Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases:A case report

BACKGROUND Autoimmune hepatitis(AIH)and primary biliary cholangitis(PBC)are two common clinical autoimmune liver diseases,and some patients have both diseases;this feature is called AIH-PBC overlap syndrome.Autoimmune thyroid disease(AITD)is the most frequently overlapping extrahepatic autoimmune disease.Immunoglobulin(IgG)4-related disease is an autoimmune disease recognized in recent years,characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues.CASE SUMMARY A 68-year-old female patient was admitted with a history of right upper quadrant pain,anorexia,and jaundice on physical examination.Laboratory examination revealed elevated liver enzymes,multiple positive autoantibodies associated with liver and thyroid disease,and imaging and biopsy suggestive of pancreatitis,hepatitis,and PBC.A diagnosis was made of a rare and complex overlap syndrome of AIH,PBC,AITD,and IgG4-related disease.Laboratory features improved on treatment with ursodeoxycholic acid,methylprednisolone,and azathioprine.CONCLUSION This case highlights the importance of screening patients with autoimmune diseases for related conditions.

Study on the effect and mechanism of Swertia mussotii Franch. in the treatment of primary biliary cholangitis based on bioinformatics and in vitro experiments

Background:Primary biliary cholangitis(PBC)is a chronic biliary autoimmune liver disease characterized by intrahepatic cholestasis.Swertia mussotii Franch.(SMF)is a Tibetan medicine with hepatoprotective and anti-inflammatory activities.In this study,the therapeutic effect and potential mechanisms of SMF on PBC were investigated by bioinformatics analysis and in vitro experimental validation,with the aim of promoting the progress of SMF and PBC research.Methods:We first explored the therapeutic effects and key targets of SMF on PBC using a network pharmacology approach,further screened the core targets using the GSE79850 dataset,and finally validated the results using molecular docking techniques and in vitro experiments.Results:By bioinformatics analysis,we identified core targets of SMF for PBC treatment(STAT3,JAK2,TNF-α,and IL-1β)and important signaling pathways:JAK-STAT,TNF,and PI3K-AKT.The molecular docking results showed that the significant components of SMF had good binding properties to the core targets.In vitro experiments showed that SMF extracts improved the extent of epithelial-mesenchymal transition in human intrahepatic biliary epithelial cells and had a significant reversal effect on epithelial-mesenchymal transition process markers and potential targets in PBC.Conclusion:SMF may exert its therapeutic effects on PBC by acting on important targets such as STAT3,JAK2,TNF-α,IL-1β,Vimentin,and E-cadherin and the pathways in which they are involved.

Role of autoantibodies in the clinical management of primary biliary cholangitis

Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease characterized by immune-driven destruction of small intrahepatic bile ducts leading a proportion of patients to hepatic failure over the years.Diagnosis at early stages in concert with ursodeoxycholic acid treatment has been linked with prevention of disease progression in the majority of cases.Diagnosis of PBC in a patient with cholestasis relies on the detection of disease-specific autoantibodies,including anti-mitochondrial antibodies,and disease-specific anti-nuclear antibodies targeting sp100 and gp210.These autoantibodies assist the diagnosis of the disease,and are amongst few autoantibodies the presence of which is included in the diagnostic criteria of the disease.They have also become important tools evaluating disease prognosis.Herein,we summarize existing data on detection of PBC-related autoantibodies and their clinical significance.Moreover,we provide insight on novel autoantibodies and their possible prognostic role in PBC patients.

Sequence of events leading to primary biliary cholangitis

Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is observed more frequently in middle-aged women.This disorder is considered an autoimmune disease,since liver injury is sustained by the presence of selfdirected antimitochondrial antibodies targeting the bile duct cells.The prognosis may vary depending on an early diagnosis and response to therapy.However,nearly a third of patients can progress to liver cirrhosis,thus requiring a liver transplant.Traditional immunosuppressive therapies,commonly employed for other autoimmune diseases,have limited effects on PBC.In fact,dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury.In this minireview,after a background on the disease and possible predisposing factors,the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail.The rise and maintenance of the autoimmune process,as well as the response of the biliary epithelia during inflammatory injury,are key factors in the progression of the disease.The so-called“ductular reaction(DR)”,intended as a reactive expansion of cells with biliary phenotype,is a process frequently observed in PBC and partially understood.However,recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis,cell senescence,and loss of biliary ducts.All these issues(onset of chronic inflammation,changes in secretive and proliferative biliary functions,DR,and its relationship with other pathological events)are discussed in this manuscript in an attempt to provide a snapshot,for clinicians and researchers,of the most relevant and sequential contributors to the progression of this human cholestatic disease.We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.

Prevalence and risk factors of osteoporosis detected by dual-energy X-ray absorptiometry among Chinese patients with primary biliary cholangitis

BACKGROUND Osteoporosis is an extrahepatic complication of primary biliary cholangitis(PBC)that increases the risk of fractures and mortality.However,Epidemiological studies of osteoporosis in patients with PBC in China and the Asia-Pacific region is lack.AIM To assess the prevalence and clinical characteristics of osteoporosis in Chinese patients with PBC.METHODS This retrospective analysis included consecutive patients with PBC from a tertiary care center in China who underwent bone mineral density(BMD)assessment using dual-energy X-ray absorptiometry between January 2013 and December 2021.We defined subjects with T-scores≤-2.5 in any sites(L1 to L4,femoral neck,or total hip)as having osteoporosis.Demographic,serological,clinical,and histological data were collected.Independent risk factors for osteoporosis were identified by multivariate logistic regression analysis.RESULTS A total of 268 patients with PBC[236 women(88.1%);mean age,56.7±10.6 years;163 liver biopsies(60.8%)]were included.The overall prevalence of osteoporosis in patients with PBC was 45.5%(122/268),with the prevalence of osteoporosis in women and men being 47.0%and 34.4%,respectively.The prevalence of osteoporosis in postmenopausal women was significantly higher than that in premenopausal women(56.3%vs 21.0%,P<0.001).Osteoporosis in patients with PBC is associated with age,fatigue,menopausal status,previous steroid therapy,body mass index(BMI),splenomegaly,gastroesophageal varices,ascites,Mayo risk score,histological stage,alanine aminotransferase,albumin,bilirubin,platelet and prothrombin activity.Multivariate regression analysis identified that older age,lower BMI,previous steroid therapy,higher Mayo risk score,and advanced histological stage as the main independent risk factors for osteoporosis in PBC.CONCLUSION Osteoporosis is very common in Chinese patients with PBC,allowing for prior screening of BMD in those PBC patients with older age,lower BMI,previous steroid therapy and advanced liver disease.

New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage

Primary biliary cholangitis(PBC)is a chronic cholestatic progressive liver disease and one of the most important progressive cholangiopathies in adults.Damage to cholangiocytes triggers the development of intrahepatic cholestasis,which progresses to cirrhosis in the terminal stage of the disease.Accumulating data indicate that damage to biliary epithelial cells[(BECs),cholangiocytes]is most likely associated with the intracellular accumulation of bile acids,which have potent detergent properties and damaging effects on cell membranes.The mechanisms underlying uncontrolled bile acid intake into BECs in PBC are associated with pH change in the bile duct lumen,which is controlled by the bicarbonate(HCO3-)buffer system“biliary HCO3-umbrella”.The impaired production and entry of HCO3-from BECs into the bile duct lumen is due to epigenetic changes in expression of the X-linked microRNA 506.Based on the growing body of knowledge on the molecular mechanisms of cholangiocyte damage in patients with PBC,we propose a hypothesis explaining the pathogenesis of the first morphologic(ductulopenia),immunologic(antimitochondrial autoantibodies)and clinical(weakness,malaise,rapid fatigue)signs of the disease in the asymptomatic stage.This review focuses on the consideration of these mechanisms.

Prognostic scores in primary biliary cholangitis patients with advanced disease

BACKGROUND Due to the chronic progressive disease characteristics of primary biliary cholangitis(PBC),patients with advanced PBC should not be ignored.Most prognostic score studies have focused on early stage PBC.AIM To compare the prognostic value of various risk scores in advanced PBC to help PBC patients obtain more monitoring and assessment.METHODS This study considered patients diagnosed with PBC during hospitalization between 2015 and 2021.The clinical stage was primarily middle and late,and patients usually took ursodeoxycholic acid(UDCA)after diagnosis.The discriminatory performance of the scores was assessed with concordance statistics at baseline and after 1 year of UDCA treatment.Telephone follow-up was conducted to analyze the course and disease-associated outcomes.The follow-up deadline was December 31,2021.We compared the risk score indexes between those patients who reached a composite end point of death or liver transplantation(LT)and those who remained alive at the deadline.The combined performance of prognostic scores in estimating the risk of death or LT after 1 year of UDCA treatment was assessed using Cox regression analyses.Predictive accuracy was evaluated by comparing predicted and actual survival through Kaplan-Meier analyses.RESULTS We included 397 patients who were first diagnosed with PBC during hospitalization and received UDCA treatment;most disease stages were advanced.After an average of 6.4±1.4 years of follow-up,82 patients had died,and 4 patients had undergone LT.After receiving UDCA treatment for 1 year,the score with the best discrimination performance was the Mayo,with a concordance statistic of 0.740(95%confidence interval:0.690-0.791).The albumin-bilirubin,GLOBE,and Mayo scores tended to overestimate transplant-free survival.Comparing 7 years of calibration results showed that the Mayo score was the best model.CONCLUSION The Mayo,GLOBE,UK-PBC,and ALBI scores demonstrated comparable discriminating performance for advanced stage PBC.The Mayo score showed optimal discriminatory performance and excellent predictive accuracy.

Role of biochemical markers and autoantibodies in diagnosis of early-stage primary biliary cholangitis

BACKGROUND Primary biliary cholangitis(PBC)is a chronic progressive autoimmune cholestatic disease.The main target organ of PBC is the liver,and nonsuppurative inflammation of the small intrahepatic bile ducts may eventually develop into cirrhosis or liver fibrosis.AIM To explore the clinical characteristics of early-stage PBC,identify PBC in the early clinical stage,and promptly treat and monitor PBC.METHODS The data of 82 patients with PBC confirmed by pathology at Tianjin Second People’s Hospital from January 2013 to November 2021 were collected,and the patients were divided into stage I,stage II,stage III,and stage IV according to the pathological stage.The general data,serum biochemistry,immunoglobulins,and autoimmune antibodies of patients in each stage were retrospectively analyzed.RESULTS In early-stage(stages I+II)PBC patients,50.0%of patients had normal alanine aminotransferase(ALT)levels,and 37.5%had normal aspartate aminotransferase(AST)levels.For the remaining patients,the ALT and AST levels were mildly elevated;all of these patients had levels of<3 times the upper limit of normal values.The AST levels were significantly different among the three groups(stages I+II vs stage III vs stage IV,P<0.05).In the early stage,29.2%of patients had normal alkaline phosphatase(ALP)levels.The remaining patients had different degrees of ALP elevation;6.3%had ALP levels>5 times the upper limit of normal value.Moreover,γ-glutamyl transferase(GGT)was more robustly elevated,as 29.2%of patients had GGT levels of>10 times the upper limit of normal value.The ALP values among the three groups were significantly different(P<0.05).In early stage,the jaundice index did not increase significantly,but it gradually increased with disease progression.However,the above indicators were significantly different(P<0.05)between the early-stage group and the stage IV group.With the progression of the disease,the levels of albumin and albumin/globulin ratio tended to decrease,and the difference among the three groups was statistically significant(P<0.05).In early-stage patients,IgM and IgG levels as well as cholesterol levels were mildly elevated,but there were no significant differences among the three groups.Triglyceride levels were normal in the early-stage group,and the differences among the three groups were statistically significant(P<0.05).The early detection rates of anti-mitochondria antibody(AMA)and AMA-M2 were 66.7%and 45.8%,respectively.The positive rate of anti-sp100 antibodies was significantly higher in patients with stage IV PBC.When AMA and AMA-M2 were negative,in the early stage,the highest autoantibody was anti-nuclear antibody(ANA)(92.3%),and in all ANA patterns,the highest was ANA centromere(38.5%).CONCLUSION In early-stage PBC patients,ALT and AST levels are normal or mildly elevated,GGT and ALP levels are not elevated in parallel,GGT levels are more robustly elevated,and ALP levels are normal in some patients.When AMA and AMA-M2 are negative,ANA especially ANA centromere positivity suggests the possibility of early PBC.Therefore,in the clinic,significantly elevated GGT levels with or without normal ALP levels and with ANA(particularly ANA centromere)positivity(when AMA and AMA-M2 are negative)may indicate the possibility of early PBC.

Clinicopathological features of 11 cases of chronic hepatitis B infection complicated with primary biliary cholangitis

BACKGROUND Only a few cases of chronic hepatitis B(CHB)with primary biliary cholangitis(PBC)have been reported based on histological evidence from liver biopsies.AIM To observe the clinicopathological features and outcomes of 11 patients with CHB infection complicated by PBC.METHODS Eleven patients with CHB and PBC who underwent liver biopsy at the Zhenjiang Third Hospital,affiliated with Jiangsu University,and Wuxi Fifth People’s Hospital,from January 2005 to September 2020,were selected.All patients initially visited our hospital with CHB and were pathologically diagnosed with CHB and PBC.RESULTS Only five had elevated alkaline phosphatase levels,nine were positive for antimitochondrial antibody(AMA)-M2,and two were negative for AMA-M2.Two had jaundice and pruritus symptoms,10 had mildly abnormal liver function,and one had severely elevated bilirubin and liver enzyme levels.The pathological characteristics of CHB complicated by PBC overlapped with those of PBCautoimmune hepatitis(AIH).When necroinflammation of the portal area is not obvious,the pathological features of PBC are predominant,similar to the features of PBC alone.When the interface is severe,biliangitis will occur,with a large number of ductular reactions in zone 3.Unlike the PBC-AIH overlap pathology,this pathology is characterized by a small amount of plasma cell infiltration.Unlike PBC,lobulitis is often observed.CONCLUSION This is the first large case series to show that the rare pathological features of CHB with PBC are similar to those of PBC-AIH and small duct injury was observed.

Clinical utility of two-dimensional shear-wave elastography in monitoring disease course in autoimmune hepatitis-primary biliary cholangitis overlap syndrome

BACKGROUND Autoimmune hepatitis-primary biliary cholangitis(AIH-PBC)overlap syndrome has a worse prognosis than AIH or PBC alone.Therefore,accurately staging liver fibrosis and dynamically monitoring disease progression are essential.AIM To investigate the performance of two-dimensional shear-wave elastography(2DSWE)for noninvasively staging liver fibrosis and assessing the clinical utility of repeated 2D-SWE for monitoring treatment response in AIH-PBC overlap syndrome.METHODS A total of 148 patients diagnosed with AIH-PBC overlap syndrome were retrospectively enrolled.Among them,82 patients had a 2D-SWE follow-up time of more than 1 year.The Scheuer scoring system was used to evaluate stages of hepatic inflammation and liver fibrosis.The performance of 2D-SWE for staging liver fibrosis was evaluated with the liver biopsy.Changes in liver stiffness(LS)measured by 2D-SWE in patients with or without complete biochemical remission were evaluated.RESULTS LS value was strongly correlated with liver fibrosis stage(Spearman r=0.84,P<0.0001).The areas under the receiver operating characteristic curves of LS for diagnosing significant fibrosis(≥S2),severe fibrosis(≥S3),and cirrhosis(S4)were 0.91,0.97,and 0.96,respectively.Patients with complete biochemical remission had a considerable decrease in LS values(P<0.0001).More importantly,the declined LS in patients with S0-S2 was significantly lower than that in patients with S3-S4(P=0.0002).In contrast,patients who failed to achieve biochemical remission had a slight but not significant decrease in LS(P=0.37).CONCLUSION LS measured by 2D-SWE is an accurate and reliable method in assessing liver fibrosis,especially for diagnosing severe fibrosis(≥3)and monitoring treatment response in patients with AIH-PBC overlap syndrome.

S100 calcium binding protein A6 and associated long noncoding ribonucleic acids as biomarkers in the diagnosis and staging of primary biliary cholangitis

BACKGROUND Primary biliary cholangitis(PBC)is a chronic and slowly progressing cholestatic disease,which causes damage to the small intrahepatic bile duct by immunoregulation,and may lead to cholestasis,liver fibrosis,cirrhosis and,eventually,liver failure.AIM To explore the potential diagnosis and staging value of plasma S100 calcium binding protein A6(S100A6)messenger ribonucleic acid(mRNA),LINC00312,LINC00472,and LINC01257 in primary biliary cholangitis.METHODS A total of 145 PBC patients and 110 healthy controls(HCs)were enrolled.Among them,80 PBC patients and 60 HCs were used as the training set,and 65 PBC patients and 50 HCs were used as the validation set.The relative expression levels of plasma S100A6 mRNA,long noncoding ribonucleic acids LINC00312,LINC00472 and LINC01257 were analyzed using quantitative reverse transcription-polymerase chain reaction.The bile duct ligation(BDL)mouse model was used to simulate PBC.Then double immunofluorescence was conducted to verify the overexpression of S100A6 protein in intrahepatic bile duct cells of BDL mice.Human intrahepatic biliary epithelial cells were treated with glycochenodeoxycholate to simulate the cholestatic environment of intrahepatic biliary epithelial cells in PBC.RESULTS The expression of S100A6 protein in intrahepatic bile duct cells was up-regulated in the BDL mouse model compared with sham mice.The relative expression levels of plasma S100A6 mRNA,log10 LINC00472 and LINC01257 were upregulated while LINC00312 was down-regulated in plasma of PBC patients compared with HCs(3.01±1.04 vs 2.09±0.87,P<0.0001;2.46±1.03 vs 1.77±0.84,P<0.0001;3.49±1.64 vs 2.37±0.96,P<0.0001;1.70±0.33 vs 2.07±0.53,P<0.0001,respectively).The relative expression levels of S100A6 mRNA,LINC00472 and LINC01257 were up-regulated and LINC00312 was down-regulated in human intrahepatic biliary epithelial cells treated with glycochenodeoxycholate compared with control(2.97±0.43 vs 1.09±0.08,P=0.0018;2.70±0.26 vs 1.10±0.10,P=0.0006;2.23±0.21 vs 1.10±0.10,P=0.0011;1.20±0.04 vs 3.03±0.15,P<0.0001,respectively).The mean expression of S100A6 in the advanced stage(III and IV)of PBC was up-regulated compared to that in HCs and the early stage(II)(3.38±0.71 vs 2.09±0.87,P<0.0001;3.38±0.71 vs 2.57±1.21,P=0.0003,respectively);and in the early stage(II),it was higher than that in HCs(2.57±1.21 vs 2.09±0.87,P=0.03).The mean expression of LINC00312 in the advanced stage was lower than that in the early stage and HCs(1.39±0.29 vs 1.56±0.33,P=0.01;1.39±0.29 vs 2.07±0.53,P<0.0001,respectively);in addition,the mean expression of LINC00312 in the early stage was lower than that in HCs(1.56±0.33 vs 2.07±0.53,P<0.0001).The mean expression of log10 LINC00472 in the advanced stage was higher than those in the early stage and HCs(2.99±0.87 vs 1.81±0.83,P<0.0001;2.99±0.87 vs 1.77±0.84,P<0.0001,respectively).The mean expression of LINC01257 in both the early stage and advanced stage were up-regulated compared with HCs(3.88±1.55 vs 2.37±0.96,P<0.0001;3.57±1.79 vs 2.37±0.96,P<0.0001,respectively).The areas under the curves(AUC)for S100A6,LINC00312,log10 LINC00472 and LINC01257 in PBC diagnosis were 0.759,0.7292,0.6942 and 0.7158,respectively.Furthermore,the AUC for these four genes in PBC staging were 0.666,0.661,0.839 and 0.5549,respectively.The expression levels of S100A6 mRNA,log10 LINC00472,and LINC01257 in plasma of PBC patients were decreased(2.35±1.02 vs 3.06±1.04,P=0.0018;1.99±0.83 vs 2.33±0.96,P=0.036;2.84±0.92 vs 3.69±1.54,P=0.0006),and the expression level of LINC00312 was increased(1.95±0.35 vs 1.73±0.32,P=0.0007)after treatment compared with before treatment using the paired t-test.Relative expression of S100A6 mRNA was positively correlated with log10 LINC00472(r=0.683,P<0.0001);serum level of collagen type IV was positively correlated with the relative expression of log10 LINC00472(r=0.482,P<0.0001);relative expression of S100A6 mRNA was positively correlated with the serum level of collagen type IV(r=0.732,P<0.0001).The AUC for the four biomarkers obtained in the validation set were close to the training set.CONCLUSION These four genes may potentially act as novel biomarkers for the diagnosis of PBC.Moreover,LINC00472 acts as a potential biomarker for staging in PBC.

Primary biliary cholangitis metachronously complicated with combined hepatocellular carcinoma-cholangiocellular carcinoma and hepatocellular carcinoma

Primary biliary cholangitis(PBC) is a progressive cholestatic liver disease characterized by the presence of highly specific antimitochondrial antibodies, portal inflammation and lymphocyte-dominated destruction of the intrahepatic bile ducts, which leads to cirrhosis. While its pathogenesis remains unclear, PBC that shows histological progression to fibrosis carries a high risk of carcinogenesis; the same is true of viral liver diseases. In patients with PBC, the development of hepatocellular carcinoma(HCC) is rare; the development of combined hepatocellular carcinoma and cholangiocellular carcinoma(c HCC-CCC) is extraordinary. Herein, we report a rare case of PBC metachronously complicated by c HCC-CCC and HCC, which, to the best of our knowledge, has never been reported. We present a case report of a 74-year-old Japanese woman who was diagnosed as PBC in her 40's by using blood tests and was admitted to our department for further management of an asymptomatic liver mass. She had a tumor of 15 mm in size in segment 8 of the liver and underwent a partial resection of the liver. Subsequent pathological findings resulted in the diagnosis of c HCC-CCC, arising from stage 3 PBC. One year after the initial hepatectomy, a second tumor of 10 mm in diameter was found in segment 5 of the liver; a partial resection of the liver was performed. Subsequent pathological findings led to HCC diagnosis. The component of HCC in the initial tumor displayed a trabecular growth pattern while the second HCC showed a pseudoglandular growth pattern, suggesting that metachronous tumors that arise from PBC are multicentric.

Serum metabolic profiling of targeted bile acids reveals potentially novel biomarkers for primary biliary cholangitis and autoimmune hepatitis

BACKGROUND Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are two unexplained immune diseases.The golden standard for diagnosis of these diseases requires a liver biopsy.Liver biopsy is not widely accepted by patients because of its invasive nature,and atypical liver histology can confuse diagnosis.In view of the lack of effective diagnostic markers for PBC and AIH,combined with the increasingly mature metabolomics technologies,including full-contour metabolomics and target.AIM To determine non-invasive,reliable,and sensitive biochemical markers for the differential diagnosis of PBC and AIH.METHODS Serum samples from 54 patients with PBC,26 patients with AIH and 30 healthy controls were analyzed by Ultra-high performance liquid chromatographytandem mass spectrometry serum metabolomics.The metabolites and metabolic pathways were identified,and the metabolic changes,metabolic pathways and inter-group differences between PBC and AIH were analyzed.Fifteen kinds of target metabolites of bile acids(BAs)were quantitatively analyzed by SRM,and the differential metabolites related to the diagnosis of PBC were screened by receiver operating characteristic curve analysis.RESULTS We found the changes in the levels of amino acids,BAs,organic acids,phospholipids,choline,sugar,and sugar alcohols in patients with PBC and AIH.Furthermore,the SRM assay of BAs revealed the increased levels of chenodeoxycholic acid,lithocholic acid(LCA),taurolithocholic acid(TLCA),and LCA+TLCA in the PBC group compared with those in the AIH group.The levels of BAs may be used as biomarkers to differentiate PBC from AIH diseases.The levels of glycochenodeoxycholic acid,glycochenodeoxycholic sulfate,and taurodeoxycholic acid were gradually elevated with the increase of Child-Pugh class,which was correlated with the severity of disease.CONCLUSION The results demonstrated that the levels of BAs could serve as potential biomarkers for the early diagnosis and assessment of the severity of PBC and AIH.

Concomitant extrahepatic autoimmune diseases do not compromise the long-term outcomes of primary biliary cholangitis

Background:Primary biliary cholangitis(PBC)patients often have concomitant extrahepatic autoimmune(EHA)diseases including Sjögren’s syndrome(SS),systemic sclerosis(SSc),rheumatoid arthritis(RA),and autoimmune thyroid disease.The present study aimed to describe the prevalence of EHA diseases in PBC and explore the impact of EHA diseases on the long-term outcomes of PBC in Chinese patients.Methods:Medical records of PBC patients diagnosed in our institute were retrospectively reviewed.Pa-tients were followed up by a standardized telephone interview.The endpoints were defined as liver-related death and/or liver transplantation.Results:Totally 247 of the 985(25.1%)PBC patients enrolled in the study had at least one concomi-tant EHA disease.Sjögren’s syndrome(n=140,14.2%)was the most frequent one,followed by rheuma-toid arthritis(RA)(n=56,5.7%)and Hashimoto’s thyroiditis(n=45,4.6%).Patients with EHA dis-eases were more common in females(P<0.001)and in those with a family history of autoimmune disease(P=0.017).Overall,no differences were found between PBC patients with and without EHA dis-eases in terms of biochemical response rates to ursodeoxycholic acid,the incidence of hepatic events,or transplant-free survival.RA and EHA≥2 were protective factors for hepatic events in univariate Cox analysis,but the results became insignificant in multivariate analysis.Conclusions:Concomitant EHA diseases were common in PBC patients but did not compromise the long-term outcomes of PBC.

Poor performance of anti-mitochondrial antibodies for the diagnosis of primary biliary cholangitis in female Colombian patients:A singlecenter study

BACKGROUND Primary biliary cholangitis(PBC)is a serious disease that causes significant morbidity.PBC is confirmed with liver biopsy but autoantibodies are frequently used as proxies for diagnosis.The performance of autoantibodies for the diagnosis of PBC seems to vary widely across populations.AIM To assess the diagnostic performance of several autoantibodies for the diagnosis of PBC in Latin American individuals.METHODS We studied 85 female adult Colombians,43 cases with biopsy-confirmed PBC and 42 controls in whom a liver biopsy ruled out PBC.Plasma anti-mitochondrial antibodies(AMAs),anti-smooth muscle antibodies(ASMAs)and anti-nuclear antibodies(ANAs),as well as total immunoglobulin(Ig)M and IgG were determined using immunofluorescence or enzyme-linked immunosorbent assay in all study participants within 1 year of the biopsy.For all variables,values analyzed were those closest to the date of the biopsy.Patients with viral or alcoholic hepatitis were excluded.RESULTS Mean age at diagnosis was 58.7 years for cases and 56.9 years for controls,and the body mass index was lower among cases.Most cases received ursodeoxycholic acid,while most controls received vitamin E.Sjögren syndrome and Hashimoto’s thyroiditis were the most frequent autoimmune comorbidities of PBC.The prevalence of AMA positivity among PBC cases was unexpectedly low.The sensitivity and specificity values were respectively 44.2%and 76.2%for AMA,74.4%and 38.1%for ANA,14.0%and 73.8%for ASMA,26.7%and 80.0%for IgG,and 57.1%and 85.7%for IgM.The combination of positive AMA plus positive IgM had 91%positive predictive value for PBC.Among AMA-negative cases,the most prevalent antibodies were ANA(87.5%).In all,62%of AMA-positive and 84.6%of IgM-positive individuals had fibrosis in their biopsy.CONCLUSION AMA positivity was very low among female Latin American patients with PBC.The performance of all antibodies was quite limited.These results highlight the urgent need for better PBC biomarkers.

Primary biliary cholangitis in pregnancy:A systematic review with meta-analysis

Background: The outcomes and disease associations in pregnant women with primary biliary cholangitis(PBC) have not been largely explored. This study aimed to determine the level of evidence associated with maternal and fetal outcomes and other disease associations in female patients with PBC. Data sources:: A comprehensive literature search was conducted. Maternal and fetal outcomes were obtained from patients with a previous, current or subsequent diagnosis of PBC. A random-effects model was employed, using odds ratios(ORs) with 95% confidence intervals(CIs). Results: Eleven studies, with 2179 female PBC patients were included. Pregnant women with PBC were significantly more likely to have a miscarriage(OR = 1.27, 95% CI: 1.02-1.58;P = 0.03), and a history of abortion(OR = 1.50, 95% CI: 1.09-2.07;P = 0.01), with absent heterogeneity( I 2 = 0%). PBC pregnant women were significantly more likely to deliver via vaginal birth(OR = 1.69, 95% CI: 1.33-2.14;P < 0.001) with low level heterogeneity( I^(2) < 0.001%). Patients had a statistically significant increased likelihood of lifetime smoking(OR = 1.95, 95% CI: 1.17-3.23;P = 0.01). Egger’s regression revealed no evidence of publication bias. Conclusions: This meta-analysis provides pooled evidence that a PBC pregnancy is associated with fetal morbidity and maternal lifestyle associations that may influence pregnancy outcomes. More studies are needed to establish disease associations that may directly affect pregnancy outcomes. These data are essential for clinicians managing these patients before, during or after pregnancy.

Autoimmune enteropathy and primary biliary cholangitis after proctocolectomy for ulcerative colitis:A case report and review of the literature

BACKGROUND Autoimmune enteropathy(AIE)and primary biliary cholangitis(PBC)are both immune-mediated diseases.AIE or PBC complicated with ulcerative colitis(UC)are rare.There are no cases of AIE and PBC diagnosed after proctocolectomy for UC reported before,and the pathogenesis of these comorbidities has not been revealed.CASE SUMMARY A middle-aged woman diagnosed with UC underwent subtotal colectomy and ileostomy due to the steroid-resistant refractory disease,and a restorative proctectomy with ileal pouch-anal anastomosis and proximal neoileostomy was postponed due to active residual rectal inflammation in January 2016.A few months after the neoileostomy,she began to suffer from recurrent episodes of watery diarrhea.She was diagnosed with postcolectomy enteritis and stoma closure acquired a good therapeutic effect.However,her symptoms of diarrhea relapsed in 2019,with different histological features of endoscopic biopsies compared with 2016,which showed apoptotic bodies,a lack of goblet and Paneth cells,and villous blunting.A diagnosis of AIE was established,and the patient’s stool volume decreased dramatically with the treatment of methylprednisolone 60 mg/d for 1 wk and tacrolimus 3 mg/d for 4 d.Meanwhile,her constantly evaluated cholestatic enzymes and high titers of antimitochondrial antibodies indicated the diagnosis of PBC,and treatment with ursodeoxycholic acid(16 mg/kg per day)achieved satisfactory results.CONCLUSION Some immune-mediated diseases may be promoted by operation due to microbial alterations in UC patients.Continuous follow-up is essential for UC patients with postoperative complications.

False positive anti-hepatitis A virus immunoglobulin M in autoimmune hepatitis/primary biliary cholangitis overlap syndrome:A case report

BACKGROUND Autoimmune hepatitis(AIH)is an immune-mediated liver disease affecting all age groups.Associations between hepatitis A virus(HAV)and AIH have been described for many years.Herein,we report a case of an AIH/primary biliary cholangitis(PBC)overlap syndrome with anti-HAV immunoglobulin M(IgM)false positivity.CASE SUMMARY A 55-year-old man was admitted with manifestations of anorexia and jaundice along with weakness.He had marked transaminitis and hyperbilirubinemia.Viral serology was positive for HAV IgM and negative for others.Autoantibody screening was positive for anti-mitochondria antibody but negative for others.Abdominal ultrasound imaging was normal.He was diagnosed with acute hepatitis A.After symptomatic treatment,liver function tests gradually recovered.Several months later,his anti-HAV IgM positivity persisted and transaminase and bilirubin levels were also more than 10 times above of the upper limit of normal.Liver histology was prominent,and HAV RNA was negative.Therefore,AIH/primary biliary cholangitis(PBC)overlap syndrome diagnosis was made based on the“Paris Criteria”.The patient was successfully treated by immunosuppression.CONCLUSION This case highlights that autoimmune diseases or chronic or acute infections,may cause a false-positive anti-HAV IgM result because of cross-reacting antibodies.Therefore,the detection of IgM should not be the only method for the diagnosis of acute HAV infection.HAV nucleic acid amplification tests should be employed to confirm the diagnosis.

Understanding fatigue in primary biliary cholangitis:From pathophysiology to treatment perspectives

Fatigue is considered one of the most frequent and debilitating symptoms in primary biliary cholangitis(PBC),affecting over 50%of PBC patients.One in five patients with PBC suffer from severe fatigue,which significantly impairs quality of life.Fatigue is made up of a central and a peripheral component,whose pathophysiology is still greatly unresolved.Central fatigue is characterised by a lack of self-motivation and can manifest both in physical and mental activities(lack of intention).Peripheral fatigue includes neuromuscular dysfunction and muscle weakness(lack of ability).Peripheral fatigue could be explained by an excessive deviation from aerobic to anaerobic metabolism leading to excessive lactic acid accumulation and therefore accelerated decline in muscle function and prolonged recovery time.As opposed to itching,and with the exception of endstage liver disease,fatigue is not related to disease progression.The objective of this review is to outline current understanding regarding the pathophysiology of fatigue,the role of comorbidities and contributing factors,the main tools for fatigue assessment,the failed therapeutic options,and future treatment perspectives for this disabling symptom.Since fatigue is an extremely common and debilitating symptom and there is still no licensed therapy for fatigue in PBC patients,further research is warranted to understand its causative mechanisms and to find an effective treatment.

Alcohol intake is associated with a decreased risk of developing primary biliary cholangitis

BACKGROUND Primary biliary cholangitis(PBC)is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile ducts.There are few well-established risk factors and epidemiological studies are needed to further evaluate the pathogenesis of the disease.AIM To evaluate the relationship between alcohol intake,smoking and marijuana use with PBC development.METHODS We conducted a prevalent case control study of 200 cases and 200 age(within a five year age band)and sex-matched controls,identified from the Victorian PBC prevalence study.We assessed lifetime alcohol intake and smoking behaviour(both tobacco and marijuana)prior to PBC onset and used conditional logistic regression for analyses.RESULTS Alcohol intake consistently showed a dose-dependent inverse association with case status,and this was most substantial for 21-30 years and 31-40 years(Ptrend<0.001).Smoking was associated with PBC,with a stronger association with a longer duration of smoking[e.g.,adjusted OR 2.27(95%CI:1.12-4.62)for those who had smoked for 20-35 years].There was no association between marijuana use and PBC.CONCLUSION Alcohol appears to have an inverse relationship with PBC.Smoking has been confirmed as an environmental risk factor for PBC.There was no association between marijuana use and PBC.