Primary Biliary Cholangitis Cases Research Articles

Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis.

Fibrate addition to ursodeoxycholic acid (UDCA) therapy has been shown to improve both liver biochemistry and long-term prognosis in primary biliary cholangitis (PBC) patients showing an incomplete biochemical response to UDCA alone. We herein describe the clinical outcome of seven cases of PBC that received the new selective peroxisome proliferator-activated receptor α modulator, pemafibrate, in combination with UDCA therapy to investigate the biochemical and plasma lipid responses to the drug. Of 124 initially enrolled PBC patients, 12 treated with UDCA alone and seven receiving UDCA plus bezafibrate showed alkaline phosphatase (ALP) levels above the upper limit of normal (330U/L). Ultimately, seven patients with PBC and dyslipidemia who had agreed to biweekly visits at our hospital for UDCA plus pemafibrate combination therapy were retrospectively analyzed. In the four cases that switched from bezafibrate to pemafibrate, ALP became significantly decreased (0.031) and γ-glutamyltransferase tended to decrease (0.063) over the 3months following pemafibrate addition. Two patients showed a greater than 50% reduction in ALP. No remarkable differences were observed for plasma lipid levels, alanine aminotransferase, aspartate aminotransferase, or the liver fibrosis marker Mac-2 binding protein glycosylation isomer between these time points. No adverse drug reactions were recorded. Pemafibrate might be another option for PBC patients with an incomplete response to UDCA therapy.

Genome-wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis.

Anti‐nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome‐wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single‐nucleotide polymorphisms rs492899 (P = 3.27 × 10−22; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34‐3.66) and rs1794280 (P = 5.78 × 10−28; OR, 3.89; 95% CI, 3.05‐4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti‐sp100‐positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA‐DRβ1‐Asn77/Arg74, DRβ1‐Ser37, and DPβ1‐Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10−9; OR, 2.97; 95% CI, 2.06‐4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

Burden of Primary Biliary Cholangitis Among Inpatient Population in the United States

Primary biliary cholangitis (PBC) is an autoimmune liver disease that can lead to cirrhosis and liver failure. Our aim was to assess the recent trends in the mortality rates and health care utilization of patients with PBC seen in the inpatient setting in the United States. We used the National (Nationwide) Inpatient Sample data (2005‐2014). The study population included adults with PBC, using International Classification of Diseases, Ninth Revision codes. Trends in PBC‐related discharges, total charges, length of stay (LoS), and in‐hospital mortality were evaluated. Hierarchical generalized linear models were performed for determining predictors of mortality and total hospital charges. Between the study years of 2005 and 2014, a total of 22,665 hospitalized cases with PBC were identified (mean age 63 years; 84% female, 76% white). The number of PBC‐related discharges increased from 3.24 per 100,000 in 2005 to 3.68 per 100,000 in 2014, with an average annual increase of 1.4% (95% confidence interval [CI]: 0.4%‐2.4%). Fifty‐seven percent had Medicare as their primary payer, 37% had cirrhosis, and 1.3% had hepatocellular carcinoma. Between 2005 and 2014, the average total charges for PBC increased from $53,901 to $57,613 (annual percent change [APC], 1.7%; 95% CI: −0.2%‐3.5%), LoS decreased from 6.9 days to 5.4 days (APC, −2.2%; 95% CI: −3.2% to −1.1%), and mortality rate decreased from 3.8% to 2.8% (APC, −5.4%; 95% CI: −8.4% to −2.4%). Multivariable analysis revealed that ascites were independently associated with increased risk of in‐hospital mortality (odds ratio: 1.77; 95% CI: 1.50‐2.08), increased charge (percent change: 22.5%; 95% CI: 18.6%‐26.7%), and increased LoS (percent change: 29.7%; 95% CI: 25.7%‐33.9%). Conclusion: The number of PBC cases has increased in recent years. Mortality and LoS have decreased, and the total charges have remained the same.

Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.

Clinical analysis of de novo HBV infection after liver transplantation in non-HBV- related liver disease

Objective: The aim of this study was to summarize and analyze the clinical features and characteristics of de novo HBV infection after liver transplantation in non-HBV-related liver disease. Methods: We retrospectively analyzed the clinical data of 13 patients with new HBV infection in 376 cases of liver transplantation patients with non-HBV related liver diseases from April 2002 to December 2013 in our hospital. Results: Among 376 patients with non-HBV-related liver disease after liver transplantation, 13 patients developed new HBV infection, and the rate of new HBV infection was 3.46%. Of the 13 cases, 5 were males and 8 were females. The follow-up time was 14.7 -128.7 months, and the average time from surgery to new HBV infection was 19.06 months. The primary diseases were as follows: 5 cases of primary biliary cholangitis, 3 cases of alcoholic liver disease, 2 cases of drug-induced liver damage, 1 cases of post-hepatitis C cirrhosis, congenital biliary atresia and congenital liver fibrosis. All patients were positive for HBsAg, HBeAg, anti-HBc, 11 were positive for HBV DNA, and 2 were negative for HBV DNA. 6 cases had abnormal liver function and 7 cases had normal liver function. All patients were treated with antiviral therapy with nucleoside (acid) analogues. HBsAg was negative in 6 patients; HBsAg remained positive in 7 cases, including HBsAg, HBeAg, anti-HBc positive in 6 cases, HBsAg, anti-HBe, anti- HBc was positive in 1 case, HBV DNA was still positive in 1 patient, and HBV DNA was negative in 6 patients; liver function was normal in all patients. Conclusion: Non-HBV- related liver transplantation are high-risk group of new HBV infection, with the highest incidence of autoimmune liver disease. It is speculated that it may be related to the long-term use of hormones after the transplantation. The prognosis of newly diagnosed HBV infection after liver transplantation is fine as long as it can be found and treated early.

Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis.

Relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives. (Hepatology 2018;68:166-171).

An adult case of primary biliary cholangitis accompanied by a patent ductus venosus showing type-I congenital absence of the portal vein

An adult case of primary biliary cholangitis accompanied by a patent ductus venosus showing type-I congenital absence of the portal vein

Two Cases of Primary Biliary Cholangitis with Hepatocellular Carcinoma in a Non-cirrhotic Stage

Two Cases of Primary Biliary Cholangitis with Hepatocellular Carcinoma in a Non-cirrhotic Stage

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics.

Factors Associated With Prevalence and Treatment of Primary Biliary Cholangitis in United States Health Systems

Reported prevalence of primary biliary cholangitis (PBC) varies widely. Demographic features and treatment patterns are not well characterized in the United States (US). We analyzed data from the Fibrotic Liver Disease (FOLD) Consortium, drawn from 11 geographically diverse health systems, to investigate epidemiologic factors and treatment of PBC in the US. We developed a validated electronic health record-based classification model to identify patients with PBC in the FOLD database from 2003 through 2014. We used multivariable modeling to assess the effects of factors associated with PBC prevalence and treatment with ursodeoxycholic acid (UDCA). We identified 4241 PBC cases among over 14.5 million patients in FOLD health systems; median follow-up was 5 years. Accuracy of the classification model was excellent, with an area under the receiver operating characteristic curve value of 93%, 94% sensitivity, and 87% specificity. The average patient age at diagnosis was 60 years; 21%were Hispanic, 8% were African American, and 7% were Asian American/American Indian/Pacific Islander. Half of the cohort (49%) had elevated levels of alkaline phosphatase, and overall, 70% were treated with UDCA. The estimated 12-year prevalence of PBC was 29.3 per 100,000 persons. Adjusted prevalence values were highest among women (42.8 per 100,000), White patients (29.6 per 100,000), and patients 60-70 years old (44.7 per 100,000). Prevalence was significantly lower among men and African Americans (10.7 and 19.7 per 100,000, respectively) than women and whites; men and African Americans were also less likely to receive UDCA treatment (odds ratios, 0.6 and 0.5, respectively; P < .05). In an analysis of a large cohort of patients with PBC receiving routine clinical care, we observed significant differences in PBC prevalence and treatment by gender, race, and age.

Increased cholestatic enzymes in two patients with long-term history of ulcerative colitis: consider primary biliary cholangitis not always primary sclerosing cholangitis

Several hepatobiliary disorders have been reported in ulcerative colitis (UC) patients with primary sclerosing cholangitis (PSC) being the most specific. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis,...

Epidemiology and Natural History of Primary Biliary Cholangitis in the Chinese: A Territory-Based Study in Hong Kong between 2000 and 2015.

Objectives:Studies on the epidemiology of primary biliary cholangitis (PBC) in the Chinese population are lacking. We aimed to determine the epidemiology of PBC in Hong Kong (HK) with a population of 7.3 million.Methods:We retrieved data from the electronic database of the HK Hospital Authority, the only public healthcare provider in Hong Kong. PBC cases between 2000 and 2015 were identified by International Classification of Diseases (ICD)-9 code. We estimated the age-/sex-adjusted incidence rate and prevalence of PBC, and analyzed the adverse outcomes (hepatocellular carcinoma (HCC), liver transplantation, and death).Results:One thousand and sixteen PBC patients aged ≥20 years were identified (female-to-male ratio 4:1; median age 60.6 years, interquartile range (IQR) 51.8–72.6 years; median follow-up 5.6 years, IQR 1.6–8.7 years). The average age/sex-adjusted annual incidence rate and prevalence were 8.4 per million person-years and 56.4 per million, respectively. Between 2000 and 2015, the age/sex-adjusted annual incidence rate increased from 6.7 to 8.1 per million person-years (Poisson P=0.002), while age/sex-adjusted prevalence increased from 31.1 to 82.3 per million (Poisson P<0.001). Fifty patients developed HCC, and 49 underwent liver transplantation. Case fatality risk decreased from 10.8 to 6.4% (Poisson P=0.003). The 5- and 10-year overall survival rates were 81.5 and 78.3%, whereas the transplant-free survival rates were 78.0% and 74.3%, respectively. Increasing age, cirrhosis and being treatment-naïve were associated with lower transplant-free survival.Conclusions:There is a considerable increase in the incidence and prevalence of PBC in the Chinese population over the past 16 years, with significant morbidity and mortality.

Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria

Simplified criteria for diagnosis of autoimmune hepatitis are based on autoantibodies, serum immunoglobulin G, histologic features, and negative viral serology. A score of 6 points is necessary for the designation of probable autoimmune hepatitis and 7 points or more for definite autoimmune hepatitis. The presence of three histologic features is required for categorizing a case as typical (2 points): interface hepatitis with portal lymphocytic/lymphoplasmacytic cells extending into lobule, emperipolesis, and rosettes. In the absence of all three features, a chronic hepatitis picture is considered compatible with autoimmune hepatitis (1 point). This study examines the validity of these histologic features for the diagnosis of autoimmune hepatitis. Clinical data and liver biopsies were reviewed for 88 autoimmune hepatitis, 20 primary biliary cholangitis, and 13 non-autoimmune acute hepatitis cases. Interface/lobular activity, number of plasma cells, copper/CK7 stains, and presence/absence of biliary features were assessed in autoimmune hepatitis and primary biliary cholangitis cases. The simplified criteria score was calculated. Modified histologic criteria were formulated on the basis of interface/lobular activity, number of plasma cells, and presence/absence of biliary features. Using the proposed histologic features, histologic score of 2 increased from 8 to 77%, while total simplified score of >6 increased from 69 to 86%. There was no increase in total simplified score for primary biliary cholangitis or non-autoimmune acute hepatitis. Rosettes and emperipolesis are difficult to interpret, and lack sensitivity and sensitivity for autoimmune hepatitis diagnosis. The current histologic criteria used in the current simplified score lead to underscoring of autoimmune hepatitis cases. The modified histologic criteria based on the inflammatory activity, extent of plasma cells, and results of copper/CK7 staining increased the histologic score in autoimmune hepatitis and led to a probable/definite diagnosis of autoimmune hepatitis in 17% of cases that would have otherwise been classified as non- autoimmune hepatitis by simplified score.

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

Primary Biliary Cholangitis in a Teenage Boy

Introduction: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease (AILD) that predominantly affects women (female-to-male ratios ranging from 9:1 to 22:1) in their 50's or 60's. Unlike other AILDs, PBC has rarely been reported in childhood. Based on literature review, there have been only 3 documented cases of pediatric-onset PBC, diagnosed in 3 girls at the age of 12, 15 and 16 years old respectively. To date, the occurrence of PBC in male children has not been reported. Case report: A 16 year-old boy was referred to our Centre in 2013 for abnormal liver function tests. He was asymptomatic and his liver enzyme levels at that time were as follows: total bilirubin, 0.70 mg/dL (normal, < 1.2); γ-glutamyltransferase (γ-GT), 640 U/L (normal, 10-49 U/L); serum aspartate aminotransferase (AST), 70 U/L (normal, 10-37 U/L); and serum alanine aminotransferase (ALT), 154 U/L (normal, 10-37 U/L). Abdominal ultrasound showed no abnormalities. Antimitochondrial antibody (AMA) was positive; serum quantitative immunoglobulins (Ig) showed IgM to be 308 mg/dL (normal, < 300 mg/dL), IgG and IgA were both normal. Antinuclear antibody, smooth muscle antibody, and liver/kidney microsomal antibody were all negative. Serum α1-antitrypsin, copper, and ceruloplasmin levels were normal. Serology for hepatitis A, B, and C was negative. Magnetic Resonance Cholangiopancreatography was normal. A liver biopsy specimen showed stage I PBC. The boy was then started on ursodeoxycholic acid 15 mg/Kg/day. Although asymptomatic and despite therapy, one year later liver enzyme levels showed no improvement (total bilirubin, 0.84 mg/dL; γ-GT, 467 U/L; AST, 78 U/L and, ALT, 172 U/L). In 2015, at the age of 18, he was transitioned to the Hepatology clinic, and by that time he had developed severe pruritus, for which he was started on cholestyramine. Liver enzymes at this point showed biochemical worsening: total bilirubin, 2.99 mg/dL; γ-GT, 849 U/L; ALP, 518 U/L; AST, 165 U/L and, ALT, 296 U/L. Liver biopsy was repeated and showed progression to stage II PBC. Discussion: We present the first biopsy proven AMA-positive PBC in a teenage boy. Three year follow-up showed biochemical and histological progression despite therapy. By raising awareness of pediatric-onset PBC, further cases may be diagnosed.

Primary biliary cholangitis in China.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by immunomediated destruction of small and medium-sized intrahepatic bile ducts. In 1987, a cDNA for a 74 kDa mitochondrial autoantigen was cloned and identified as the E2 component of the mitochondrial pyruvate dehydrogenase complex, which improved the diagnosis and changed research directions in this field. In 1958, the first Chinese case of PBC was reported. But until 1990, a comprehensive description of the characteristics of Chinese PBC patients was published. In China we now know that PBC is not rare and usually does not progress to cirrhosis. The number of Chinese patients with PBC has increased each and every year. This increase may be associated with the changes of liver disease spectrum, the application of convenient autoantibody detection kits, and the comprehensive understanding of the disease. It may also reflect, however, a westernization change in environmental features with China. There is now significant and important basic and clinical research on PBC in China, with major contributions in diagnostic criteria, treatment, and on basic biology. This has led to exciting proposals based on Chinese PBC cohorts. Chinese hepatologists and scientists are now focusing their efforts on PBC. These efforts have led to new diagnostic biomarkers, novel therapeutic methods (stem cells and Chinese traditional medicine), and unique immunological mechanisms, including roles for T-follicular helper cells and monocyte subpopulations, both of which are involved in the breach of immune tolerance for PBC.