Citations

Background and Aims: Among those with primary sclerosing cholangitis (PSC), perihilar cholangiocarcinoma (pCCA) is often diagnosed at a late stage and is a leading source of mortality. Detection of pCCA in PSC when curative action can be taken is challenging. Our aim was to create a deep learning model that analyzed MRI to detect early-stage pCCA and compare its diagnostic performance with expert radiologists. Approach and Results: We conducted a multicenter, international, retrospective cohort study involving adults with large duct PSC who underwent contrast-enhanced MRI. Senior abdominal radiologists reviewed the images. All patients with pCCA had early-stage cancer and were registered for liver transplantation. We trained a 3D DenseNet-121 model, a form of deep learning, using MRI images and assessed its performance in a separate test cohort. The study included 398 patients (training cohort n=150; test cohort n=248). pCCA was present in 230 individuals (training cohort n=64; test cohort n=166). In the test cohort, the respective performances of the model compared to the radiologists were: sensitivity 87.9% versus 50.0%, p <0.001; specificity 84.1% versus 100.0%, p <0.001; area under receiving operating curve 86.0% versus 75.0%, p <0.001. Even when a mass was absent, the model had a higher sensitivity for pCCA than radiologists (91.6% vs. 50.6%, p <0.001) and maintained good specificity (84.1%). Conclusions: The 3D DenseNet-121 MRI model effectively detects early-stage pCCA in PSC patients. Compared to expert radiologists, the model missed fewer cases of cancer.

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.

AbstractAutoimmune 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.

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)

Changes over time in the presenting features and clinical course of patients with primary biliary cholangitis are poorly described. We sought to describe temporal trends in patient and disease characteristics over a 44‐year period across a large international primary biliary cholangitis cohort of 4,805 patients diagnosed between 1970 and 2014, from 17 centers across Europe and North America. Patients were divided into five cohorts according to their year of diagnosis: 1970‐1979 (n = 143), 1980‐1989 (n = 858), 1990‐1999 (n = 1,754), 2000‐2009 (n = 1,815), and ≥2010 (n = 235). Age at diagnosis, disease stage, response to ursodeoxycholic acid, and clinical outcomes were compared. Mean age at diagnosis increased incrementally by 2‐3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P < 0.001). The female to male ratio (9:1) and antimitochondrial antibody positivity (90%) were not significantly variable. The proportion of patients presenting with mild biochemical disease (according to Rotterdam staging) increased from 41.3% in the 1970s to 72.2% in the 1990s (P < 0.001) and remained relatively stable thereafter. Patients with a mild histological stage at diagnosis increased from 60.4% (1970‐1989) to 76.5% (1990‐2014) (P < 0.001). Correspondingly, response to ursodeoxycholic acid according to Paris‐I criteria increased; 51.7% in the 1970s and 70.5% in the 1990s (P < 0.001). Recent decades were also characterized by lower decompensation rates (18.5% in the 1970s to 5.8% in the 2000s, P < 0.001) and higher 10‐year transplant‐free survival (48.4%, 68.7%, 79.7%, and 80.1% for each respective cohort; P < 0.001). Conclusion: In recent decades, a pattern of primary biliary cholangitis presentation consistent with an older age at diagnosis alongside reduced disease severity has been noted; the observed trends may be explained by an increase in routine testing of liver function and/or a changing environmental trigger. (Hepatology 2018;67:1920‐1930).

AbstractBackground & AimsPrimary 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.MethodsFirst‐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.ResultsForty 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.ConclusionsOur 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.