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.

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.

A rare complication of measles infection presented with subacute sclerosing panencephalitis: Report of two cases in India

Rationale:Subacute sclerosing panencephalitis(SSPE)is a progressive neurological disorder caused by persistent measles virus infection.SSPE predominantly affects children and adolescents.The symptoms usually develop 6-15 years after measles infection and ultimately leading to death in many cases.Patient concerns:Patient 1 presented with cognitive decline and myoclonus and the Patient 2 presented with diminution of vision with myoclonic jerks.Diagnosis:Based on the clinical features with a characteristic electroencephalogram pattern and the presence of a high titer of anti-measles IgG in serum and cerebrospinal fluid,these patients were diagnosed as SSPE.Interventions:Antiepileptics were started for controlling myoclonus along with supportive treatment.Outcomes:Both patients were discharged on antiepileptics and supportive care.Lessons:Whenever there are unusual clinical manifestations with unknown vaccination status,SSPE can be suspected and the cerebrospinal fluid should be examined for anti-measles antibodies.Our case study also highlights the importance of universal coverage of measles vaccination.To reduce the incidence of measles and associated deaths,it is important to maintain a high level of immunization coverage for the measles vaccine and to strengthen all the integral components of the national immunization program.

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.

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.

Sclerosing epithelioid fibrosarcoma of the pancreas:A case report

BACKGROUND A sclerosing epithelioid fibrosarcoma(SEF)is a rare malignant fibroblastic soft tissue tumor that rarely occurs in intra-abdominal organs.A case of a SEF in the pancreatic head is reported herein,including its clinical manifestations,preoperative imaging features,gross specimen and pathological findings.CASE SUMMARY A 33-year-old male patient was admitted to Peking Union Medical College Hospital in December 2023 due to a one-year history of intermittent upper abdominal pain and the discovery of a pancreatic mass.The patient underwent an enhanced computed tomography scan of the abdomen,which revealed a welldefined,round mass with clear borders and calcifications in the pancreatic head.The mass exhibited progressive,uneven mild enhancement,measuring approximately 6.6 cm×6.3 cm.The patient underwent laparoscopic pylorus-preserving pancreaticoduodenectomy.Postoperative pathological examination revealed that the lesion was consistent with a SEF.At the 3-month postoperative follow-up,the patient did not report any short-term complications,and there were no signs of tumor recurrence.CONCLUSION SEFs are rare malignant fibrous soft tissue tumors.SEFs rarely develop in the pancreas,and its preoperative diagnosis depends on imaging findings,with confirmation depending on pathological examination and immunohistochemistry.Currently,only four cases of pancreatic SEF have been reported in studies written in English.This case is the first reported case of a pancreatic SEF by a clinical physician.

Journey to diagnosis:An unfinished exploration of IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis(IgG4-SC)is an inflammatory disease that leads to bile duct stricture,characterized by the infiltration of IgG4-positive plasma cells into the bile duct wall,thickening of the bile duct wall,and narrowing of the lumen.The differential diagnosis of IgG4-SC mainly includes primary sclerosing cholangitis,cholangiocarcinoma,and pancreatic cancer.IgG4-SC is often associated with autoimmune pancreatitis and can be accurately diagnosed based on clinical diagnostic criteria.However,isolated IgG4-SC is difficult to distinguish from biliary tumors.Given the significant differences in biological behavior,treatment,and prognosis between these diseases,accurately identifying isolated IgG4-SC has very important clinical significance.

Limited validity of Mayo endoscopic subscore in ulcerative colitis with concomitant primary sclerosing cholangitis

BACKGROUND Ulcerative colitis(UC)with concomitant primary sclerosing cholangitis(PSC)represents a distinct disease entity(PSC-UC).Mayo endoscopic subscore(MES)is a standard tool for assessing disease activity in UC but its relevance in PSC-UC remains unclear.AIM To assess the accuracy of MES in UC and PSC-UC patients,we performed histological scoring using Nancy histological index(NHI).METHODS MES was assessed in 30 PSC-UC and 29 UC adult patients during endoscopy.NHI and inflammation were evaluated in biopsies from the cecum,rectum,and terminal ileum.In addition,perinuclear anti-neutrophil cytoplasmic antibodies,fecal calprotectin,body mass index,and other relevant clinical characteristics were collected.RESULTS The median MES and NHI were similar for UC patients(MES grade 2 and NHI grade 2 in the rectum)but were different for PSC-UC patients(MES grade 0 and NHI grade 2 in the cecum).There was a correlation between MES and NHI for UC patients(Spearman's r=0.40,P=0.029)but not for PSC-UC patients.Histopathological examination revealed persistent microscopic inflammation in 88%of PSC-UC patients with MES grade 0(46%of all PSC-UC patients).Moreover,MES overestimated the severity of active inflammation in an additional 11%of PSCUC patients.CONCLUSION MES insufficiently identifies microscopic inflammation in PSC-UC.This indicates that histological evaluation should become a routine procedure of the diagnostic and grading system in both PSC-UC and PSC.

Sclerosing Mucoepidermoid Cancer: A Unique Entity

Sclerosing mucoepidermoid thyroid cancer (SMECE) is a rare entity with less than 100 cases reported in the literature. Previously considered to have an indolent course, however, recent evidence has reported an aggressive nature ranging from local invasion to distant metastasis. We present a 66-year-old Caucasian female with SMECE who initially presented neck compressive symptoms. A thyroid ultrasound (US) revealed a solid hypoechoic mass replacing the left thyroid lobe. Fine needle aspiration cytology (FNAC) of the nodule resulted in suspicion of Papillary Thyroid Cancer, Bethesda category 5. The patient underwent total thyroidectomy and surgical pathology showed SMECE. Post-therapy whole-body scan following treatment with 150 mCi I-131 showed no residual or metastatic disease. SMECE is more common in females, between the third to eighth decade of life. Preoperative diagnosis may not be accurate given variable cytopathologic features. Differential diagnoses include primary squamous cell carcinoma of the thyroid, squamous differentiation of other thyroid malignancies, anaplastic thyroid cancer and nodular sclerosing variety of Hodgkin’s lymphoma. Due to its rarity, treatment of SMECE has ranged from thyroid surgery without or with radioactive iodine therapy, to surgery and external beam radiation and even chemotherapy.

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 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.

Idiopathic sclerosing mesenteritis presenting with small bowel volvulus in a patient with antiphospholipid syndrome:A case report

BACKGROUND Sclerosing mesenteritis is a rare disorder involving inflammation of the mesentery.Its etiology remains unclear,but it is believed to be associated with previous abdominal surgery,trauma,autoimmune disorders,infection,or malignancy.Clinical manifestations of sclerosing mesenteritis are varied and include chronic abdominal pain,bloating,diarrhea,weight loss,formation of an intra-abdominal mass,bowel obstruction,and chylous ascites.Here,we present a case of idiopathic sclerosing mesenteritis with small bowel volvulus in a patient with antiphospholipid syndrome.CASE SUMMARY A 68-year-old female presented with recurrent small bowel obstruction.Imaging and pathological findings were consistent with sclerosing mesenteritis causing mesenteric and small bowel volvulus.Computed tomography scans also revealed pulmonary embolism,and the patient was started on a high dose of corticosteroid and a therapeutic dose of anticoagulants.The patient subsequently improved clinically and was discharged.The patient was also diagnosed with antiphospholipid syndrome after a hematological workup.CONCLUSION Sclerosing mesenteritis is a rare condition,and patients with no clear etiology should be considered for treatment with immunosuppressive therapy.

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.

Sclerosing odontogenic carcinoma of maxilla:A case report

BACKGROUND Sclerosing odontogenic carcinoma is a rare primary intraosseous neoplasm that was featured recently as a single entity in the World Health Organization classification of Head and Neck Tumors 2017,with only 14 cases published to date.The biological characteristics of sclerosing odontogenic carcinoma remain indistinct because of its rarity;however,it appears to be locally aggressive,with no regional or distant metastasis reported to date.CASE SUMMARY We reported a case of sclerosing odontogenic carcinoma of the maxilla in a 62-year-old woman,who presented with an indolent right palatal swelling,which progressively increased in size over 7 years.Right subtotal maxillectomy with surgical margins of approximately 1.5 cm was performed.The patient remained disease free for 4 years following the ablation surgery.Diagnostic workups,treatment,and therapeutic outcomes were discussed.CONCLUSION More cases are needed to further characterize this entity,understand its biological behavior,and justify the treatment protocols.Resection with wide margins of approximately 1.0 to 1.5 cm is proposed,while neck dissection,post-operative radiotherapy,or chemotherapy are deemed unnecessary.

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.

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.

IgG4-related sclerosing disease

Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.

Sclerosing cholangitis following severe trauma: Description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms

MM： Persistent cholestasis is a rare complication of severe trauma or infections. Little is known about the possible pathomechanisms and the clinical course.METHODS： Secondary sclerosing cholangitis was diagnosed in five patients with persistent jaundice after severe trauma （one burn injury, three accidents, one power current injury）. Medical charts were retrospectively reviewed with regard to possible trigger mechanisms for cholestasis, and the clinical course was recorded.RESULTS： Diagnosis of secondary sclerosing cholangitis was based in all patients on the primary sclerosing cholangitis （PSC）-Iike destruction of the intrahepatic bile ducts at cholangiography after exclusion of PSC. In four patients, arterial hypotension with subsequent ischemia may have caused the bile duct damage, whereas in the case of power current injury direct thermal damage was assumed to be the trigger mechanism. The course of secondary liver fibrosis was rapidly progressive and proceeded to liver cirrhosis in all four patients with a follow-up 〉2 years. Therapeutic possibilities were limited.CONCLUSION： Posttraumatic sderosing cholangitis is a rare but rapidly progressive disease, probably caused by ischemia of the intrahepatic bile ducts via the peribiliary capillary plexus due to arterial hypotension.Gastroenterologists should be aware of this disease in patients with persistent cholestasis after severe trauma.

Sclerosing cholangitis associated with autoimmune pancreatitis differs from primary sclerosing cholangitis

AIM:To clarify the characteristic features of biliary le-sions in patients with autoimmune pancreatitis(AIP) and compare them with those of primary sclerosing cholangitis(PSC) .METHODS:The clinicopathological characteristics of 34 patients with sclerosing cholangitis(SC) associated with AIP were compared with those of 4 patients with PSC.RESULTS:SC with AIP occurred predominantly in el-derly men.Obstructive jaundice was the most frequent initial symptom in SC with AIP.Only SC patients with AIP had elevated serum IgG4 levels,and sclerosing diseases were more frequent in these patients.SC pa-tients with AIP responded well to steroid therapy.Seg-mental stenosis of the lower bile duct was observed only in SC patients with AIP,but a beaded and pruned-tree appearance was detected only in PSC patients.Dense infi ltration of IgG4-positive plasma cells was de-tected in the bile duct wall and the periportal area,as well as in the pancreas,of SC patients with AIP.CONCLUSION:SC with AIP is distinctly different from PSC.The two diseases can be discriminated based on cholangiopancreatographic findings and serum IgG4 levels.

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.