pbc and psc revisited salomaomarcela ... biliary cirrhosis cholangitis (pbc) ... sheila sherlock,...

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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.

©2016 MFMER | slide-3

PBC and PSC RevisitedMarcela Salomao, MD

USCAP Annual Meeting, 2016


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.


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


“Name change initiative for PBC”

Driven by patients“correct the inaccuracy”“remove the cirrhosis stigma”

Primary biliary cholangitis


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


©2016 MFMER | slide-11 ©2016 MFMER | slide-12

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Stage 3Fibrosis and mild duct loss• Ductular prolifearation and bile duct atrophy



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


Sarcoidosis


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


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


Primary Sclerosing Cholangitis (PSC)


- 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/


©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


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


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.


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


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


Thank you!

pbc and psc revisited salomaomarcela ... biliary cirrhosis cholangitis (pbc) ... sheila sherlock,...

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