.This article provided a review of the diagnosis and treatment of a patient with IgG4-related sclerosing cholangitis(SC)and essential thrombocythemia(ET),along with an analysis of relevant literature to enhance comprehension of this disease.CASE SUMMARY A 56-year-old male was admitted to two hospitals with deteriorating jaundice and pruritus prior to hospitalization.Beyond our expectations,the patient was first diagnosed with IgG4-SC and ET with the Janus kinase 2 V617F mutation.Interestingly,the administration of acetate prednisone significantly resulted in improvements in both IgG4-SC and ET.Clinicians need to pay attention to immune disorders and inflammation as they contribute to the development of various disease phenotypes.CONCLUSION When IgG4-SC is suspected without histopathological evidence,diagnostic therapy and long-term regular follow-up can lead to positive treatment outcomes.Clinicians should be mindful of the potential presence of concurrent hematologic diseases in patients with immune disorders.

Cholangiocarcinoma, Primary Sclerosing Cholangitis, or IgG4-Sclerosing Cholangitis: Similar Presentations with Different Managements

In our case, we present a case of an 80-year-old male who was referred to the gastroenterologist for evaluation of a suspicious mass. CT imaging at the time had shown intrahepatic and extrahepatic biliary dilations, and the patient was thought to have a pancreatic or a common bile duct mass. A mass biopsy showed no malignancy, and further evaluation was warranted. The patient was found to have elevated IgG4 levels and was diagnosed with IgG4-sclerosing cholangitis (IgG4-SC). IgG4 has been found to create a wide array of pathologies, including autoimmune pancreatitis, dacryoadenitis, and sialadenitis. These pathologies have been grouped under an IgG4-Related Disease (IgG4-RD) category. In some cases, this IgG4-RD can present as a subclass of primary sclerosing cholangitis due to immune depositions and swelling of the CBD. Due to the strictures caused by the sclerosing cholangitis, intrahepatic and extrahepatic dilations might be found on endoscopic ultrasound (EUS). It is imperative to differentiate this from a malignant mass as the early recognition and treatment of IgG4-SC can lead to complete resolution. In this case report, we present a case of a patient who was found to have IgG4-SC and responded well to steroid treatment.

Liver transplant in patients with primary sclerosing cholangitis:A retrospective cohort from Northeastern Brazil

BACKGROUND Primary sclerosing cholangitis(PSC)manifests within a broad ethnic and racial spectrum,reflecting different levels of access to health care.AIM To evaluate the clinical profile,complications and survival rates of patients with PSC undergoing liver transplantation(LTx)at a Brazilian reference center.METHODS All patients diagnosed with PSC before or after LTx were included.The medical records were reviewed for demographic and clinical variables,including outcomes and survival.The level of statistical significance was set at P<0.05.RESULTS Our cohort represented 1.6%(n=34)of the 2113 patients receiving liver grafts at our service over the past two decades.Most were male(n=19;56%).The average age(40±14 years)was similar for men and women(P=0.347).The mean follow-up time from diagnosis to LTx was 68 mo.Most patients had the classic form of PSC.Three women had PSC/autoimmune hepatitis overlap syndrome,and one patient had small-duct PSC.Alkaline phosphatase levels at diagnosis and pre-LTx model for end-stage liver disease.scores were significantly higher in males.Inflammatory bowel research(IBD)was investigated by colonoscopy in 26/34(76%)and was present in most cases(18/26;69%).IBD was less common in women than in men(44.4%vs.55.6%)(P=0.692).Cholangiocarcinoma(CCA)was diagnosed in 2/34(5.9%)patients by histopathology of the explant(survival:3 years 6 mo,and 4 years 11 mo).Two patients had complications requiring a second LTx(one after 7 d due to hepatic artery thrombosis and one after 17 d due to primary graft dysfunction).Five patients(14.7%)developed biliary stricture.The overall median post-LTx survival was 66 mo.Most deaths occurred in the first year(infection n=2,primary liver graft dysfunction n=3,unknown cause n=1).The 1-year and 5-year survival rates of this cohort were 82.3%and 70.6%,respectively,matching the mean overall survival rates of LTx patients at our center(87.1%and 69.43%,respectively)(P=0.83).CONCLUSION Survival after 1 and 5 years was similar to that of other LTx indications.The observed CCA survival rate suggests CCA may be an indication for LTx in selected cases.

Liver transplant in primary sclerosing cholangitis:Current trends and future directions

Primary sclerosing cholangitis(PSC)is a chronic and progressive immunemediated cholangiopathy causing biliary tree inflammation and scarring,leading to liver cirrhosis and end-stage liver disease.Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases.Despite the rising incidence of PSC,there is no proven medical therapy that can alter the natural history of the disease.While liver transplantation(LT)is the most effective approach for managing advanced liver disease caused by PSC,post-transplantation recurrence of PSC remains a challenge.Therefore,ongoing research aims to develop better therapies for PSC,and continued efforts are necessary to improve outcomes for patients with PSC.This article provides an overview of PSC’s pathogenesis,clinical presentation,and management options,including LT trends and future aspects.It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC.Additionally,the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed.Ongoing research into PSC’s pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.

Intrahepatic cholangiocarcinoma in patients with primary sclerosing cholangitis and ulcerative colitis: Two case reports

BACKGROUND Primary sclerosing cholangitis(PSC)is an extraintestinal manifestation of ulcerative colitis(UC).PSC is a well-known risk factor for intrahepatic cholangiocarcinoma(ICC),and ICC is known to have a poor prognosis.CASE SUMMARY We present two cases of ICC in patients with PSC associated with UC.In the first case,a tumor was found by magnetic resonance imaging(MRI)in the liver of a patient with PSC and UC who presented to our hospital with right-sided rib pain.The second patient was asymptomatic,but we unexpectedly detected two liver tumors in an MRI performed to evaluate bile duct stenosis associated with PSC.ICC was strongly suspected by computed tomography and MRI in both cases,and surgery was performed,but unfortunately,the first patient died of ICC recurrence 16 mo postoperatively,and the second patient died of liver failure 14 mo postoperatively.CONCLUSION Careful follow-up of patients with UC and PSC with imaging and blood tests is necessary for early detection of ICC.

Review of primary sclerosing cholangitis with increased IgG4 levels

Primary sclerosing cholangitis(PSC) is a chronic progressive liver disease. Subtypes of PSC have been described, most recently PSC with elevated serum and/or tissue IgG4 subclass. We aim to summarise the clinical phenotype,disease associations, differential diagnosis, response to therapy and pathogenic mechanisms underlying PSC-high IgG4 subtype. We reviewed Pub Med,MEDLINE and Embase with the search terms "primary sclerosing cholangitis","IgG4", and "IgG4-related sclerosing cholangitis(IgG4-SC)". Elevated serum IgG4 are found in up-to one-quarter, and abundant IgG4-plasma cell infiltrates in the liver and bile ducts are found in up-to one-fifth of PSC patients. This group have a distinct clinical phenotype, with some studies reporting a more aggressive course of liver and associated inflammatory bowel disease, compared to PSCnormal IgG4 and the disease mimic IgG4-SC. Distinguishing PSC-high IgG4 from IgG4-SC remains challenging, requiring careful assessment of clinical features,organ involvement and tissue morphology. Calculation of serum IgG4:IgG1 ratios and use of a novel IgG4:IgG RNA ratio have been reported to have excellent specificity to distinguish IgG4-SC and PSC-high IgG4 but require validation in larger cohorts. A role for corticosteroid therapy in PSC-high IgG4 remains unanswered, with concerns of increased toxicity and lack of outcome data. The immunological drivers underlying prominent IgG4 antibodies in PSC are incompletely defined. An association with PSC-high IgG4 and HLA class-II haplotypes(B*07, DRB1*15), T-helper2 and T-regulatory cytokines(IL4, IL10,IL13) and chemokines(CCL1, CCR8) have been described. PSC-high IgG4 have a distinct clinical phenotype and need careful discrimination from IgG4-SC,although response to immunosuppressive treatments and long-term outcome remains unresolved. The presence of IgG4 likely represents chronic activation to persistent antigenic exposure in genetically predisposed individuals.

Small duct primary sclerosing cholangitis: A discrete variant or a bridge to large duct disease, a practical review

The natural history,associations with inflammatory bowel disease(IBD),and long-term outcomes of large duct primary sclerosing cholangitis(ldPSC)have been well documented.Small duct primary sclerosing cholangitis(sdPSC)is a much less common and relatively more benign variant.The natural history of sdPSC has been difficult to characterize given the limited number of studies in the literature especially with regards to the subset of patients who progress to large duct involvement.It has been unclear whether sdPSC represented a subset of ldPSC,an earlier staging of ldPSC,or a completely separate and distinct entity of its own.Strong associations between sdPSC and IBD have been established with suspicion that concurrent sdPSC-IBD may be a key prognostic factor in determining which patients are at risk of progression to ldPSC.Little is known regarding the discrete circumstances that predisposes some patients with sdPSC to progress to ldPSC.It has been suspected that progression to large biliary duct involvement subjects this subset of patients to potentially developing lifethreatening complications.Here the authors conducted a thorough review of the published sdPSC literature using Pubmed searches and cross-referencing to compile all accessible studies regarding cohorts of sdPSC patients in order better characterize the subset of sdPSC patients who progress to ldPSC and the associated outcomes.

Diagnosis of IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis(IgG4-SC)is often associated with autoimmune pancreatitis.However,the diffuse cholangiographic abnormalities observed in IgG4-SC may resemble those observed in primary sclerosing cholangitis(PSC),and the presence of segmental stenosis suggests cholangiocarcinoma(CC).IgG4-SC responds well to steroid therapy,whereas PSC is only effectively treated with liver transplantation and CC requires surgical intervention.Since IgG4-SC was first described,it has become a third distinct clinical entity of sclerosing cholangitis.The aim of this review was to introduce the diagnostic methods for IgG4-SC.IgG4-SC should be carefully diagnosed based on a combination of characteristic clinical,serological,morphological,and histopathological features after cholangiographic classification and targeting of a disease for differential diagnosis.When intrapancreatic stenosis is detected,pancreatic cancer or CC should be ruled out.If multiple intrahepatic stenoses are evident,PSC should be distinguished on the basis of cholangiographic findings and liver biopsy with IgG4 immunostaining.Associated inflammatory bowel disease is suggestive of PSC.If stenosis is demonstrated in the hepatic hilar region,CC should be discriminated by ultrasonography,intraductal ultrasonography,bile duct biopsy,and a higher cutoff serum IgG4 level of 182 mg/dL.

Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis

AIM:To review the current literature for the specificclinical characteristics of inflammatory bowel disease(IBD)associated with primary sclerosing cholangitis(PSC).METHODS:A systematical review for clinical characteristics of IBD in PSC was performed by conducting a broad search for"primary sclerosing cholangitis"in Pubmed."Clinical characteristics"were specified into five predefined subthemes:epidemiology of IBD in PSC,characteristics of IBD in PSC(i.e.,location,disease behavior),risk of colorectal cancer development,IBD recurrence and de novo disease after liver transplantation for PSC,and safety and complications after proctocolectomy with ileal pouchanal anastomosis.Papers were selected for inclusion based on their relevance to the subthemes,and were reviewed by two independent reviewers.Only full papers relevant to PSC-IBD were included.Additionally the references of recent reviews for PSC(<5 years old)were scrutinized for relevant articles.RESULTS:Initial literature search for PSC yielded 4704results.After careful review 65 papers,comprising a total of 11406 PSC-IBD patients,were selected and divided according to subtheme.Four manuscripts overlapped and were included in two subthemes.Prevalence of IBD in PSC shows a large variance,ranging from 46.5%to 98.7%with ulcerative colitis(UC)being the most common type(>75%).The highest IBD rates in PSC are found in papers reviewing both endoscopic and histological data for IBD diagnosis.Although IBD in PSC is found to be a quiescent disease,pancolitis occurs often,with rates varying from 35%to 95%.Both backwash ileitis and rectal sparing are observed infrequently.The development of dysplasia or colorectal carcinoma is increased in PSC-IBD;the cumulative 10 years risk varying between 0%and11%.Exacerbation of IBD is common after liver transplantation for PSC and de novo disease is seen in1.3%to 31.3%of PSC-IBD patients.The risk for development of pouchitis in PSC-IBD is found to besignificant,affecting 13.8%to 90%of the patients after proctocolectomy with ileo anal-pouch anastomosis.CONCLUSION:IBD in primary sclerosing cholangitis represents a distinct phenotype that differs from UC and Crohn’s disease and therefore requires specialized management.

Recurrence and rejection in liver transplantation for primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to f ibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can infl uence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible infl uence of rejection on the risk of recurrent disease in the allograft.

Inflammatory bowel disease of primary sclerosing cholangitis:A distinct entity?

This is a review of the characteristic findings of inflammatory bowel disease(IBD)associated with primary sclerosing cholangitis(PSC)and their usefulness in the diagnosis of sclerosing cholangitis.PSC is a chronic inflammatory disease characterized by idiopathic fibrous obstruction and is frequently associated with IBD.IBDassociated with PSC(PSC-IBD)shows an increased incidence of pancolitis,mild symptoms,and colorectal malignancy.Although an increased incidence of pancolitis is a characteristic finding,some cases are endoscopically diagnosed as right-sided ulcerative colitis.Pathological studies have revealed that inflammation occurs more frequently in the right colon than the left colon.The frequency of rectal sparing and backwash ileitis should be investigated in a future study based on the same definition.The cholangiographic findings of immunoglobulin G4-related sclerosing cholangitis(IgG4-SC)are similar to those of PSC.The rare association between IBD and IgG4-SC and the unique characteristics of PSC-IBD are useful findings for distinguishing PSC from IgG4-SC.

Update on inflammatory bowel disease in patients with primary sclerosing cholangitis

Patients with primary sclerosing cholangitis(PSC) complicated by inflammatory bowel disease(IBD) represent a distinct subset of patients with unique characteristics,which have serious clinical implications.The aim of this literature review was to shed light to the obscure clinical and molecular aspects of the two diseases combined utilizing current data available and putting issues of diagnosis and treatment into perspective.The prevalence of IBD,mainly ulcerative colitis in PSC patients is estimated to be 21%-80%,dependent on screening programs and nationality.PSC-associated colitis is likely to be extensive,characterized by rectal sparing,backwash ileitis,and generally mild symptoms.It is also more likely to progress to colorectal malignancy,making it imperative for clinicians to maintain a high level of suspicion when tackling PSC patients.There is no optimal surveillance strategy but current guidelines advocate that colonoscopy is necessary at the time of PSC diagnosis with annual endoscopic follow-up.Random biopsies have been criticized and a shift towards targeted biopsies using chromoendoscopy,laser endomicroscopy and narrow-band imaging has been noted.Techniques directed towards genetic mutations instead of histological abnormalities hold promise for easier,more accurate diagnosis of dysplastic lesions.Chemopreventive measures against colorectal cancer have been sought in these patients.Ursodeoxycholic acid seemed promising at first but subsequent studies yielded conflicting results showing anticarcinogenic effects in low doses(8-15 mg/kg per day) and carcinogenic properties in high doses(15-30 mg/kg per day).

Primary sclerosing cholangitis as an independent risk factor for colorectal cancer in the context of inflammatory bowel disease: A review of the literature

To examine and evaluate recent evidence regarding the epidemiology, pathogenesis and management of colorectal cancer(CRC) development in inflammatory bowel disease(IBD)-primary sclerosing cholangitis(PSC) patients. Using the PubMed database, a literature search was conducted for relevant articles in English from the past 10 years. Relevant studies investigating PSC as a risk factor for CRC in IBD in the context of incidence and prevalence, pathogenesis, prevention and prognosis were included in this review. Recent evidence increasingly points to PSC as a significant risk factor in the development of CRC in patients with concomitant IBD. PSC may be an important risk factor for CRC in different populations worldwide. The mechanism for this increase in risk is still unclear. The efficacy of UDCA as a chemopreventive agent remains controversial. Liver transplantation does not halt the development of CRC, although there is not enough evidence to suggest that it is associated with increased incidence of CRC. While routine colonoscopic surveillance should be performed in patients with concurrent PSC and IBD, more high-level evidence is required to support the benefits of the procedure. While many new developments have taken place in the last decade, the pathogenesis and optimal management of CRC development in IBD-PSC patients remain unclear.

Sclerosing cholangitis secondary to bleomycin-iodinated embolization for liver hemangioma

Sclerosing cholangitis(SC)is a rarely reported morbidity secondary to transcatheter arterial chemoembolization(TACE)with bleomycin-iodinated oil(BIO)for liver cavernous hemangioma(LCH).This report retrospectively evaluated the diagnostic and therapeutic course of a patient with LDH who presented obstructive jaundice 6 years after TACE with BIO.Preoperative imaging identified a suspected malignant biliary stricture located at the convergence of the left and right hepatic ducts.Operative exploration demonstrated a full-thickness sclerosis of the hilar bile duct with right hepatic duct stricture and right lobe atrophy.Radical hepatic hilar resection with right-side hemihepatectomy and Roux-en-Y hepaticojejunostomy was performed because hilar cancer could not be excluded on frozen biopsy.Pathological results showed chronic pyogenic inflammation of the common and right hepatic ducts with SC in the portal area.Secondary SC is a long-term complication that may occur in LCH patients after TACE with BIO and must be differentiated from hilar malignancy.Hepatic duct plasty is a definitive but technically challenging treatment modality for secondary SC.

Biliary phosphatidylcholine and lysophosphatidylcholine profiles in sclerosing cholangitis

AIM:To analyze phospholipid profiles in intrahepatic bile from patients with primary sclerosing cholangitis(PSC)and secondary sclerosing cholangitis(SSC).METHODS:Intrahepatic bile specimens collected via endoscopic retrograde cholangiography from 41 patients were analyzed.Fourteen of these patients were diagnosed with PSC,10 with SSC,11 with choledocholithiasis or no identifiable biliary disease,and 6 with cholangiocellular carcinoma(CCC).Bile acid,cholesterol,protein,and bilirubin contents as well as pancreas lipase activity in bile were determined by biochemical methods.Phosphatidylcholine(PC)and lysophosphatidylcholine(LPC)species were quantified using nanoelectrospray ionization tandem mass spectrometry.RESULTS:Bile from all the examined patient groups showed a remarkably similar PC and LPC species composition,with only minor statistical differences.Total biliary PC concentrations were highest in controls(8030±1843 mol/L)and lowest in patients with CCC(1969±981 mol/L)(P=0.005,controls vs SSC and CCC,respectively,P<0.05).LPC contents in bile were overall low(4.2%±1.8%).Biliary LPC/PC ratios and ratios of biliary PC to bilirubin,PC to cholesterol,PC to protein,and PC to bile acids showed no intergroup differences.CONCLUSION:PC and LPC profiles being similar in patients with or without sclerosing cholangitis,these phospholipids are likely not of major pathogenetic importance in this disease group.

First case of IgG4-related sclerosing cholangitis associated with autoimmune hemolytic anemia

To our knowledge,patients with immunoglobulin G4-related sclerosing cholangitis(IgG4-SC)associated with autoimmune hemolytic anemia(AIHA)have not been reported previously.Many patients with IgG4-SC have autoimmune pancreatitis(AIP)and respond to steroid treatment.However,isolated cases of IgG4-SC are difficult to diagnose.We describe our experience with a patient who had IgG4-SC without AIP in whom the presence of AIHA led to diagnosis.The patient was a73-year-old man who was being treated for dementia.Liver dysfunction was diagnosed on blood tests at another hospital.Imaging studies suggested the presence of carcinoma of the hepatic hilus and primary sclerosing cholangitis,but a rapidly progressing anemia developed simultaneously.After the diagnosis of AIHA,steroid treatment was begun,and the biliary stricture improved.IgG4-SC without AIP was thus diagnosed.

Isolated intrapancreatic Ig G4-related sclerosing cholangitis

Immunoglobulin G4-related sclerosing cholangitis(Ig G4-SC) is frequently associated with type 1 autoimmune pancreatitis(AIP). Association with AIP can be utilized in the diagnosis of Ig G4-SC. However, some cases of Ig G4-SC are isolated from AIP, which complicates the diagnosis. Most of the reported cases of isolated Ig G4-SC displayed hilar biliary strictures, whereas isolated Ig G4-SC with intrapancreatic biliary stricture is very rare. Recently, we have encountered 5 isolated intrapancreatic Ig G4-SC cases that were not associated with AIP, three of which were pathologically investigated after surgical operation. They all were males with a mean age of 74.2 years. The pancreas was not enlarged in any of these cases. No irregular narrowing of the main pancreatic duct was found. Bile duct wall thickening in lesions without luminal stenosis was detected by abdominal computed tomography in all five cases, by endoscopic ultrasonography in two out of four cases and by intraductal ultrasonography in all three cases. In three cases, serum Ig G4 levels were within the normal limits. The mean serum Ig G4 level measured before surgery was 202.1 mg/d L(4 cases). Isolated intrapancreatic Ig G4-SC is difficult to diagnose, especially if the Ig G4 level remains normal. Thus, this type of Ig G4-SC should be suspected in addition to cholangiocarcinoma and pancreatic cancer if stenosis of intrapancreatic bile duct is present.