PBC and PSC Revisited - USCAPhandouts.uscap.org/2016_CM10_Salo_1.pdfPrimary Biliary Cholangitis •...
Transcript of PBC and PSC Revisited - USCAPhandouts.uscap.org/2016_CM10_Salo_1.pdfPrimary Biliary Cholangitis •...
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PBC and PSC Revisited
Marcela Salomao, MD
USCAP Annual Meeting, 2016
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• No conflict of interest to disclose
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• Review histologic features of PBC and PSC • Update on PBC nomenclature • Discuss uncommon variants of both entities • Cover important differential diagnosis
Aims
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“Name change initiative for PBC”
As of 2015, new proposed nomenclature by national and international experts from EASL, AASLD, APASL, UEG and AGA, together with PBC patient groups:
Primary biliary cholangitis 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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Primary Biliary Cholangitis
• Autoimmune chronic cholestatic disease • Middle-aged females • Fatigue, pruritus, elevated AlkP • AMA positive (95% patients); elevated IgM • UDCA therapy slows disease progression in 2/3 of
patients (Lammers WJ et al. Gastroenterology 2014)
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• T-cell mediated immune attack of bile duct epithelial cells – Anti-mitochondrial autoantibodies to PDC-E2 – Break of B/T cell tolerance to biliary epithelial cells
• Multifactorial disease
– Genetic predisposition • Cordell HJ et al. Nat Communications 2015
– Chemical environmental factors • Prince MI et al. Hepatology. 2001 • Ala A et al. Hepatology. 2006
– Infections: molecular mimicry to bacterial PDC-E2, ?retroviral • Mao TK et al. Hepatology. 2005
PBC Pathogenesis
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Two of the following 3 criteria (AASLD Recommendation) • Elevated AlkP • AMA +, >90% pts • Histologic evidence of nonsuppurative destructive
cholangitis affecting interlobular bile ducts
PBC Diagnosis
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• Lymphocytic cholangitis of small to medium bile ducts (“non-suppurative destructive cholangiopathy”)
• Hallmark of PBS: granulomatous cholangytis (florid duct lesion)
• Ductopenia, chronic cholestasis and fibrosis
Classic histopathology of PBC
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Lymphocytic cholangitis
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Florid duct lesion
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Ductular proliferation and interface hepatitis
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CK7
Ductular proliferation and bile duct atrophy
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Lobular granuloma
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Portal-based fibrosis
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Rhodanine
Ductopenia, CBP accumulation
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Cirrhosis, “halo” effect
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Cholate stasis
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• Scheuer/Batts-Ludwig: widely used in the US – Stage 1: florid duct lesion – Stage 2: ductular proliferation and more inflammation with
interface hepatitis and lymphoid aggregates – Stage 3: fibrosis and mild duct loss – Stage 4: cirrhosis and ductopenia
• Other systems have been proposed: – Kakuda Y et al. Hum Pathol. 2013
• Grading: hepatitis and cholangitis • Staging: fibrosis, CBP accumulation and duct loss
PBC Grading and Staging
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Differential diagnosis of PBC
• PSC and SSC • Infantile or childhood disease (Alagille, NSBDP, PFIC, BA) • DILI • Hodgkin’s lymphoma (post-treatment) • CR or GVHD • Idiopathic adulthood ductopenia
Duct damage and ductopenia
• sarcoidosis • infections
Granulomas
• HCV, HBV
Chronic hepatitic features
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• Cholestasis occurs earlier in PSC than PBC
• Periductal fibrosis and fibro-obliterative lesions favor PSC
• Granulomas favor PBC
PBC vs. PSC
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• Portal edema and ductular reaction/ cholestasis/resolution OR ductopenia and cirrhosis
• Cholestasis occurs early in course
Drug-induced bile duct injury
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Sarcoidosis
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• Diagnosis of exclusion • Young males (too young for AMA-negative PBC) • May represent small-duct PSC without IBD OR late-onset
of infantile NSPBD, PFIC • ABCB4 mutation recently reported in family with
cholestatic disorder manifesting in adult age
Idiopathic adult ductopenia
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• Sampling error • Less common variants:
– “Overlap” syndrome (PBC/AIH) – AMA-negative PBC – Premature ductopenic variant (Vleggaar, F et al. Gut
2001) • Isolated AMA positivity
But this is not all…
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Overlap syndrome (PBC-AIH)
• ~4% pts of PBC pts • AMA+, PBC features on biopsy and disproportionally elevated
transaminases/IgG • No formal definition • Paris Criteria: at least 2 of 3 accepted criteria for each condition • IAIHC Position Paper:
– Diagnostic criteria are “arbitrary” – “Dominant clinical feature should be treated first”
• Majority evolve into either PBC or AIH • Therapy should be individually tailored, corticosteroids should be
considered
Kuiper EM et al. Clin Gastroenterol Hepatol. 2010 Boberg KR et al. J Hepatol. 2011
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• 5-10% pts (by IF), previously regarded as “autoimmune cholangitis” • AMA-M2 may be identified by EIA or Western blot • Anti-nuclear antibodies +, 30-50% pts
– subtypes specific to PBC:
AMA-negative PBC
Lindor KD et al. Hepatology. 2009 Bizzaro N et al. Clin Rev Allergy Immunol. 2012
Sclair S et al. Clin Transl Gastroenterol. 2015
Antibody Prevalence Anti-gp210 22.2–26.2% Anti-centromere 12.6–26.1% Anti-sp100 8.7–21.6% Anti-chromatin 5.4–25% MIT3 82.2% Anti-kelch-like 12 16–40% Anti-hexokinase 1 16–45%
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Anti‐gp210 and anti‐centromere antibodies are different risk factors for the progression of primary biliary cirrhosis
Nakamura N et al. Hepatology 2006; 45(1): 118-27
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Primary Sclerosing Cholangitis
Martin JA. Am J Gastroenterol 102 (2007)
Inflammation and fibrosis of intra‐ and/or extrahepatic bile ducts and: • EHBT involvement no longer a pre-requisite • Absence of choledocholithiasis • Absence of previous surgery
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• Bile duct fibrosis and obliteration caused by long stanging inflammation, ischemia and/or obstructive injury
• Multifactorial disease (genetic and environmental) • <50 yrs; M>F • 75% IBD (UC>Crohn); 5% of UC pts have PSC • Complications:
– Cholangiocarcinoma – 20% over 30 yrs, also GBC, CRC – Recurrence post OLT in approx. 20% cases over 5 years – Biliary tract infections (bacterial and Candida)
Primary sclerosing cholangitis
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– Labs are non-specific – p-ANCA positive (80%) – Cholangiography is diagnostic: MRCP recommended
as first-line imaging (also ERCP, PTC): short, annular strictures alternating with dilated segments (beaded appearance).
– Liver biopsy: staging, small duct PSC, exclusion of other entities (overlap PSC-AIH)
PSC Diagnosis
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Concentric periductal fibrosis
Classic histopathology of PSC
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Concentric periductal fibrosis and epithelial atrophy
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Early periductal collagen accumulation
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Fibrous obliteration of bile duct
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Fibrous obliteration of small bile duct
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• Comparison of PSC and control (PBC and HCV) explants by SAM (Carrasco-Avino G et al. AJCP 2015): – Bile duct scars – Onion-skin fibrosis of terminal and medium-size BDs – Medium-size BD loss – Arterial fibrointimal hyperplasia (75% of cases) – Less inflammatory activity
Carrasco-Avino G, et al. AJCP 2015
Distinctive histologic features of PSC
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Periductal fibrosis of terminal BD
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Arterial fibrointimal hyperplasia and periductal fibrosis
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Arterial fibrointimal hyperplasia
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• Scoring depends on adequacy (Guido et al. >22 mm, >11 portal tracts)
• No specific scoring system for PSC • Ludwig and Nakanuma systems (developed to assess
PBC) – Degree of fibrosis is of important prognostic value – Nakanuma system shows strongest predictive power:
fibrosis and orcein deposition predicted Tx-free survival and time to LTx (De Vries EDM, et al. J Hepatol 2015)
PSC Grading and Staging
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Differential diagnosis
• Tumors, • Choledocholithiasis • Past surgeries
Obstructive:
• IgG4‐associated cholangitis • AIDS-related cholangiopathy • PBC
Inflammatory:
Ischemic cholangiopathy/SSC in critically ill
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IgG4-associated cholangitis
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Storiform fibrosis
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Obliterative phlebitis
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IgG4
Dense lymphoplasmacytic infiltrates with increased IgG4+ PC
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PSC IgG4‐assoc cholangitis
Age <40 60-80
Elevated serum IgG4 10-25% 100%
IgG4/IgG1 ratio <0.24 >0.24
Cholangiography Segmental strictures, beaded appearance
One or more strictures, migrating strictures
IBD and CCa Yes No
Pancreatitis No Yes
Response to steroids No Yes
Progression to cirrhosis Yes No
Challenges: can changes be identified on random liver biopsy?
Mailette de Buy Wenniger and Beuers. Curr Opin Gastroenterol 2015 Beuers et al. Dig Dis 2015
New approaches: • HISORt criteria • IgG4+ B cell clones ny NGS (highly specific) • Blood IgG4 mRNA
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Ischemic cholangiopathy
Risk Factors • Thrombotic disorders • Systemic vasculitis • Liver transplantation (ABO
incompatible) • Hepatic intra-arterial
chemotherapy • Severely ill patients
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• Limited biopsies • PSC variants:
– Small duct PSC and – “Overlap” syndrome (PSC-AIH)
• Posttransplantation biopsies • Risk of malignancy
But this is not all…
![Page 50: PBC and PSC Revisited - USCAPhandouts.uscap.org/2016_CM10_Salo_1.pdfPrimary Biliary Cholangitis • Autoimmune chronic cholestatic disease • Middle-aged females • Fatigue, pruritus,](https://reader031.fdocuments.in/reader031/viewer/2022013021/5f0b57347e708231d43008c9/html5/thumbnails/50.jpg)
• 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
Small duct PSC
![Page 51: PBC and PSC Revisited - USCAPhandouts.uscap.org/2016_CM10_Salo_1.pdfPrimary Biliary Cholangitis • Autoimmune chronic cholestatic disease • Middle-aged females • Fatigue, pruritus,](https://reader031.fdocuments.in/reader031/viewer/2022013021/5f0b57347e708231d43008c9/html5/thumbnails/51.jpg)
• Children and young adults, more frequent than in PBC • Serology is characteristic of AIH; may begin as AIH and
progress to PSC • Small-duct PSC may be more prevalent in overlap (27%,
Olsson R et al 2009) • Consider corticosteroids/immunosuppression
Overlap syndrome (PSC-AIH)
![Page 52: PBC and PSC Revisited - USCAPhandouts.uscap.org/2016_CM10_Salo_1.pdfPrimary Biliary Cholangitis • Autoimmune chronic cholestatic disease • Middle-aged females • Fatigue, pruritus,](https://reader031.fdocuments.in/reader031/viewer/2022013021/5f0b57347e708231d43008c9/html5/thumbnails/52.jpg)
• 72% 5‐year disease‐free survival in patients with early stage perihilar Cca treated with neoadjuvant chemotherapy and transplant (Murad SD et al. Gastroenterology 2012)
• ERCP for dominant strictures – Brushing cytology/biopsy – low sensitivity – FISH
• Most sensitive: high-grade dysplasia (73%) and positive FISH (82%) (Boberg KM et al. J Hepatol 2006)
Cancer surveillance in PSC
![Page 53: PBC and PSC Revisited - USCAPhandouts.uscap.org/2016_CM10_Salo_1.pdfPrimary Biliary Cholangitis • Autoimmune chronic cholestatic disease • Middle-aged females • Fatigue, pruritus,](https://reader031.fdocuments.in/reader031/viewer/2022013021/5f0b57347e708231d43008c9/html5/thumbnails/53.jpg)
• PBC and PSC are chronic, progressive, cholestatic liver diseases that share some clinical and histologic manifestations
• PBC: – Nomenclature change from “cirrhosis” to “cholangitis” – Early biopsies may show nonspecific/reactive hepatitis – Must remember DDx (infections, sarcoidosis, DILI) and variants
(overlap, AMA-negative PBC) • PSC:
– Liver biopsy often not diagnostic: used for staging and to rule out small duct PSC and overlap syndromes
– No known etiology nor therapy is available – Clinical information is key to rule out important ddx (eg. IgG4-RD and
ischemic cholangitis) – Pre-malignant condition
Summary