Incidence Of Primary Biliary Cholangitis Research Articles

Incidence and prevalence of primary biliary cholangitis in the Netherlands – A nationwide cohort study

Background & AimsAlthough primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nation-wide Dutch PBC Cohort Study (DPCS). MethodsDPCS included retrospectively every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. ResultsOn January 1st 2008, there were 1458 patients with PBC in the Netherlands. Between 2008-2018, 2187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, and increased to 1.74 per 100.000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted Incidence Rate Ratio [aIRR] 4.21, 95%CI 3.76-4.71, p<0.001) and males ≥65 years (aIRR 14.41, 95%CI 9.62-21.60, p<0.001) had the highest risk to be diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100.000 persons in 2018. Average annual percent change (AAPC) in this time period was 5.94% (95%CI 5.77-6.15, p<0.05), and was the highest among the population ≥65 years (5.69%, 95%CI 5.32-6.36, p<0.001). ConclusionsIn this nationwide cohort study, we observed an increase in both incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences. Impact And ImplicationsThis nationwide Dutch PBC cohort study, including all hospitals in the Netherlands, showed that the PBC incidence and prevalence has increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population ≥65 years, which may have implications for the use of second line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population.

Liver and celiac disease. Review

Celiac hepatitis is a gluten‑dependent liver disease that usually eliminates after 12 months of a strict gluten‑free diet. What is important is that liver histology also improves after a gluten‑free diet. Hypertransaminasemia (in 13—60% of cases) is common at the untreated celiac disease (CD). Conversely, CD presents in 9% of patients with unexplained hypertransaminasemia. Patients with CD have a higher risk of both subsequent liver disease and death caused by cirrhosis compared to the general population. Pathogenetic mechanisms underlying CD, have not been sufficiently studied. The permeability of the intestinal mucosa appears to be considerably higher in patients with CD and hypertransaminasemia than in patients with CD and normal liver tests. The normalization of intestinal permeability and transaminase levels after following a gluten‑free diet demonstrates that this phenomenon is gluten‑dependent. It has been suggested that increased intestinal permeability promotes the admission of toxins, microbial and other antigens, cytokines, and/or other mediators of liver damage into the portal circulation (and hence to the liver). However, liver damage is not usually observed in other intestinal pathologies associated with increased intestinal permeability. A liver biopsy is rarely performed in celiac hepatitis. Mild and/or non‑specific histological changes are observed. Severe liver fibrosis and cirrhosis occur rarely.&#x0D; Primary biliary cholangitis and autoimmune hepatitis may be associated with CD. The incidence of CD in patients with primary biliary cholangitis is 1—7%, while the incidence of primary biliary cholangitis in patients with CD is 0.1—3%. CD is revealed in 4—6% of patients with autoimmune hepatitis, both type 1 and type 2. Cases of primary sclerosing cholangitis combined with CD have been reported, too.&#x0D; No correlation has been found between CD and chronic hepatitis C. Treatment of hepatitis C with interferon‑a and/or ribavirin may activate occult or latent CD. The incidence of CD in patients with non‑alcoholic fatty liver disease ranges from 3% to 7%.&#x0D; The prevalence of CD in patients after liver transplantation for a variety of reasons ranges from 3% to 4.3%.&#x0D; Liver‑caused mortality is increased in patients with CD, although the absolute risk of mortality from liver failure is low.

Understanding immune mechanisms to create novel treatments for primary biliary cholangitis

Understanding immune mechanisms to create novel treatments for primary biliary cholangitis Professor Channakeshava S Umeshappa from Dalhousie University discusses the burden of primary biliary cholangitis and how understanding immune mechanisms may help to treat it. Primary biliary cholangitis (PBC) is characterised by chronic inflammation of the interlobular bile ducts, leading to fibrosis, cirrhosis, and liver failure if left untreated. Symptoms of PBC include fatigue, jaundice, itchy skin, abdominal pain, nausea or vomiting, dry eyes and mouth, and bone and joint aches. The incidence of PBC is increasing worldwide,(1) but is most common in Europe and North America.(2) PBC has a female predominance, affecting primarily middle-aged women (over 90% of the PBC cases). Clinically, it is often diagnosed by detecting anti-mitochondrial autoantibodies and elevated alkaline phosphatase enzymes in blood tests.

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two-sample Mendelian randomization study.

Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear. The genetic associations with IBD were obtained from publicly available genome-wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two-sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse-variance-weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220-1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057-1.430) and CD (IVW OR = 1.269; 95% CI: 1.159-1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984-1.164). Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management.

Clinical significance of serum antinuclear antibodies in patients with autoimmune hepatitis and comorbidity.

Autoimmune hepatitis (AIH) is often complicated with immune diseases, which greatly affected the course and clinical outcome of AIH. We aimed to systematically assess clinical characteristics, prognosis in autoimmune hepatitis accompanied by immune diseases. Clinical records of 358 patients with AIH from Beijing Ditan Hospital in China were retrospectively reviewed. The clinical features of AIH with immune diseases were compared retrospectively, including clinical characteristics, prognosis and outcome. Prevalence of immune diseases in patients with AIH was 26.5%. Connective tissue disease (CTD) was the commonest immune diseases associated with AIH (33/358, 9.2%), and the incidence of primary biliary cholangitis (PBC) and thyroid dysfunction (TD) was low (4.7% and 8.5%, respectively). At diagnosis, AIH-PBC patients had higher IgM and ALP, lower weight, Hgb, ALT and AFP (P < 0.05). Meanwhile, AIH-CTD patients had lower mean platelet volume, serum K and triglyceride (P < 0.05). AIH-TD patients had a lower proportion of ANA positive (P < 0.05). The overall survival time of AIH-TD was significantly shorter than AIH patients (P = 0.0011), but there were no differences in AIH-PBC and AIH-CTD. Furthermore, ANA negative (HR: 0.21, 95%CI 0.13-0.35, P < 0.001) can be a factor to predict the poor prognosis of AIH, and also in AIH-TD patients. About 26.5% of AIH patients had at least one immune disease, and TD coexisted with AIH impaired patients' survival. ANA negative can be used as an independent indicator to predict the poor prognosis of AIH and AIH-TD.

Epidemiological trends and outcomes of primary biliary cholangitis in South Korea between 2009 and 2019.

There are no longitudinal studies on the epidemiology of primary biliary cholangitis (PBC) in Korea. This study aimed to elucidate the temporal trends in the epidemiology and outcomes of PBC in South Korea between 2009 and 2019. The epidemiology and outcomes of PBC were estimated using data from the Korean National Health Service database. Temporal trends in the PBC incidence and prevalence were analyzed using join-point regression. Transplant-free survival was analyzed according to age, sex, and ursodeoxycholic acid (UDCA) treatment using Kaplan-Meier and Cox regression analyses. The age and sex-standardized incidence between 2010 and 2019 (total patients, 4230) was 1.03 per 100,000 per year on average and increased from 0.71 to 1.14 per 100,000 with an annual percent change (APC) of 5.5. The age and sex-standardized prevalence between 2009 and 2019 was 8.21 per 100,000 on average and increased from 4.30 to 12.32 per 100,000 with an APC of 10.9. The increasing trend in prevalence was prominent in males and elderly individuals. Among patients with PBC, 98.2% received UDCA with 77.3% adherence. The 5-year transplant-free overall survival rate was 87.8%. Male sex and low adherence to UDCA were associated with all-cause death or transplantation (hazard ratios of 1.59 and 1.89, respectively), and liver-related death or transplantation (hazard ratios of 1.43 and 1.87, respectively). The incidence and prevalence of PBC in Korea increased significantly between 2009 and 2019. Male sex and low adherence to UDCA were poor prognostic factors for PBC.

Characteristic geoepidemiology of primary biliary cholangitis in Taiwan: A nationwide population-based study.

Data on the geoepidemiology and outcomes of primary biliary cholangitis (PBC) in Asia are limited; thus, we aimed to collect and assess this information for Taiwan. A nationwide population-based cohort study was undertaken using data from the Taiwan National Health Insurance Research Database. Primary biliary cholangitis was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification code 571.6 based on alkaline phosphatase and antimitochondrial antibody measurements and ursodeoxycholic acid treatment. During 2002-2015, 2737 patients (2137 female patients; mean age, 57.78years) had PBC. The average annual age- and sex-adjusted prevalence and incidence rates of PBC were 8.092/105 and 1.148/105 , respectively. Prevalent cases peaked in patients aged 50-59years; the female-to-male ratio was 4.21. Annual prevalence rates increased with time (average percentage change, 12.03%; p<0.0001). The annual incidence rates decreased with time (-7.39%; p=0.000011) in female patients (-8.94%; p=0.000003) but remained steady in male patients. Female-to-male and northern-to-southern relative risks of PBC incidence rates ranged from 2.2675 to 4.3318 and from 1.5707 to 3.1725, respectively. The 14-year hepatocellular carcinoma (HCC) cumulative incidence was 9.11%, and the mortality rate was 32.44%; the cumulative incidences of dyslipidemia, thyroid disease, and extrahepatic cancers were 65.13%, 24.40%, and 12.79%, respectively. Higher cumulative incidences of HCC (p=0.0064) and mortality (p<0.0001) were noted in male than female PBC patients; southern Taiwan PBC patients had higher cumulative incidences of mortality (p<0.0001) than their northern counterparts. In Taiwan, decreasing trends in incidence rates and the female-to-male ratio of PBC patients and specific sex and geographic impacts on the incidence rates and outcomes of PBC demand further investigation.

Ursodeoxycholic Acid Decreases Incidence of Primary Biliary Cholangitis and Biliary Complications After Liver Transplantation.

Content available: Audio Recording.

Ursodeoxycholic Acid Decreases Incidence of Primary Biliary Cholangitis and Biliary Complications After Liver Transplantation: A Meta-Analysis.

After liver transplantation (LT), the role of ursodeoxycholic acid (UDCA) is not well characterized. We examine the effect of UDCA after LT in the prophylaxis of biliary complications (BCs) in all-comers for LT and the prevention of recurrent primary biliary cholangitis (rPBC) in patients transplanted for PBC. Two authors searched PubMed/MEDLINE and Embase from January 1990 through December 2018 to identify all studies that evaluate the effectiveness of UDCA prophylaxis after LT for BCs in all LT recipients and rPBC after LT in patients transplanted for PBC. Odds ratios (ORs) were calculated for endpoints of the BC study. Pooled recurrence rates were calculated for rPBC. The study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. A total of 15 studies were included, comprising 530 patients in the analysis for BCs and 1727 patients in the analysis for rPBC. UDCA was associated with decreased odds of BCs (OR, 0.70; 95% confidence interval [CI], 0.52-0.93; P=0.01) and biliary stones and sludge (OR, 0.49; 95% CI, 0.24-0.77; P=0.004). Prophylactic use of UDCA did not affect the odds of biliary stricture. For patients transplanted for PBC, the rate of rPBC was lower with the prophylactic use of UDCA (IR 16.7%; 95% CI, 0.114%-22.0%; I2 = 36.1%) compared with not using prophylactic UDCA (IR 23.1%; 95% CI, 16.9%-29.3%; I2 = 86.7%). UDCA after LT reduces the odds of BC and bile stones and sludge in all-comer LT recipients and reduces or delays the incidence of rPBC in patients transplanted for PBC. UDCA use after LT could be considered in all LT recipients to reduce the odds of BC and may be particularly beneficial for patients transplanted for PBC by reducing the incidence of rPBC.

Primary biliary cholangitis

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an organ-specific autoimmune disease predominantly affecting middle-aged women. It does not occur in children. PBC prevalence varies depending on the geographic location of the country. Over the past 30 years, there has been an increased incidence of PBC, while significant progress has been made in understanding the pathogenesis of PBC due to the development of innovative technologies in molecular biology, immunology and genetics. The presence of antimitochondrial antibodies and cholestasis on biochemical analysis is sufficient to make a diagnosis, without the need for liver biopsy. Small- and medium-sized bile ducts are the targets of PBC. In the first stage of the disease, granulomatous destruction of the bile ducts occurs; in the second stage, loss of bile ducts, their proliferation, increased size of the portal tracts with chronic inflammation; in the third stage - fibrosis with septal formation, loss of bile ducts and cholestasis; in the fourth stage - liver cirrhosis. Previously, the survival rate of PBC patients ranged from 7.5 to 16 years. However, it has improved significantly with ursodeoxycholic acid and obeticholic acid treatment. If there is no effect from treatment and end-stage liver failure sets in, liver transplantation is performed.

The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude

Background & AimsThe epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases’ rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude.MethodsWe performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees.ResultsThe cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79–2.60) to 4.86 (95% CI, 3.93–6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65–2.43) to 3.28 (95% CI, 2.53–4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60–1.11) to 1.02 (95% CI, 0.64–1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude.ConclusionsWe describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.

Regional variation and temporal trend of primary biliary cholangitis epidemiology: A systematic review and meta-analysis.

We aimed to estimate the worldwide incidence and prevalence, with focus on the geographical differences and temporal trends. Studies on epidemiology of primary biliary cholangitis (PBC) in PubMed, Embase, and Cochrane Library were systematically retrieved from inception to October 2, 2020. Random-effect model was applied to estimate the pooled PBC incidence and prevalence rates. Subgroup analysis, meta-regression, and sensitivity analysis were conducted to find out the cause for heterogeneity. Out of 3974 records identified through database searching, 47 population-based studies were finally included. The pooled global incidence and prevalence of PBC were 1.76 and 14.60 per 100000 persons, respectively. Both the PBC incidence and prevalence were lower in the Asia-Pacific region (0.84, 9.82 per 100000 persons) than that in North America (2.75, 21.81 per 100000 persons) and Europe (1.86, 14.59 per 100000 persons) (P<0.05). The incidence and prevalence showed an increasing tendency in all three regions, with the fastest growth of prevalence in North America (P<0.05). We found a similar incidence and a lower prevalence of PBC in Northern Europe than that in Southern Europe. A higher incidence and prevalence were observed in female individuals and in the elderly (60-79). The PBC incidence and prevalence varied widely across regions, with North America being the highest, followed by Europe, and the lowest in the Asia-Pacific region. Both the incidence and prevalence showed an increasing tendency worldwide, especially in North America.

Clinical, Molecular, and Histopathological Aspect of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune liver disease which tends to be chronic and progressive in nature that is marked by the presence of cholangitis and small size biliary duct destruction which may cause cirrhosis or even liver failure. PBC incidence increases because PBC can now be diagnosed earlier and is due to the increasing survival rate of PBC patients. Diagnosis of PBC can be confirmed in asymptomatic state if in the indirect immunofluorescence (IIF) examination revealed AMA positive, and there is an abnormal liver function. Etiopathogenesis of PBC is multifactorial which involves genetic and environmental factors. Genetic factors which contribute to the incidence of PBC are HLA and non-HLA genes, while in the environmental factors, the triggering factors of PBC are bacterial infection and xenobiotic. Interaction of these factors causes the development of E2 subunit pyruvate dehydrogenase complex (PDC-E2) and antimitochondrial antibody (AMA) as the causing autoantigen of biliary duct desctruction in PBC, mediated by the immune system. PBC stage is divided into minimal, mild, moderate and severe. Ursodeoxycholic acid (UDCA) is the first line therapy for PBC, while obeticholic acid (OCA) and fibrate is used as the second line. Liver transplantation is the definitive therapy for PBC where disease progresses into the advanced stage, although the patients have received medical treatment.

Epidemiology and clinical course of primary biliary cholangitis in Eastern Slovakia.

To determine both the incidence and the prevalence of primary biliary cholangitis (PBC) in Eastern Slovakia and to describe its clinical course and the response to ursodeoxycholic acid (UDCA). We recorded data of patients with PBC, who were followed up in gastroenterology and hepatology centers in Eastern Slovakia during the period from June 30, 1999, through June 30, 2019. The annual incidence of PBC varied from 0.7 to 1.5 cases per 100,000 inhabitants between 2014 and 2018. PBC prevalence steadily increased from initial 10.2 cases per 100,000 inhabitants in 2014 to 14.9 cases per 100,000 inhabitants in June 2019. The mean age at the time of diagnosis was 56.3 ± 10.9years. 95.7% of patients were females, and female/male gender ratio was 22.3:1. In June 2019, prevalence in the female population was 28 cases per 100,000 women. At the time of diagnosis, three-quarters of patients were symptomatic and 10% of patients had liver cirrhosis. The mean follow-up was 7.3 ± 5.2years. Response to UDCA was observed in 72.1% of patients. Patients with higher baseline alkaline phosphatase (ALP) levels, liver cirrhosis at entry or at the end of follow-up and women younger than 45years responded worse to UDCA. One-quarter of patients had liver cirrhosis at the end of follow-up. During follow-up, 1.6% of patients underwent liver transplantation and 5.5% of patients died. Five-year and 10-year liver-related mortalities were 2.7% and 4.3%, respectively. PBC prevalence in Eastern Slovakia is increasing, and most of the patients respond to therapy with UDCA.

Epidemiological and clinical features of primary biliary cholangitis in two Croatian regions: a retrospective study

AimTo assess the measures of disease frequency and determine the clinical features of primary biliary cholangitis (PBC) in two Croatian regions.MethodsDatabases of two tertiary hospitals, one located in the continental and one in the coastal region of Croatia, were retrospectively searched for PBC patients diagnosed from 2007 to 2018. Epidemiologic data analysis was restricted to patients from each hospital’s catchment area. We analyzed factors related to response to therapy and event-free survival (EFS), defined as absence of ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma, liver transplantation (LT), or death. In addition, we determined clinical and demographic data of transplanted PBC patients.ResultsOut of 83 PBC patients, 86.7% were female, with a median age at diagnosis of 55 years. Average PBC incidence for the 11-year period was 0.79 and 0.89 per 100 000 population, whereas the point prevalence on December 31, 2017 was 11.5 and 12.5 in the continental and coastal region, respectively. Of 76 patients with complete medical records, 21% had an advanced disease stage, 31.6% had an associated autoimmune condition, and all received ursodeoxycholic acid. EFS rate at 5 years was 95.8%. In an age and sex-adjusted multivariate Cox regression model, the only factor significantly associated with inferior EFS was no response to therapy (HR = 18.4; P = 0.018). Of all Croatian patients who underwent LT, 3.8% had PBC, with the survival rate at 5 years after LT of 93.4%.ConclusionThis study gives pioneer insights into the epidemiological and clinical data on PBC in Croatia, thus complementing the PBC map of Southeast Europe.

Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis.

Epidemiological studies on primary biliary cholangitis (PBC) show heterogeneity. The aim of the present study was to synthesize the prevalence, incidence and clinical course of PBC in the Asia-Pacific region. PubMed, Medline, Cochrane library and EMBASE were searched for epidemiology and clinical course of PBC published up to July, 2019. Meta-analysis was conducted on the epidemiology and clinical course (decompensation, hepatocellular carcinoma and death/liver transplantation) of PBC patients. Random-effect model and fixed-effect model were used to evaluate the pooled prevalence, incidence, mortality/liver transplantation and their 95% confidence intervals as appropriate. Subgroup analysis was performed by stratification with gender, pre- and post-UDCA era, sub-region and publication year. Meta-regression was used to examine the heterogeneity. Out of 3460 studies, 18 studies from 7 countries/regions were finally included. The overall prevalence of PBC was 118.75 cases per million (95% CI 49.96-187.55) in the Asia-Pacific region, with the high, medium and low prevalence being in Japan and China (191.18 cases per million), New Zealand (99.16 cases per million) and South Korea and Australia (39.09 cases per million), respectively. The incidence of PBC was 8.55 cases per million per year (95% CI 8.05-9.06). The 5-year accumulative incidence of decompensation, HCC and death/liver transplantation in PBC patients was 6.95% (95% CI 2.07-11.83%), 1.54% (95% CI 0.9-2.19%) and 4.02% (95% CI 2.49-5.54%), respectively. In the Asia-Pacific region, the prevalence and incidence of PBC are higher than once expected. PBC tends to be diagnosed at older age and has a relatively low incidence of HCC in this region.

Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis

Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.