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Background and Aims: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. Method(s): We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. Result(s): 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 +/- 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. Conclusion(s): Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.Copyright © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. more...

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon. more...

Aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 Index (Fib4) have been validated against liver biopsy for detecting advanced hepatic fibrosis in HFE hemochromatosis. We determined the diagnostic utility for advanced hepatic fibrosis of Hepascore and transient elastography compared with APRI and Fib4 in 134 newly diagnosed HFE hemochromatosis subjects with serum ferritin levels > 300 µg/L using area under the receiver operator characteristic curve (AUROC) analysis and APRI- (> 0.44) or Fib4- (> 1.1) cut-offs for AHF, or a combination of both. Compared with APRI, Hepascore demonstrated an AUROC for advanced fibrosis of 0.69 (95% CI 0.56-0.83; sensitivity = 69%, specificity = 65%; P = 0.01) at a cut-off of 0.22. Using a combination of APRI and Fib4, the AUROC for Hepascore for advanced fibrosis was 0.70 (95% CI 0.54-0.86, P = 0.02). Hepascore was not diagnostic for detection of advanced fibrosis using the Fib4 cut-off. Elastography was not diagnostic using either APRI or Fib4 cut-offs. Hepascore and elastography detected significantly fewer true positive or true negative cases of advanced fibrosis compared with APRI and Fib4, except in subjects with serum ferritin levels > 1000 µg/L. In comparison with APRI or Fib4, Hepascore or elastography may underdiagnose advanced fibrosis in HFE Hemochromatosis, except in individuals with serum ferritin levels > 1000 µg/L. more...

Background: IgG4-Sclerosing Cholangitis (IgG4-SC) is an uncommon clinical entity that has an uncertain prognosis and incompletely defined clinical management pathway. Existing data are predominantly from Japanese populations with limited data from Western countries. We sought to describe the presentation, management and outcomes of an Australian IgG4-SC population Methods: Retrospective data collection from major liver centres affiliated with the ALA Clinical Research Network with site selection based on an affirmative response to an expression of interest Patients were included as IgG4-SC if they fulfilled the criteria for definite or probable IgG4-SC according to the IgG4-SC 2012 clinical diagnostic criteria Baseline demographic and biochemical data were obtained in addition to treatment response Follow-up data included disease progression, relapse, development of malignancy and survival Results: 53 patients from 18 institutions met the inclusion criteria (M/F 40/13; Age 64 2+/-1 9 year [range 14.5 - 84.1 years]). Caucasian (68%) and Asian (28%) A previous diagnosis of PSC had been made in 3 (6%) subjects and a suspected biliary tract malignancy or pancreatic tumour in 5 (9%) Three subjects had evidence of cirrhosis The most frequent presenting symptom was jaundice (62%) and abdominal pain (32%) and 34% had co-existing diabetes mellitus Bilirubin (80+/-13mumol/L), ALT (267+/-43 U/L) and IgG4 (6.2+/-0.8 g/L) were significantly elevated at diagnosis and 38% had Ca19-9 > 37 kU/L (range 1-2248 kU/L). The bile duct lesion was: Type 1 (distal bile duct stricture only; 57%), Type 2A (13%), Type 2B (2%), Type 3 (13%) and Type 4 (9%) IgG4-SC was associated with other IgG4-related diseases, most commonly: autoimmune pancreatitis (AIP) (55%), dacryoadenitis/sialadenitis (15%) 87% received prednisolone as initial treatment and 60% achieved remission while a further 19% experienced a partial response with a median time to best response of 3 4 months Endoscopic dilatation was p more...

Background and Aim: IgG4-sclerosing cholangitis (IgG4-SC) is a recently recognized but uncommon clinical entity that has an uncertain prognosis and an incompletely defined clinical management pathway. Existing data are predominantly from Japanese populations, with limited data from Western countries, and there are no published Australian data. We therefore sought to describe the presentation, management, and outcomes of an Australian IgG4-SC population. Method(s): Data were retrospectively obtained from major liver centers affiliated with the Australian Liver Association Clinical Research Network, with site selection based on an affirmative response to an expression of interest. Patients were included as having IgG4-SC if they fulfilled the criteria for definite or probable IgG4-SC according to the IgG4-SC 2012 clinical diagnostic criteria. Baseline demographic and biochemical data were obtained, in addition to treatment response. Follow-up data included disease progression, relapse, development of malignancy, and survival. Data are expressed as mean +/- SE unless otherwise stated. Result(s): Overall, 53 patients from 18 institutions met the inclusion criteria (male/female, 40/13; age, 64.2 +/- 1.9 years; range, 14.5-84.1 years). Caucasian (68%) and Asian (28%) were the most frequent ethnicities. A previous diagnosis of primary sclerosing cholangitis had been made in three patients (6%), and a suspected biliary tract malignancy or pancreatic tumor in five (9%). Three patients had evidence of cirrhosis at the time of diagnosis. The most common presenting symptom was jaundice (62%), followed by abdominal pain (32%), and 34% had coexisting diabetes. Levels of bilirubin (80 +/- 13 mumol/L), alanine aminotransferase (267 +/- 43 U/L), and IgG4 (6.2 +/- 0.8 g/L) were significantly elevated at diagnosis, and 38% had Ca19- 9 > 37 kU/L (range, 1-2248 kU/L). The bile duct lesion was type 1 (distal bile duct stricture only) in 57%, type 2A in 13%, type 2B in 2%, type 3 in 13% more...

BACKGROUND: Mycophenolate mofetil is a commonly used salvage therapy for patients with autoimmune hepatitis (AIH). AIM: To evaluate the predictors of response to mycophenolate rescue therapy to facilitate clinical decision making. METHODS: We performed a retrospective observational cohort study of AIH patients managed in 17 major Australian liver centres who received mycophenolate after an inadequate response or intolerance to corticosteroids with/without thiopurine(s). Baseline demographic, clinical and laboratory variables were compared between responders and nonresponders. A multivariable logistic regression model was developed using forward selection to identify independent predictors of treatment response. RESULTS: A total of 105 patients received mycophenolate rescue therapy of whom 63 (60%) achieved biochemical remission. On univariable analysis, older age (P = 0.003), INR < 1.1 (P = 0.02), and lower immunoglobulin gamma (IgG; P < 0.002) levels were associated with treatment response, while no association was found with cirrhosis status (P = 0.07) or treatment indication (P = 0.63). On multivariable analysis, lower pre-treatment serum IgG level (P = 0.01), higher age at commencing mycophenolate (P = 0.01) and higher INR (P = 0.03) were the only significant independent predictors. An IgG level <17 g/L had a positive and negative predictive value for response of 71% and 60% respectively, while age ≥54 years when commencing mycophenolate had a positive and negative predictive value for response of 80% and 59% respectively. CONCLUSION: Mycophenolate remains an excellent treatment option for patients with AIH refractory to or intolerant of standard therapy with those most likely to benefit being older and/or having lower pre-treatment IgG levels. more...

Background and Aims: Treatment with mycophenolate mofetil (MMF) as rescue therapy for patients with autoimmune hepatitis (AIH), who have suboptimal outcomes with standard therapy, is safe and moderately effective, although response rates appear lower in patients with cirrhosis. The aim of this study was to evaluate the predictors of response to MMF in patients with AIH to facilitate clinical decision making with MMF as second-line therapy. Method(s): Baseline demographic, clinical, and laboratory characteristics were recorded for all patients with AIH who received MMF after an inadequate response or intolerance to treatment with corticosteroids with/without thiopurine(s). Comparisons between responders and non-responders were performed using the chi-squared test for equal proportion, Student's t test for parametric variables, and Wilcoxon rank-sum tests otherwise. A multivariable logistic regression model was developed using stepwise selection procedures to identify independent predictors of response to MMF. Result(s): A total of 105 patients with AIH (age, 53 years; 88% female; 86% Caucasian; 97% Type 1; 37% cirrhosis) who received MMF as second-line therapy were identified across 17 liver centers. Overall, 63 patients (60%) achieved biochemical remission on MMF after a median treatment duration of 12 weeks. Treatment response was similar between those receiving MMF for non-response versus intolerance to standard therapy (57% vs 62%). On univariate analysis, sex (P = 0.9), age at commencing MMF (P < 0.0001), INR (P = 0.015), serum aspartate aminotransferase (AST) level (P = 0.009), alanine aminotransferase level (P = 0.05), bilirubin level (P = 0.003), and IgG level (P = 0.0001) were associated with treatment response, while there was a weak association between cirrhosis status and response (P = 0.070). The results of multivariate analysis of independent predictors of response to MMF are shown in Table 1. Pre-treatment serum IgG level was the only significant indep more...

Background & Aims: Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine. Method(s): We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment. Result(s): The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P =.07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events. Conclusion(s): In this retrospective study of patients with AIH who received mycophenolate more...

Background and Aims: In nonalcoholic steatohepatitis (NASH), the main factor associated with hepatic outcomes is fibrosis progression. NASH is defined by liver cell injury (hepatocyte ballooning [BAL]), lobular inflammation (LI) and steatosis. Development of antiinflammatory, antifibrotic or mixed agents for the treatment of NASH requires better understanding of the relationship between disease activity and fibrosis. Methods: Screening liver biopsies from CENTAUR (NCT02217475; phase 2 trial of cenicriviroc versus placebo in subjects with NASH and fibrosis), were evaluated by a central pathologist. Those deemed adequate for pathological interpretation were included in this analysis (N = 557) regardless of study eligibility. Nonalcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis stage were evaluated using NASH Clinical Research Network (CRN) classification. Portal inflammation (PI), LI and steatosis were each graded 0–3. Associations between histologic features were quantified by Spearman rank correlation and tested by the Fisher exact test. Results: Rates of fibrosis stages 0,1,2,3, and 4 were 22%, 27%, 21%, 24% and 6%, respectively. For NAS, 28% of subjects had NAS ≤3, 23% had NAS = 4, 21% had NAS = 5, and 28% had NAS ≥6. Subjects with no cirrhosis showed an association between fibrosis stages and LI (r = 0.41), BAL (r = 0.60), and PI (r = 0.55). Subjects with moderate (Grade 2) or severe (Grade 3) LI had a prevalence of significant (stage ≥2) fibrosis of 57% versus 22% in those with no (Grade 0) or mild (Grade 1) LI (p < 0.001). Subjects with severe (Grade 2) BAL had a prevalence of 82% significant fibrosis versus 35% in those without BAL (p < 0.001). Subjects with moderate/severe PI had a prevalence of 78% significant fibrosis versus 23% in those with no/mild PI (p < 0.001). No strong association was found between fibrosis stage and steatosis grade. Alanine aminotransferase levels were higher with increasing grades of LI and BAL. Observed rates more...

Background & Aims Telaprevir plus pegylated interferon/ribavirin (TPV + PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) and TPV + PegIFN/RBV. Methods Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r + DSV + weight-based RBV, OBV/PTV/r + DSV (treatment-naïve, GT1b-infected patients only), or 12 weeks of TPV + PegIFN + weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. Results Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r + DSV + RBV and TPV + PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r + DSV + RBV, OBV/PTV/r + DSV, and TPV + PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r + DSV + RBV and TPV + PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r + DSV ± RBV than TPV + PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p <0.05) and rates of hemoglobin decline to <10 g/dl (0-4% and 34-47%, respectively, p <0.05) were lower for OBV/PTV/r + DSV ± RBV than TPV + PegIFN/RBV. Conclusions Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12 week, multi-targeted OBV/PTV/r + DSV ± RBV regimens and 66-82% with 24-48 total weeks of TPV + PegIF more...

Background: Conventional therapy of autoimmune hepatitis (AIH) is with corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to standard therapy. Thus, we evaluated the efficacy and safety of mycophenolate mofetil (MMF) in AIH patients who had failed or were intolerant to corticosteroids with or without azathioprine. Method(s): A retrospective study was performed of AIH patients who received MMF alone or in combination with prednisolone after failure or intolerance of standard therapy. Patients were recruited from 16 liver clinics across Australia via the ALA Clinical Research Network. Records were reviewed for baseline demographics and liver disease characteristics, initial therapy, indications for MMF initiation, treatment outcome and complications. Result(s): A total of 96 patients (mean age 45.3 yrs, females 86.5%, Caucasian 53% and cirrhosis 19.8%) received treatment with MMF for AIH across the 16 centres including 95 in combination with corticosteroids. The majority (73%) had received prior combination therapy with corticosteroids plus azathioprine/6-mercaptopurine. The indication for MMF was non-response in 43% and intolerance to standard therapy in 53%. The median starting and maximal doses of MMF received was 1 g/d and 2 g/d, respectively; the median treatment duration was 31.9 months. Overall, 44 (45.9%) patients achieved biochemical remission on MMF after a median treatment duration of 11 weeks, 8 (18%) of whom relapsed during follow up. Of the 40 patients treated for non-response, 17 (42.5%) achieved biochemical remission after a median of 12 weeks, while 8 (20%) had an incomplete response and 3 (7.5%) had treatment failure. Of the 49 patients receiving MMF for intolerance/toxicity, 27 (55%) achieved remission, with 4 (8%) having an incomplete response and 1 (2%) treatment failure. Eight patients required dose-reduction, and 16 discontinued MMF mainly due to lack of efficacy (n = 6) or intolerance (n = 6) more...

Background Conventional therapy of autoimmune hepatitis (AIH) is with corticosteroids with or without azathioprine. However 20% of patients do not respond or are intolerant to standard therapy. Thus, we evaluated the efficacy and safety of mycophenolate mofetil (MMF) in AIH patients who had failed or were intolerant to corticosteroids with or without azathioprine. Methods A retrospective study was performed of AIH patients who received MMF alone or in combination with prednisolone after failure or intolerance of standard therapy. Patients were recruited from 16 liver clinics across Australia via the ALA Clinical Research Network. Records were reviewed for baseline demographics and liver disease characteristics, initial therapy, indications for MMF initiation, treatment outcome and complications. Results A total of 96 patients (mean age 45.3 yrs, females 86.5%, Caucasian 53%, cirrhosis 19.8%) received treatment with MMF for AIH across the 16 centres including 95 in combination with corticosteroids. The majority (73%) had received prior combination therapy with corticosteroids plus azathioprine/6-mercaptopurine. The indication for MMF was non-response in 43% and intolerance to standard therapy in 53%. The median starting and maximal doses of MMF received was 1gm/d and 2gm/d respectively; the median treatment duration was 31.9 months. Overall, 44 (45.9%) patients achieved biochemical remission on MMF after a median treatment duration of 11 weeks, 8 (18%) of whom relapsed during follow up. Of the 40 patients treated for non-response, 17 (42.5%) achieved biochemical remission after a median of 12 weeks, while 8 (20%) had an incomplete response and 3 (7.5%) had treatment failure. Of the 49 patients receiving MMF for intolerance/toxicity, 27 (55%) achieved remission, with 4 (8%) having an incomplete response and 1 (2%) treatment failure. 8 patients required dose-reduction and 16 discontinued MMF mainly due to lack of efficacy (n=6) or intolerance (n=6). Serious adverse eve more...

A significant synergy exists between heavy alcohol consumption and hepatitis virus infection (hepatitis B and C), which may suggest a common pathway for hepatocarcinogenesis. Psychological interventions such as motivational interviewing (MI) can generate urgently needed psychological, physiological and lifestyle changes to people who use alcohol. No randomised controlled trials (RCTs) were found investigating effectiveness of MI in patients with chronic viral hepatitis and who drink alcohol. more...

Introduction: In Australia, and many other countries, the standard treatment for HCV genotype 1 is triple therapy with Pegylated interferon-alpha-2a/2b, ribavirin (PR) and a first generation direct-acting antiviral (DAA), such as boceprevir (BOC). Uncertainty over the timing of regulatory approval and reimbursement for newer DAAs has led to increasing impetus to treat now to reduce disease progression, especially in advanced liver disease. Current BOC treatment experience data to date is mostly from the northern hemisphere. Thus, we aimed to evaluate the efficacy and safety of BOC based triple therapy in a large Australian cohort reflective of real-world clinical practice. Method(s): A retrospective, observational analysis was conducted in 1026 patients enrolled in an early access program in 65 hepatitis treatment centres. Patients received a PR 4 week lead in followed by either response-guided or fixeddose duration of BOC for 44 weeks according to standard guidelines. Demographic, clinical and virological data were entered into a central database. Cirrhosis was characterised by a composite of radiological imaging, histology (METAVIR 4) and/or transient elastography (median stiffness >12.5 kPa). Virological response (VR) was defined as undetectable HCV RNA using a sensitive quantitative PCR assay. Result(s): 407 patients were included in this interim analysis, of whom 308 patients had end of treatment data and 157 had week 12 follow up data. The majority were male (68%) and Caucasian (90%), with mean age of 51 years. Cirrhosis was present in 24% (Child-Pugh A) and 55% had prior PR treatment. HCV genotype 1 distribution was 53% 1a, 16% 1b, 3% 1a/1b, and 28% undifferentiated. IL28B genotype distribution was 20% CC, 35% CT, 7% TT and 38% unknown. Anaemia (Hb <10g/dL) occurred in 42% and Hb reduction >3g/dL in 70%. RBV dose reduction was needed in 33% and blood transfusion in 16%. Infections were rare and there were no deaths. Early treatment discontinuation occurred in more...