Endocrine Autoimmune Disease as a Fragility of Immune Surveillance against Hypersecreting Mutants.

Some endocrine organs are frequent targets of autoimmune attack. Here, we addressed the origin of autoimmune disease from the viewpoint of feedback control. Endocrine tissues maintain mass through feedback loops that balance cell proliferation and removal according to hormone-driven regulatory signals. We hypothesized the existence of a dedicated mechanism that detects and removes mutant cells that missense the signal and therefore hyperproliferate and hypersecrete with potential to disrupt organismal homeostasis. In this mechanism, hypersecreting cells are preferentially eliminated by autoreactive T cells at the cost of a fragility to autoimmune disease. The "autoimmune surveillance of hypersecreting mutants" (ASHM) hypothesis predicts the presence of autoreactive T cells in healthy individuals and the nature of self-antigens as peptides from hormone secretion pathway. It explains why some tissues get prevalent autoimmune disease, whereas others do not and instead show prevalent mutant-expansion disease (e.g., hyperparathyroidism). The ASHM hypothesis is testable, and we discuss experimental follow-up.

Identifying Patients With Primary Biliary Cholangitis and Cirrhosis Using Administrative Data in a National Cohort.

BACKGROUND: The accuracy of administrative codes to capture patients with both primary biliary cholangitis (PBC) and cirrhosis could be challenging because of the potential for incorrect coding due to the old nomenclature "Primary Biliary Cirrhosis." Therefore, the aim of this study was to examine the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for PBC and cirrhosis. METHODS: This was a retrospective cohort study using data from the VA Corporate Data Warehouse. Eligibility criteria included adult patients diagnosed to have PBC and cirrhosis based on one inpatient or two outpatient ICD 9 or 10 codes, and were validated against chart review of each participant. RESULTS: We identified 1408 patients who were found to have ICD codes for both cirrhosis and PBC. The ICD 9/10 codes for PBC and cirrhosis had a PPV of 0.75 (95% CI 0.73-0.75) for cirrhosis, 0.75 for PBC (95% CI 0.73-0.78), and 0.52 (0.50-0.55) for PBC and cirrhosis. When portal hypertension was combined with ICD 9/10 codes, the PPV of cirrhosis improved to 0.92 (0.90-0.94), and that of PBC cirrhosis improved to 0.64 (0.60-0.67). By combining ICD 9/10 codes for portal hypertension and receipt of ursodeoxycholic acid (UDCA), the PPV for cirrhosis improved to 0.91 (0.88-0.94), PBC increased to 0.78 (0.74-0.82), and that for PBC cirrhosis to 0.69 (0.65-0.74). CONCLUSIONS: In a large national cohort, the use of ICD 9/10 codes had modest reliability for identifying participants with PBC and cirrhosis. The PPV for cirrhosis can be improved by incorporating ICD 9/10 codes for portal hypertension with receipt of UDCA.

Autoimmune Liver Diseases and Rheumatoid Arthritis-Is There an Etiopathogenic Link?

Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.

Systemic sclerosis and primary biliary cholangitis share an antibody population with identical specificity.

Anti-centromere (ACA) and antimitochondrial antibodies (AMA) are specific for limited-cutaneous systemic sclerosis (lcSSc) and primary biliary cholangitis (PBC), respectively, and can coexist in up to 25 and 30% of SSc and PBC patients. Here, we evaluated whether anti-centromeric protein A (CENP-A) antibodies cross-react with mitochondrial antigens. To this end, sera from two lcSSc patients (pt1 and pt4), one of them (pt4) also affected by PBC, were used as the source of ACA, previously shown to recognize different groups of amino acids (motifs) in the CENP-A region spanning amino acids 1-17 (Ap1-17). Pt1 and pt4 Ap1-17-specific IgG were purified by affinity-chromatography on insolubilized Ap1-17-peptide column and tested by western blotting with nuclear and cytoplasmic protein extract from HeLa cells. Immunoreactive proteins were identified by mass spectrometry and validated by immunodot. The results showed that affinity-purified SSc/PBC pt4 anti-Ap1-17 and not SSc pt1 anti-Ap1-17 Ab, specifically cross-reacted with the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen in PBC. Sequence homology analysis indicated that the motif A-x-x-P-x-A-P recognized by pt4 anti-Ap1-17 IgG and shared by CENP-A and PDC-E2, is also expressed by some members of the Human Herpesvirus family, suggesting that they may trigger the production of these cross-reacting antibodies.

[Suspected autoimmune coagulation factor IX deficiency difficult to diagnose due to concurrent lupus anticoagulant].

A woman in her 70s who was undergoing treatment for an overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis developed persistent genital bleeding. Coagulation tests revealed a longer activated partial thromboplastin time, a 7% decrease in coagulation factor IX activity (FIX:C) and a FIX inhibitor (of 3 BU/ml). Lupus anticoagulant (LA), anticardiolipin antibody, and anti-ß2 glycoprotein I antibody were positive, and the activated partial thromboplastin time cross-mixing test suggested the presence of LA. Additionally, all intrinsic coagulation factors decreased, but activity of all factors except FIX showed dilution linearity, which suggested a false decrease in activity due to LA. Although definitive diagnosis was difficult due to concurrent LA, this case was strongly suspected to be autoimmune coagulation FIX deficiency complicated by LA. Bypass therapy was not performed because the patient had no anemia and was positive for LA, and immunosuppressive therapy with prednisolone was initiated immediately. Eleven weeks after diagnosis, FIX:C was 41% and zFIX inhibitor was less than 1 BU/ml, leading to remission.

A molecular mechanism of UDCA engagement with GPBAR and subsequent G protein interaction revealed by scattered alanine scanning.

As the most known therapeutic component of bear bile acids, ursodeoxycholic acid (UDCA) is an FDA-approved drug for the treatment of primary biliary cirrhosis (PBC), the dissolution of cholesterol gallstones. UDCA produces many beneficial effects on metabolism and immune responses via its interaction with the membrane G protein-coupled bile acid receptor (GPBAR); however, how UDCA interacts with GPBAR and its selective cellular effects remain elusive. In this study, we delineated the interaction of UDCA with GPBAR and activation mechanism of GPBAR by scattered alanine scanning and molecular docking. Our results indicated that transmembrane helix 2 (TM2), TM3, TM5 and TM6 of GPBAR contribute to the interaction of UDCA in GPBAR binding pocket. Moreover, we predicted that the engagement of the 3-OH of UDCA with phenolic oxygen of Y2406.51 in GPBAR plays a key role in GPBAR activation. Unexpectedly, in addition to the well-known roles of intracellular loop2 (ICL2) residues, we identified that ICL3 residues play an important role in G protein coupling to GPBAR in response to UDCA binding. Our study provides a preliminary molecular mechanism of how GPBAR recognizes UDCA and subsequent activation and G protein interaction, which may facilitate the development of new bile acid derivatives as therapeutics.

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA.

BACKGROUND: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS: Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS: Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS: Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.

Transverse myelitis associated with primary biliary cirrhosis: clinical, laboratory, and neuroradiological features.

PURPOSE: Only five patients diagnosed with transverse myelitis (TM) associated with primary biliary cirrhosis (PBC) have been reported in the literature to date. We report two additional patients with TM associated with PBC at our hospital and review all seven cases. MATERIALS AND METHODS: An association between neuromyelitis optic spectrum disease (NMOSD) and PBC is reported for the first time in one of our patients. The second patient was diagnosed with TM associated with PBC without Sjögren's syndrome (SS). A literature review was performed using the PubMed database. RESULTS: All patients diagnosed with TM associated with PBC were female with a median age of 53 years. TM was associated with SS in 71.4% of the patients. Complete TM and incomplete TM were diagnosed in 71.4% and 28.6% of the patients. The erythrocyte sedimentation rate was increased in 83.3% of patients. All patients were positive for anti-mitochondrial antibodies. Other autoantibodies, including anti-nuclear antibodies, rheumatoid factor, anti-SSA antibody, were detected in some patients. Cerebrospinal fluid analysis was abnormal in 83.3% of patients. The spinal cord lesions involved more than three vertebral segments in 85.7% of patients. Glucocorticoids were administered in 85.7% of patients, and good responses were observed. CONCLUSIONS: The association between TM and PBC may be missed by neurologists. More attention should be paid to the association between NMOSD and PBC. Most patients show SS and may experience relapse, and there is a good rationale for early commencement of immunosuppressive therapy.

Optimal Tuning of Random Survival Forest Hyperparameter with an Application to Liver Disease.

Background: Random Forest (RF) is a technique that optimises predictive accuracy by fitting an ensemble of trees to stabilise model estimates. The RF techniques were adapted into survival analysis to model the survival of patients with liver disease in order to identify biomarkers that are highly influential in patient prognostics. Methods: The methodology of this study begins by applying the classical Cox proportional hazard (Cox-PH) model and three parametric survival models (exponential, Weibull and lognormal) to the published dataset. The study further applied the supervised learning methods of Tuning Random Survival Forest (TRSF) parameters and the conditional inference Forest (Cforest) to optimally predict patient survival probabilities. Results: The efficiency of these models was compared using the Akaike information criteria (AIC) and integrated Brier score (IBS). The results revealed that the Cox-PH model (AIC = 185.7233) outperforms the three classical models. We further analysed these data to observe the functional relationships that exist between the patient survival function and the covariates using TRSF. Conclusion: The IBS result of the TRFS demonstrated satisfactory performance over other methods. Ultimately, it was observed from the TRSF results that some of the covariates contributed positively and negatively to patient survival prognostics.

Recent advances in clinical practice: epidemiology of autoimmune liver diseases.

Autoimmune liver diseases are chronic inflammatory hepatobiliary disorders that when classically defined encompass three distinctive clinical presentations; primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Meaningful changes in disease epidemiology are reported, with increasing incidence and prevalence of AIH and PSC in Europe, and rising prevalence of PBC across Europe, North America and the Asia-Pacific region. However, there appears to be very significant global variation with contemporary incidence rates of disease per 100 000 ranging from 0.84 to 2.75 for PBC, 0.1 to 4.39 for PSC and 0.4 to 2.39 for AIH. Prevalence corresponds, and per 100 000 estimates for PBC range from 1.91 to 40.2, for PSC between 0.78 and 31.7 and for AIH from 4.8 to 42.9. Population-based studies and multicentre observational cohort series provide improved understanding of the clinical course that patients experience, highlighting variations in presenting phenotypes geographically and temporally. Collectively, while autoimmune liver diseases are rare, the clinical burden is disproportionately high relative to population incidence and prevalence. Age, sex and race also impact clinical outcomes, and patient morbidity and mortality are reflected by high need for gastroenterology, hepatology and organ transplant services.

Bile Acid Profiles Are Distinct among Patients with Different Etiologies of Chronic Liver Disease.

A significant increase of bile acid (BA) levels has been recognized as a general metabolic phenotype of diverse liver diseases. Monitoring of BA profiles has been proposed for etiology differentiation on liver injury. Here, we quantitatively profiled serum BAs of healthy controls and 719 patients with chronic liver disease of five etiologies, hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), alcohol-induced liver disease (ALD), and primary biliary cirrhosis (PBC), and investigated the generality and specificity of different etiologies. The raw data have been deposited into MetaboLights (ID: MTBLS2459). We found that patients with HBV, HCV, and NASH appeared to be more similar, and ALD and PBC patients clustered together. BA profiles, consisting of a total concentration of the 21 quantified BAs [total BAs (TBAs)], 21 BA proportions, and 24 BA relevant variables, were highly different among the etiologies. Specifically, the total BAs was higher in ALD and PBC patients compared with the other three groups. The proportion of conjugated deoxycholates was the highest in HBV-infected patients. The ratio of 12α-hydroxylated (12α-OH) to non-12α-OH BAs was the highest in NASH patients. The proportion of taurine-conjugated BAs was the highest in ALD patients. For PBC patients, the proportion of ursodeoxycholate species was the highest, and the ratio of primary to secondary BAs was the lowest. Comparatively, the difference of BA profiles among cirrhosis patients was consistent but weaker than that of all patients. The correlations between BA profiles and clinical indices were also quite different in different pathological groups, both in all patients and in patients with cirrhosis. Overall, our findings suggested that BA compositions are distinct among patients with different etiologies of chronic liver disease, and some BA-relevant variables are of clinical potentials for liver injury type differentiation, although further validations on more etiologies and populations are needed.

Glycan biomarkers of autoimmunity and bile acid-associated alterations of the human glycome: Primary biliary cirrhosis and primary sclerosing cholangitis-specific glycans.

We have recently introduced multiple reaction monitoring (MRM) mass spectrometry as a novel tool for glycan biomarker research and discovery. Herein, we employ this technique to characterize the site-specific glycan alterations associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Glycopeptides associated with disease severity were also identified. Multinomial regression modelling was employed to construct and validate multi-analyte diagnostic models capable of accurately distinguishing PBC, PSC, and healthy controls from one another (AUC = 0.93 ± 0.03). Finally, to investigate how disease-relevant environmental factors can influence glycosylation, we characterized the ability of bile acids known to be differentially expressed in PBC to alter glycosylation. We hypothesize that this could be a mechanism by which altered self-antigens are generated and become targets for immune attack. This work demonstrates the utility of the MRM method to identify diagnostic site-specific glycan classifiers capable of distinguishing even related autoimmune diseases from one another.

The ursodeoxycholic acid response score predicts pathological features in primary biliary cholangitis.

AIM: The ursodeoxycholic acid response score (URS) can predict the biochemical response to 12 months of ursodeoxycholic acid (UDCA) treatment in patients with primary biliary cholangitis (PBC). We investigated the relationship between the URS and the histopathological features before and after UDCA treatment. METHODS: Patients with PBC (n = 126) were examined for the association between the probability of response (POR) to UDCA based on the URS formulas and clinicopathological features. Furthermore, 30 patients were examined for the association between the POR and pathological changes. RESULTS: The POR area under the receiver operating characteristic curve (AUROC) for predicting the biochemical response to UDCA was 0.861. The PORs of stage 1 in the Nakanuma system and grade 0 in the CK7 grading in hepatocytes were significantly higher than those of stage 3 and grade 3, respectively. The AUROCs for the prediction of stage ≥2, stage ≥3 and stage 4 in the Nakanuma system at pretreatment were 0.592, 0.710 and 0.817, respectively. The AUROCs for the prediction of grade ≥1, grade ≥2 and grade 3 in the CK7 hepatocyte grading were 0.741, 0.824 and 0.970, respectively. Furthermore, the AUROC for predicting the histological stage progression after UDCA treatment in the Scheuer classification and the Nakanuma system were 0.712 and 0.799, respectively. CONCLUSIONS: The URS not only predicts the biochemical response, but also reflects the Nakanuma system and the CK7 hepatocyte grading at pretreatment. This scoring system can identify an inadequate histological response to UDCA treatment in the Scheuer classification and the Nakanuma system.

Incidence of Hepatocellular Carcinoma in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

BACKGROUND: The risk and determinants of HCC in patients with primary biliary cholangitis (PBC) are unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and risk factors associated with HCC risk among patients with PBC. METHODS: We searched PubMed, EMBASE, MEDLINE, Cochrane databases and reference lists from relevant articles to identify cohort studies that examined incidence of HCC in patients with PBC from inception through November 2019. RESULTS: A total of 29 studies including 22,615 patients met the eligibility criteria. The median cohort size was 292 patients followed for an average of 76 months. The pooled incidence rate for patients with PBC was 4.17 per 1000 patient-years (95% CI 3.17-5.47). On subgroup analysis, the incidence of HCC in patients with PBC cirrhosis was 15.7 per 1000 patient-years (95% CI 8.73-28.24). The HCC incidence rate was 9.82 per 1000 person-years (95% CI 5.92-16.28) in men and 3.82 per 1000 person-years (95% CI 2.85-5.11) in women. CONCLUSIONS: Cirrhosis is the strongest risk factor for HCC in patients with PBC. Male gender was also a risk factor. Our meta-analysis supports current recommendations of HCC surveillance in patients with PBC cirrhosis. Further studies are needed to evaluate risk factors in this population.

Manganese and copper levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis.

The liver and the biliary tree form the main excretory route of manganese (Mn) and copper (Cu). Cholestasis, can lead to the accumulation of these trace elements in the organism, resulting in toxicity to the basal ganglia of the central nervous system. The aim of our study was to reveal the influence of long-term cholestasis on the Mn and Cu levels in the blood of patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We recruited patients with PBC (n = 20) and PSC (n = 32). A control group (n = 40) was also set up. We also examined serum bile acid concentrations and liver enzyme activities. We did not observe any significant differences in any of these parameters between the PBC and PSC groups. The Mn and Cu levels in the PBC and PSC patients differed significantly from the that in the control group (p < 0.0001 and p < .021, respectively). Patients in whom the laboratory cholestasis markers normalized during ursodeoxycholic acid treatment (18/52;35%) presented with significantly lower levels of Mn and Cu (p = .015 and p = .012, respectively). Ten PSC patients showed normal levels of Mn and Cu six months after liver transplantation. Fine tremors, rigidity, dysarthria, and hypomimia were reported in nine (23%), eight (20%), four (10%), and eight (20%) patients, respectively. In addition to monitoring the cholestasis levels, liver function, and Mn and Cu levels during the long-term treatment of PBC and PSC patients, it is important to also regularly monitor the occurrence and development of extrapyramidal symptoms of Parkinson's-like syndromes.

[Sjogren's disease/syndrome in combination with autoimmune liver damage. 20-years observation]. / Bolezn'/sindrom Shegrena v sochetanii s autoimmunnym porazheniem pecheni. 20-letnee nablyudenie.

Sjogren's disease (BS) is a systemic autoimmune disease, the main symptoms of which are associated with dry eyes, mouth, skin, respiratory and gastrointestinal tract, etc., but there are a large number of extra-vascular symptoms that can accompany this disease: weakness, swelling of the lymph nodes, respiratory failure, pain and swelling of the joints, rash, dysphagia, gastro-esophageal reflux, lymphoma, etc. In addition, the etiology of this disease remains unknown, and the pathogenesis is partially studied. The diagnosis of Sjogren's disease is complicated by a variety of clinical manifestations, as well as subacute and chronic variants of the course of the disease, in addition, the diagnostic criteria are periodically changed. It is recommended to adhere to the domestic diagnostic criteria considering the presence of laboratory signs of an autoimmune disease. The article presents a clinical observation of a patient with the development of the main symptoms and signs of BS and autoimmune hepatitis for 20 years. Recurrent mumps or chronic bilateral enlargement of the parotid salivary glands may be the first symptom of Sjogren's disease, which is recommended to extend the examination in order to identify other, sometimes latent signs of the disease.

TGF-ß2 silencing to target biliary-derived liver diseases.

OBJECTIVE: TGF-ß2 (TGF-ß, transforming growth factor beta), the less-investigated sibling of TGF-ß1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-ß2 in biliary-derived liver diseases. DESIGN: As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-ß2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels. RESULTS: TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue. CONCLUSIONS: Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-ß2 silencing and provide a direct rationale for TGF-ß2-directed drug development.

Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis.

OBJECTIVE: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. METHODS: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. RESULTS: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. CONCLUSION: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance.

Replication study and meta-analysis indicate a suggestive association of RUNX3 locus with primary biliary cholangitis.

Susceptibility to primary biliary cholangitis (PBC) is in part genetically determined. In our previous PBC genome-wide association study (GWAS) in 1118 Han Chinese PBC and 4036 controls, we noted that multiple SNPs in the runt-related transcription factor 3 (RUNX3) regions showed a nominally significant association. The tag SNP rs7529070 was genotyped using a TaqMan assay in a separately collected 1435 PBC and 3205 controls. A meta-analysis with a combined 2553 PBC and 7241 controls showed that rs7529070 is still nominally associated with PBC (p = 1.7 × 10-4, odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08-1.28). Further analysis indicated that the risk allele of rs7529070 (G allele) is in complete linkage disequilibrium (LD) (r2 = 1) with the G allele of rs4648889, which is known to be associated with increased RUNX3 expression. Bioinformatic analysis with existing expression data showed that the expression of RUNX3 is significantly increased in PBC patients (p = 0.001) and the expression level is correlated with disease severity. Consistently, we also found significantly increased RUNX3 expression (p < 0.01) in the livers of dnTGFßRII mice (a PBC mouse model). This study suggests that the RUNX3 locus may associate with PBC in Han Chinese.

Increasing prevalence of primary biliary cholangitis in Victoria, Australia.

BACKGROUND AND AIM: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. METHODS: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. RESULTS: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). CONCLUSIONS: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.