The prognostic role of magnetic resonance imaging in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology characterized by inflammation and obliterative fibrosis of the biliary tree. Although the course is highly variable, PSC is often progressive, leading to biliary cirrhosis and its complications. Overall, PSC is a severe disease and median transplant-free survival ranges from 13 years in patients seen at tertiary referral centres to 20 years in a population-based cohort. Liver transplantation is the only life-extending therapeutic intervention for patients with end-stage liver disease. No medical therapy has proven to be effective to halt disease progression. The clinical course of the disease is highly variable among different patients. Identification of prognostic factors is essential for tailoring the follow-up strategies and/or testing new therapeutic modalities in subgroups of PSC patients with poor prognosis. Magnetic resonance cholangiography is recommended as the first diagnostic modality in patients with suspected PSC and its potential role in assessing prognosis is justified by its non-invasive nature, its reproducibility and its adequate performance in assessing biliary alterations in PSC that resulted comparable to that of endoscopic cholangiography. The aim of this thesis was to assess the prognostic value of magnetic resonance imaging in these patients. I thus assessed the prognostic value of two MR risk scores in predicting the risk of adverse outcomes and I evaluated whether the use in combination of MR risk score with liver stiffness may improve risk stratification of these patients. I evaluated the radiological and clinical course of PSC patients with intrahepatic bile ducts cystic dilatations found at magnetic resonance cholangiography and I assessed the prognostic value of this finding. Finally, I assessed the existence of magnetic resonance cholangiography and clinical criteria of improvement after endoscopic treatment for severe strictures. The results of this research demonstrated that two simple MR risk score were associated to the risk of adverse outcomes in PSC patients and that the use in combination of MR risk score without gadolinium-based contrast agent injection with liver stiffness was able to improve risk stratification in these patients. I reported on a subgroup of patients with cystic dilatations of intrahepatic bile ducts and I documented that these patients were characterized by a younger age at PSC diagnosis, a rapid radiological and clinical evolution, and a significantly lower median transplant free survival from PSC diagnosis compared with PSC patients without cystic dilatations. Finally, I documented that some magnetic resonance cholangiography features together with biochemical features, may contribute to identify PSC patients likely to improve after endoscopic treatment for severe strictures of extrahepatic bile ducts. In conclusion, I here provided some evidences in favour of the use of magnetic resonance imaging for prognostic, other than diagnostic, purposes in PSC

Protective potential of the gallbladder in primary sclerosing cholangitis

Background & Aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC.Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC.Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis.Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.Impact and implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gall-bladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.& COPY; 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Pregnancy and Diseases of the Biliary Tree

Pregnancy is a relevant moment in woman life and it is physiologically associated with several metabolic, hormonal, immunological and nutritional changes that can be associated, in predisposed women, to pregnancy-related diseases. Pregnancy can also occur in women affected by pre-existing chronic disease. The aim of the chapter is to highlight the relation between pregnancy and biliary disease. In particular, the chapter focuses on three main topics: I) gallstone disease in pregnancy; II) intrahepatic cholestasis of pregnancy; III) pregnancy in chronic cholestatic disease, i.e. primary biliary cholangitis and primary sclerosing cholangitis, focusing on fertility, gestation, delivery, maternal and fetal outcomes

The prognostic role of magnetic resonance imaging in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology characterized by inflammation and obliterative fibrosis of the biliary tree. Although the course is highly variable, PSC is often progressive, leading to biliary cirrhosis and its complications. Overall, PSC is a severe disease and median transplant-free survival ranges from 13 years in patients seen at tertiary referral centres to 20 years in a population-based cohort. Liver transplantation is the only life-extending therapeutic intervention for patients with end-stage liver disease. No medical therapy has proven to be effective to halt disease progression. The clinical course of the disease is highly variable among different patients. Identification of prognostic factors is essential for tailoring the follow-up strategies and/or testing new therapeutic modalities in subgroups of PSC patients with poor prognosis. Magnetic resonance cholangiography is recommended as the first diagnostic modality in patients with suspected PSC and its potential role in assessing prognosis is justified by its non-invasive nature, its reproducibility and its adequate performance in assessing biliary alterations in PSC that resulted comparable to that of endoscopic cholangiography. The aim of this thesis was to assess the prognostic value of magnetic resonance imaging in these patients. I thus assessed the prognostic value of two MR risk scores in predicting the risk of adverse outcomes and I evaluated whether the use in combination of MR risk score with liver stiffness may improve risk stratification of these patients. I evaluated the radiological and clinical course of PSC patients with intrahepatic bile ducts cystic dilatations found at magnetic resonance cholangiography and I assessed the prognostic value of this finding. Finally, I assessed the existence of magnetic resonance cholangiography and clinical criteria of improvement after endoscopic treatment for severe strictures. The results of this research demonstrated that two simple MR risk score were associated to the risk of adverse outcomes in PSC patients and that the use in combination of MR risk score without gadolinium-based contrast agent injection with liver stiffness was able to improve risk stratification in these patients. I reported on a subgroup of patients with cystic dilatations of intrahepatic bile ducts and I documented that these patients were characterized by a younger age at PSC diagnosis, a rapid radiological and clinical evolution, and a significantly lower median transplant free survival from PSC diagnosis compared with PSC patients without cystic dilatations. Finally, I documented that some magnetic resonance cholangiography features together with biochemical features, may contribute to identify PSC patients likely to improve after endoscopic treatment for severe strictures of extrahepatic bile ducts. In conclusion, I here provided some evidences in favour of the use of magnetic resonance imaging for prognostic, other than diagnostic, purposes in PSC

Liver Immunology, Principles and Practice, Third Edition Chapter 24: Primary Biliary Cholangitis: Autoimmune Hepatitis Overlap Syndrome

*Some patients present with features of both primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) either simultaneously or consecutively. • The term overlap syndrome (OS) is used to describe these settings, but lack of universal agreement on what precisely constitutes an OS has generated considerable confusion. • The low prevalence of OS (roughly 10% of PBC) has made it impracticable to perform randomized controlled trials. • It remains unclear whether this syndrome forms a distinct entity or, more likely, a variant of PBC, or AIH. • Moderate-to-severe interface hepatitis is a fundamental component and histology is vital in evaluating patients with overlap presentation. Use of the International Autoimmune Hepatitis Group criteria for the diagnosis of OS is not recommended. • For PBC-AIH OS, EASL has provided diagnostic criteria and, in most cases, it is possible to define one primary disorder (“dominant” disease), usually PBC. • Patients with OS seem to have a more severe disease compared to conventional PBC. • Treatment of OS is empiric and includes ursodeoxycholic acid (UDCA) for the cholestatic component and immunosuppressive agents for the hepatitic component, either simultaneously or sequentially. Immunosuppressive treatment in addition to UDCA is recommended in patients with severe interface hepatitis and deserves consideration in those with moderate interface hepatitis. • The dominant clinical feature should be treated first and therapy adjusted according to the response. • OS is not uncommon but should not be over-diagnosed in order not to expose unnecessarily PBC patients to the risk of steroid side effects. Therapy has to be individualized and not be static

Overlap syndrome

Overlap syndromes (OS) between primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent rare forms of PBC, PSC and AIH, which are characterized by the presence of features of two diseases, typically PBC and AIH or PSC and AIH in the same patient. The diagnosis of OS is based on the presence or sequential development of biochemical, serological, histologic and cholangiographic features of the two diseases. Paris criteria are the recommended criteria for the diagnosis of PBC-AIH OS, whereas no strict diagnostic criteria have yet been established for the diagnosis of PSC-AIH OS. Liver biopsy is mandatory when an OS is suspected and interface hepatitis is a fundamental component for the diagnosis of OS. Patients with OS may present with one or more associated extrahepatic autoimmune disease. Treatment of OS is empiric and includes ursodeoxycholic acid (UDCA) for the cholestatic component and immunosuppressive agents for the hepatitic component, either simultaneously or sequentially. Immunosuppressive treatment in addition to UDCA is recommended in patients with severe interface hepatitis and deserves consideration in those with moderate interface hepatitis. The dominant clinical feature should be treated first and therapy adjusted according to the response. Relapse after IS agent’s withdrawal is elevated in patients with OS. Graft and patients’ survival after liver transplantation in patients with OS are comparable to that observed in patients transplanted for single autoimmune liver diseases

Letter: the use of magnetic resonance scores (Anali) for risk stratification in PSC

International audienceGBCA gadolinium-based contrast agent MR magnetic resonance MRC magnetic resonance cholangiography PSC primary sclerosing cholangitis VCTE vibration controlled transient elastography Dear editor, We read with interest the review written by Mahzar and Russo about non-invasive prognostic tests for primary sclerosing cholangitis (PSC) 1. Although rare, PSC is a serious disease, associated with potentially lethal complications, notably cirrhosis and cholangiocarcinoma 2. Liver transplantation is the only curative treatment for PSC and median transplant-free survival is approximately 12-21 years after diagnosis 3. Identification of prognostic factors is essential for tailoring the follow-up strategies and testing new therapeutic modalities in homogeneous groups of PSC patients. As detailed in this review, over the last twenty years, different teams across the world, including ours, have identified several noninvasive prognostic tests for PSC patients 1. First, our team demonstrated in a large retrospective study that liver stiffness measured by vibration-controlled transient elastography (VCTE) was an independent predictive marker of survival in PSC patients 4. Next, we built 2 magnetic resonance (MR) risk scores (with and without gadolinium-based contrast agent (GBCA) administration) 5 , called Anali scores, and showed that they were able to predict adverse outcome-free survival (defined by survival without liver transplantation or cirrhosi