Treatment response and clinical event-free survival in autoimmune hepatitis: A Canadian multicentre cohort study.

BACKGROUND & AIMS: Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH. METHODS: We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. RESULTS: In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. CONCLUSION: In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. IMPACT AND IMPLICATIONS: Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects.

Algebraic topology-based machine learning using MRI predicts outcomes in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can lead to cirrhosis and hepatic decompensation. However, predicting future outcomes in patients with PSC is challenging. Our aim was to extract magnetic resonance imaging (MRI) features that predict the development of hepatic decompensation by applying algebraic topology-based machine learning (ML). METHODS: We conducted a retrospective multicenter study among adults with large duct PSC who underwent MRI. A topological data analysis-inspired nonlinear framework was used to predict the risk of hepatic decompensation, which was motivated by algebraic topology theory-based ML. The topological representations (persistence images) were employed as input for classification to predict who developed early hepatic decompensation within one year after their baseline MRI. RESULTS: We reviewed 590 patients; 298 were excluded due to poor image quality or inadequate liver coverage, leaving 292 potentially eligible subjects, of which 169 subjects were included in the study. We trained our model using contrast-enhanced delayed phase T1-weighted images on a single center derivation cohort consisting of 54 patients (hepatic decompensation, n = 21; no hepatic decompensation, n = 33) and a multicenter independent validation cohort of 115 individuals (hepatic decompensation, n = 31; no hepatic decompensation, n = 84). When our model was applied in the independent validation cohort, it remained predictive of early hepatic decompensation (area under the receiver operating characteristic curve = 0.84). CONCLUSIONS: Algebraic topology-based ML is a methodological approach that can predict outcomes in patients with PSC and has the potential for application in other chronic liver diseases.

Ethnicity, disease severity, and survival in Canadian patients with primary biliary cholangitis.

BACKGROUND AND AIMS: We investigated associations between ethnicity, survival, and disease severity in a diverse Canadian cohort of patients with primary biliary cholangitis (PBC). APPROACH AND RESULTS: Patients with PBC were included from the Canadian Network for Autoimmune Liver Disease. Ethnicity was defined using a modified list adopted from Statistics Canada, and ethnicities with small samples were grouped. Clinical events were defined as liver decompensation, HCC, liver transplantation, or death. Clinical event-free and liver transplantation-free survival were analyzed using Cox regression. Trajectories of serum liver function tests were assessed over time using mixed-effects regression. Health-related quality of life was assessed using the Short Form 36, the PBC-40 questionnaire, and the 5-D Itch scale and analyzed using mixed-effects regression. The cohort included 1538 patients with PBC from six sites and was comprised of 82% White, 4.7% Indigenous, 5.5% East Asian, 2.6% South Asian, and 5.1% miscellaneous ethnicities. Indigenous patients were the only ethnic group with impaired liver transplant-free and event-free survival compared to White patients (HR, 3.66; 95% CI, 2.23-6.01; HR, 3.09; 95% CI, 1.94-4.92). Indigenous patients were more likely to have a clinical event before diagnosis (10%) than all other ethnic groups despite similar age at diagnosis. Indigenous patients presented with higher alkaline phosphatase, total bilirubin, and GLOBE scores than White patients; and these relative elevations persisted during follow-up. CONCLUSIONS: Indigenous Canadians with PBC present with advanced disease and have worse long-term outcomes compared to White patients.

Real-World Effectiveness of Obeticholic Acid in Patients with Primary Biliary Cholangitis.

Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real-world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA-naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow-up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated-measures models were used to assess changes in biochemistry over time. Sixty-four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 109/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L (P < 0.001), GGT of 138 U/L (P < 0.001), ALT of 11.9 U/L (P < 0.001), AST of 5.7 U/L (P < 0.05), and IgM of 0.70 g/L (P < 0.001) over 12 months; TB remained stable (P = 0.98). Forty-four patients met POISE-inclusion criteria, 39% (n = 17) of whom had 12-month biochemical measurements. In this subset, 18% (n = 3/17) met the 12-month POISE primary endpoint, but considering follow-up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. Conclusion: Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real-world setting.

Risk of gallbladder cancer in patients with primary sclerosing cholangitis and radiographically detected gallbladder polyps.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC. METHODS: A retrospective cohort study of patients followed in secondary and tertiary care settings in two large PSC clinics in North America was performed. RESULTS: In total, 453 patients were included with a median (IQR) follow-up time of 7.7 (4.1-12) years. A gallbladder polyp was radiographically detected in 16% (n = 71) with median size (range) of 4 (2-18) mm. In this group, post-cholecystectomy histology (n = 17) reported benign or no polyp in 77% (n = 13), dysplasia in 5.9% (n = 1) and malignancy in 18% (n = 3). The GBC rate was 8.8 (95% CI 1.8-25.7) per 1000 person-years in patients with a radiographically detected gallbladder polyp. GBC was associated with polyps >10 mm, interval growth or mass-like lesions on pre-operative imaging. In patients who did not have cholecystectomy (n = 50), the polyp was only transiently seen in 80% (n = 40), remained stable or decreased in size in 10% (n = 5) and increased in size in 6% (n = 3). The majority of gallbladder polyps did not show significant growth over time (0.041 mm/year [95% CI -0.017 to 0.249]). CONCLUSIONS: Most gallbladder polyps in patients with PSC are benign. Short-term surveillance imaging may be considered prior to recommending immediate cholecystectomy in patients with PSC without high-risk imaging features.

Primary biliary cholangitis: pathogenesis and therapeutic opportunities.

Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis. Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.

A Practical Review of Primary Biliary Cholangitis for the Gastroenterologist.

Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by biliary destruction and progressive intrahepatic cholestasis. PBC primarily affects women in their fifth or sixth decade of life. Although many patients are asymptomatic at presentation, fatigue, pruritus, sicca syndrome, and upper abdominal discomfort are common symptom manifestations. The etiology of PBC is thought to be related to interactions between underlying genetic predisposition and microbial and xenobiotic environmental triggers. The diagnosis is established in the setting of biochemical cholestasis and antimitochondrial or disease-specific antinuclear antibodies, with histologic evidence of nonsuppurative granulomatous cholangitis being supportive, but not required, to confirm disease. Care of patients with PBC encompasses therapies to slow disease progression, manage symptoms associated with cholestasis, and treat complications of advanced liver disease. Risk stratification based on simple clinical and laboratory parameters, either as binary response criteria and/or continuous models, helps identify the patients at greatest risk of poor outcome. First-line therapy to slow disease progression is ursodeoxycholic acid (UDCA), which is the mainstay of pharmacologic therapy for all patients with PBC. The only currently approved second-line option for patients who do not achieve adequate biochemical response or are intolerant to UDCA is the novel farnesoid X receptor agonist obeticholic acid. Off-label use of peroxisome proliferator-activated receptor agonists, including the fibrate class of drugs where available, is also recognized as an option for patients.

Autoimmune hepatitis: Current and future therapeutic options.

Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.

Current Use of Hearts From Hepatitis C Viremic Donors.

BACKGROUND: Strategies to improve donor heart utilization are required in the setting of limited donor availability. One innovative strategy is to consider the use of hepatitis C viremic (HCV) nucleic acid amplification test positive donors in hepatitis C-negative recipients, given the availability of highly effective direct acting antiviral agents. We utilized United Network for Organ Sharing data to evaluate the geographic distribution, clinical characteristics, and post-transplant outcomes of HCV+ donor hearts. METHODS AND RESULTS: The United Network for Organ Sharing registry was queried for all HCV+ recovered donors and those considered for heart donation classified by sex, age group, United Network for Organ Sharing region, and cause of death from January 1, 2014, to December 31, 2017. Propensity score matching (3:1) was applied to the recipients based on the index for mortality prediction after cardiac transplantation score and donor risk index. A total of 1306 HCV+ donors were recovered from 2014 to 2017 of whom 1078 (82.5%) were 18 to 49 and predominantly from the Appalachia region (United Network for Organ Sharing regions 2, 3, and 11). A total of 64 (5%) HCV+ donor hearts were transplanted in this interval. The match-adjusted risk difference in survival was estimated to be 0.87% ( P=0.83) at 12 months. CONCLUSIONS: To meet the demands of heart transplantation, we must consider additional strategies to expand the donor pool. From 2014 to 2017, despite availability of highly effective direct acting antiviral therapy, only 5% of HCV+ donor hearts were accepted for transplantation. National efforts may be required to capitalize on this resource while we continue to carefully monitor the safety of this novel approach.

Pathophysiology of primary biliary cholangitis.

Primary biliary cholangitis is a prototypical autoimmune disease characterized by an overwhelming female predominance, a distinct clinical phenotype, and disease specific anti-mitochondrial antibodies targeted against a well-defined auto-antigen. In a genetically susceptible host, multi-lineage loss of tolerance to the E2 component of the 2-oxo-dehydrogenase pathway and dysregulated immune pathways directed at biliary epithelial cells leads to cholestasis, progressive biliary fibrosis, and cirrhosis in a subset of patients. Several key insights have shed light on the complex pathogenesis of disease. First, characteristic anti-mitochondrial antibodies (AMAs) target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs. Next, breakdown of the protective apical bicarbonate rich umbrella may sensitize BECs to aberrant apoptotic pathways leaving the antigenic PDC-E2 epitope immunologically tact within an apoptotic bleb. A multi-lineage immune response ensues characterized by an imbalance between effector and regulatory activity resulting in progressive and self-perpetuating biliary injury. Genome wide studies shed light on important pathways involved in disease, key among them being IL-12. Epigenetic mechanisms and microRNAs may play help shed light on the missing heritability and female preponderance of disease. Taken together, these findings have dramatically advanced our understanding of disease and may lead to important therapeutic advances.

External validation of the United Kingdom-primary biliary cholangitis risk scores of patients with primary biliary cholangitis treated with ursodeoxycholic acid.

The United Kingdom-Primary Biliary Cholangitis (UK-PBC) risk scores are a set of prognostic models that estimate the risk of end-stage liver disease in patients with PBC at 5-, 10- and 15-year intervals. They have not been externally validated outside the United Kingdom. In this retrospective, external validation study, data were abstracted from outpatient charts and discrimination and calibration of the UK-PBC risk scores were assessed. A total of 464 patients with PBC treated with ursodeoxycholic acid were included. The median diagnosis age was 52.4 years, and 88% were female patients. The cumulative incidence of events was 6%, 9%, and 15% at 5, 10, and 15 years, respectively. Concordance (c-statistic) was 0.88, 0.85, and 0.84 using the 5-, 10- and 15-year risk scores, respectively, which was slightly lower than values observed in the United Kingdom validation cohort. Using the 5-year risk score, more events were observed than predicted (25 versus 16.8; P = 0.046); using the 10-year risk score, there was no difference between the observed and predicted number of events (35 versus 44.9; P = 0.14); conversely, using the 15-year risk score, fewer events were observed than predicted (46 versus 67.5; P = 0.009). Limiting evaluation by the 15-year UK-PBC risk score to those with >10 years of follow-up demonstrated no difference between observed and predicted events. Using the 5-year risk score, patients within the highest quartile had statistically significant worse event-free survival compared to the rest of the cohort: 82% versus 98% at 5 years, 73% versus 97% at 10 years, and 58% versus 93% at 15 years. Conclusion: In patients assessed at a North American tertiary medical center, the UK-PBC risk score had excellent discrimination and was reasonably calibrated both in the short and long term. (Hepatology Communications 2018;2:676-682).

Accepting hepatitis C virus-infected donor hearts for transplantation: Multistep consent, unrealized opportunity, and the Stanford experience.

The current mismatch between supply and demand of organs has prompted transplant clinicians to consider innovative solutions to broaden the donor pool. Advancements of direct-acting antiviral agent (DAA) therapy for hepatitis C virus (HCV) have allowed entertaining the use of viremic donor organs in nonviremic recipients. In this report, we describe the evolution of HCV treatment, ethics and informed consent, cost-effectiveness of HCV medications in treating acute HCV post-transplantation, and the Stanford experience with two HCV-viremic donor heart transplantations. We describe excellent short-term outcomes post-heart transplantation with HCV NAT-positive organs. The availability of this therapy may expand the donor pool. While we await larger-scale clinical data on the effectiveness and safety of DAA therapy in patients after heart transplantation, many transplant centers have already started accepting organs from HCV-infected donors, balancing the unknown long-term risks versus the benefits of shorter wait times and expansion of the donor pool. Protocols and multidisciplinary teams are needed to effectively communicate risk to potential recipients, to ensure timely DAA access, and to implement appropriate clinical follow-up in order to achieve excellent clinical outcomes and to maximize the donor pool by utilizing HCV-infected organs for heart transplantation.

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

Low incidence of primary biliary cirrhosis (PBC) in the first-degree relatives of PBC probands after 8 years of follow-up.

BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is characterized by chronic cholestasis and disease-specific antimitochondrial antibodies (AMA). A high prevalence of AMAs in first-degree relatives (FDRs) of PBC probands has been reported, although the natural history of such patients has not been described. We aimed to assess the risk of developing PBC in AMA+ FDRs of patients with PBC. METHODS: First-degree relatives recruited to the Mayo Clinic PBC Genetic Epidemiology Registry and Biorepository were followed for disease onset after recruitment. Development of PBC was ascertained via self-report during a telephone interview and/or via proband report on a questionnaire. Chi-squared test and t-test were used to assess the differences between categorical and continuous variables respectively. A mixed-effects model was used to assess the change in biochemical profiles over time. RESULTS: Forty AMA+ and 423 AMA- subjects were included and followed for a median of 8.9 and 8.4 years respectively. Overall, 3% (n = 15) of FDRs were diagnosed with PBC, and AMA+ FDRs had a higher risk than AMA- FDRs (24% vs. 0.7%, P < 0.01). However, among undiagnosed FDRs, only 4% of AMA+ (n = 1) and 0.4% of AMA- (n = 1) FDRs were diagnosed with PBC (P = 0.17) during the follow-up period. None of the AMA+ FDRs with normal alkaline phosphatase at baseline developed PBC in follow-up. CONCLUSIONS: Our results suggest a low risk of developing PBC over time in FDRs of patients with PBC, particularly those without biochemical evidence of cholestasis at baseline. These data are useful in counselling and reassuring relatives of their overall favourable prognosis.

Duration of Inflammatory Bowel Disease Is Associated With Increased Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis and IBD.

OBJECTIVES: Primary sclerosing cholangitis (PSC) often coexists with inflammatory bowel disease (IBD) and can be complicated by cholangiocarcinoma (CCA), a lethal malignancy for which reliable predictors remain unknown. We aimed to characterize the influence of colectomy and IBD duration on risk of CCA in patients with PSC-IBD. METHODS: A retrospective review of patients with PSC-IBD seen at the Mayo Clinic, Rochester, between January 2005 and May 2013 was performed. The primary outcome was time to development of CCA and our goal was to determine whether the risk differed between patients with and without colectomy. Risk factors were assessed using univariable and multivariable Cox proportional hazard models where colectomy, IBD disease duration, and development of advanced liver disease were treated as time-dependent covariates. RESULTS: A total of 399 patients with PSC-IBD were included in the study, of whom 137 had a colectomy and 123 patients developed CCA. Age-adjusted univariate Cox proportional hazard models demonstrated that colectomy (hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.05-2.22, P=0.02) and duration of IBD (HR 1.37, 95% CI 1.15-1.63, P<0.01) were associated with an increased risk of CCA, and colonic neoplasia (HR 1.52, 95% CI 0.97-2.37, P=0.06) and colectomy for colonic neoplasia (HR 1.62, 95% CI 1.01-2.61, P=0.05) approached significance. Among patients with a history of colectomy, colonic neoplasia as the indication for surgery was associated with a particularly increased risk of CCA (HR 2.91, 95% CI 1.24-6.84, P=0.01) compared with medically refractory disease. On multivariate analysis, duration of IBD remained significantly associated with CCA (HR 1.33, 95% CI 1.11-1.60, P<0.01). The influence of IBD duration on CCA risk was not modified after colectomy (P=0.69). CONCLUSIONS: Prolonged duration of IBD is associated with an increased risk of CCA in patients with PSC-IBD, and colectomy itself does not modify this risk. These findings identify a subset of patients who are at high risk of this lethal complication and in need of close surveillance.

Genome-Wide Association Studies in Primary Biliary Cirrhosis.

Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.