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ACCME/DisclosuresThe USCAP requires that anyone in a position to influence or control the content of CME disclose
any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their
spouse/partner have, or have had, within the past 12 months, which relates to the content of
this educational activity and creates a conflict of interest.
Dr. Marcela Salomao declares she has no conflict(s) of interest to disclose.
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PBC and PSC RevisitedMarcela Salomao, MD
USCAP Annual Meeting, 2016
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Primary Biliary Cirrhosis Cholangitis(PBC)
Primary Biliary Cirrhosis Cholangitis(PBC)
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Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, Ma X, Mackay IR, Parés A, Tanaka A, Vierling JM, Poupon R.
J Hepatol. 2015 Nov;63(5):1285-7.Gastroenterology. 2015 Nov;149(6):1627-9.
Gut. 2015 Nov;64(11):1671-2. Hepatology. 2015 Nov;62(5):1620-2.
Clin Gastroenterol Hepatol. 2015 Nov;13(11):1867-9.Am J Gastroenterol. 2015 Nov;110(11):1536-8.
Dig Liver Dis. 2015 Nov;47(11):924-6. Clin Res Hepatol Gastroenterol. 2015 Oct;39(5):e57-9.
Shimoda S, Tanaka A.Nihon Shokakibyo Gakkai Zasshi. 2016;113(1):36-7.
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Hans Popper, MDSheila Sherlock, MD
“ambiguous term”
Sherlock S. Gastroenterology 1959Rubran E. Am J Pathol 1965.
Chronic intrahepatic obstructive jaundice “misnomer” Chronic nonsuppurative destructive cholangitis
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“Name change initiative for PBC”
Driven by patients“correct the inaccuracy”“remove the cirrhosis stigma”
Primary biliary cholangitis
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PBC Pathogenesis
• T-cell mediated immune attack of bile duct epithelial cells
• Break of B/T cell tolerance to biliary epithelial cells
• Anti-mitochondrial autoantibodies (PDC-E2 )
- Xenobiotics
- Bacterial molecules
- Genetic predisposition
Ala A, et al. Hepatology 2006.McNally RJK et al. Am J Epidemiol 2014.
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PBCDiagnosisTwo of the following 3 criteria (AASLD Recommendation):• Elevated alkaline phosphatase• AMA +, >90% pts • Histologic evidence of nonsuppurative
destructive cholangitis affecting interlobular bile ducts
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Stage 3Fibrosis and mild duct loss• Ductular prolifearation and bile duct atrophy
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Challenges• Sampling error• Less common variants:
• Overlap syndrome (PBC/AIH) • Premature ductopenic variant• AMA-negative PBC
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AMA-negative PBC• 5-10% pts (by IF)
• AMA-M2 may be identified by EIA or Western blot
• Anti-nuclear antibodies, 30-50% pts • subtypes specific to PBC
Antibody PrevalenceAnti-gp210 22.2–26.2%Anti-centromere 12.6–26.1%Anti-sp100 8.7–21.6%Anti-chromatin 5.4–25%Anti-kelch-like 12 16–40%Anti-hexokinase 1 16–45%
Lindor KD et al. Hepatology. 2009Bizzaro N et al. Clin Rev Allergy Immunol. 2012
Sclair S et al. Clin Transl Gastroenterol. 2015 ©2016 MFMER | slide-18
Differential Diagnosis of PBC
• PSC and SSC• Drug-induced cholangitis/VDS• Hodgkin’s lymphoma (post-
treatment)• Idiopathic adulthood ductopenia• Infantile/childhood disease• CR or GVHD
• PSC and SSC• Drug-induced cholangitis/VDS• Hodgkin’s lymphoma (post-
treatment)• Idiopathic adulthood ductopenia• Infantile/childhood disease• CR or GVHD
Ductopenia
• Sarcoidosis • Infections• Sarcoidosis • Infections
Granulomas
• HBV• HCV• HBV• HCVChronic
hepatitis
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Sarcoidosis
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Drug-induced bile duct injuryVanishing bile duct syndrome
amoxicillin/clavulanateother penicillinsfluoroquinolones
sulfonamidesantifungal agents
NSAIDsphenothiazines
tricyclic antidepressantsaromatic anticonvulsants
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• Cholestasis and bile duct injury• Ductopenia without fibrosis• Clinical history
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PBC Disease Progression and Complications• UDCA therapy slows disease progression in 2/3
of patients • HCC
• 2015: Global PBC Study Group, 4500 patients• 3.4 cases per 1000 patient years • Increased risk: biochemical non-responders
Trivedi et al. Gut 2015Lammers WJ et al. Gastroenterology 2014
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Primary Sclerosing Cholangitis (PSC)
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- Genetic predisposition (MHC risk loci)
- Gut microbiota
- Innate immune system
PSC Pathogenesis
PAMP
PSC-associated HLA molecules
Gut-primed T cells, NK cells TGFβ fibrosis
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PSC Diagnosis
• Labs are non-specific• p-ANCA positive (80%)• Cholangiography is diagnostic: MRCP
recommended as first-line imaging: short, annular strictures alternating with dilated segments (beaded appearance).
• Liver biopsy: staging, small duct PSC, exclusion of other entities (overlap PSC-AIH)
http://radiopaedia.org/
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©2016 MFMER | slide-27 ©2016 MFMER | slide-28Carrasco-Avino G, et al. Am J Clin Pathol 2015
Distinctive histologic features of
PSC
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Challenges• Sampling error• Posttransplantation biopsies• PSC variants:
• Overlap syndrome (PSC-AIH)• Small duct PSC
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Small Duct PSC• 6-16% of PSC cases
• Clinical and laboratorial features of PSC with normal cholangiography
• Slower progression, better survival rates and less Cca
• 20% progress to large duct PSC in median 7.4 yrs
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Differential Diagnosis of PSCObstructive• Tumors• Stones• Surgical complicationsInflammatory• IgG4-associated cholangitis• PBC
Vascular• Ischemic cholangiopathy• AIDS-related cholangiopathy
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IgG4-associated cholangitis (IAC) vs. PSC
IgG4©2016 MFMER | slide-34
IAC vs. PSCHISORt and specific features on liver biopsies
Portal infiltrates: spared bile ducts (halo) with perivenular accentuation (50%)
Lobular inflammation Fibroinflammatory nodules (50%) More than 10 IgG4+ cells/hpf (60% cases)
.Figure from Deshpande et al. Arch Pathol Lab Med. 2015.
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Ischemic cholangiopathy vs. PSC• Liver transplantation (HA thrombosis, ABO
incompatible)• Hepatic intra-arterial chemotherapy (FUdR)• Thrombotic disorders and systemic vasculitis• Severely ill patients
• Histology: periductal fibrosis, ductopenia
Deltenre P, Valla DC. Semin Liv Dis. 2008 (Review)Gelbmann CM, et al. Am J Gastroenterol. 2007
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Cancer Surveillance in PSC
• 72% 5-yr survival in early stage hilar cholangiocarcinoma treated with neoadjuvant chemotherapy and transplant
• ERCP for dominant strictures• Brushing cytology/biopsy – low sensitivity• FISH
• Most specific: high-grade dysplasia (73%) and positive FISH (82%)
Murad SD et al. Gastroenterology 2012Salomao M et al. Cancer Cytopathol 2015
Boberg KM et al. J Hepatol 2006
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SummaryPBC PSC
• Nomenclature change “cirrhosis” to “cholangitis”
• AMA-negative PBC: role of PBC-specific ANA antibodies, may affect prognosis
• Liver biopsy: staging and exclusion of variants
• Fibrointimal hyperplasia –novel feature
• Consider IgG4AC and IC • No treatment – role of
transplantation
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Thank you!