Chronic Biliary Disease. Dr Susan Davies & Dr Bill Griffiths
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1 Chronic Biliary Disease Dr Susan Davies & Dr Bill Griffiths
2 Chronic Biliary Disease Terminology is confusing with pathologists and hepatologists using the same language BUT with different meanings. Chronic cholestatic syndromes but no cholestasis Alteration of terminology, ductular reaction not proliferation, biliary interface not piecemeal necrosis, bilrubinostasis not cholestasis, intermediate cells c.f. metaplasia or aberrant phenotype, feathery = ballooning? Cholangiopathy - radiology or pathology? What actually is cholate stasis?
3 Further problems Disease processes are heterogeneous in distribution AND affected bile ducts may not be sampled Major biliary diseases have an autoimmune pathogenesis; inflammation can mask the biliary abnormalities Bilirubinostasis and ductular changes seen in other aetiologies; ALH, HCV, NAFLD Changes often subtle and regularly causes difficulties (central reviews)
4 Chronic Biliary Disease Important histological features
5 Ductular reaction & biliary interface
6 Peripheral haloing due to biliary interface activity
7 Ductular reaction highlighted by CK 7
8 Cholate stasis copper associated/ binding protein demonstrable Victoria Blue
9 CK7 immunohistochemistry, with hepato-biliary metaplasia/ ductal/aberrant phenotype/ intermediate phenotype
10 Ductopenia with CK 7
11 Chronic Biliary Disease Clinician s perspective on terminology Cholestatic LFTs ALP, GGT, (Bili) cf ALT Cholangiopathy = radiologically abnormal biliary system Small duct vs large duct
12 Large duct Primary Sclerosing Cholangitis
13 Questions: Biliary Disorders - clinical presentation Pruritus? Associated disorders (autoimmune, IBD etc)? Family history? Drug history? Imaging: Ultrasound / MRCP
14 Chronic Biliary Disease Role of liver biopsy if diagnosis unclear but other scenarios eg?mixed aetiology Confirm drug induced Lack of response to treatment
15 Cases
16 Case 1 72 yr female c/o pruritis LFTs - ALP 670 u/l, GGT 3775 u/l, ALT 120 u/l ANA weakly positive Negative for AMA, SMA, LKM, ds DNA USS normal Liver biopsy performed
17 Histology case 1 reticulin
18
19
20 Case 1 features Portal granulomatous inflammation with duct destruction Ductopenia Focal periportal copper associated protein Mild fibrosis Diagnosis Primary Biliary Cholangitis
21 Japanese staging system Nakanuma Histopathology 2006 Histological staging Fibrosis (F) Absent or limited in portal tracts Periportal fibrosis (incomplete septa) Bridging fibrosis Cirrhosis Bile duct loss (B) Absent <1/3 portal tracts 1/3 2/3 portal tracts >2/3 portal tracts Chronic cholestasis (C) (orcein +ve) * Absent <1/3 periportal areas 1/3 2/3 periportal areas >2/3 of periportal areas
22 Case 1 - further clinical Diagnosis: AMA negative PBC Started Ursodeoxycholic acid (UDCA) AlkPhos now 146 with otherwise normal LFTs Has developed anti-centromere antibody Oesophageal variceal bleed 2016
23 Biopsy in PBC Diagnosis unclear NB extended serology panel may help for PBCspecific antinuclear antibodies (gp210, sp100, sp140, PML, p62, LBR) Suspected mixed aetiology Non-response to UDCA
24 Case 2 65 yr female Known to have PBC for >15 years Classical serology AMA+, M2+, PDH+ Sicca syndrome Treated with UDCA At age 58 - rising IgG 26 (normal <16 g/l) Normal ALT and negative serology Proceed to liver biopsy in view of IgG
25 Histology case 2
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27
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29 Histology case 2 Mixed features: Ductopenia, biliary interface, features of cholate stasis Plasmacytosis, rosetting, florid interface & lobular hepatitis. Suggests Overlap PBC and Auto-Immune Hepatitis
30 Case 2 Diagnosis: metachronous PBC/AIH overlap Prednisolone & Azathioprine added 7 yrs on: IgG 9.6 g/l
31 PBC/AIH overlap Variable incidence 2-20%, due definitions May be simultaneous or with follow-up IAIHG histology 3 categories of AIH Interface hepatitis, lymphoplasmacytic infiltrate, rosetting Paris criteria for overlap - 2 of 3 diagnostic from each AP >x2, AMA +ve, histology - florid duct lesions ALT >x5, IgG >x2 or SMA+ve, histology mod/severe piecemeal necrosis Anti-ds DNA seem more common in overlap.
32 Case 3 70 yr female Asymptomatic, central adiposity, HTN Incidental finding of abnormal LFT ALP 250, GGT 270 Liver USS normal Negative autoantibodies and Ig s Unusual pattern of LFT for NAFLD
33 Case 3 MRCP
34
35
36
37 Orcein
38 CK 7
39 Case 3 Duct destruction/ sclerosis, periductal oedema (onion skinning) and cholangiolitis Dutopenia Cholate stasis Suggests Primary Sclerosing Cholangitis
40 Case 3 Diagnosis: small duct PSC Liver biopsy in PSC: May not be necessary if classical cholangiopathy, evidence of IBD etc Useful where diagnosis in doubt or?overlap
41 Case 4 73 yr female 6 months intermittent upper abdo pain 1.5 stone weight loss + jaundice CT showed biliary dilatation and ampullary lesion Whipples resection for ampullary adenocarcinoma Intra-operatively? Cirrhotic Liver biopsy
42
43
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46 Case 4 Biliary pattern fibrosis Oedema and acute inflammation Ductular reaction Cholate stasis No significant duct damage or ductopenia Secondary biliary cirrhosis
47 Case 5 34 year old male Incidental finding of some peripheral dilated ducts on CT for appendicitis late 2014 MRCP confirmed cholangiopathy Asymptomatic, normal LFTs Not clear if PSC or congenital Proceeded to liver biopsy
48 MRCP Abnormal biliary tree with focal dilatation and widespread strictures. Possibilities would include a cholangiopathy related to PSC, ischaemia, parasitic infection - congenital syndromes such as Caroli's seem less likely.
49
50 EPSR EVG
51
52 Victoria blue - elastic, no CAP
53 Case 5 Irregular, rounded map-like fibrosis, with abnormal ductules Little inflammation No bilirubinostasis or cholate stasis Ductal plate malformation Congenital Hepatic fibrosis
54 Ductal plate malformation Choledochal cyst Caroli s Polycystic Liver Disease Congenital Hepatic Fibrosis Von Meyenburg Complex Increasing size of affected Bile duct
55 Case 6 73 yr female Diagnosed glioblastoma multiforme and treated with debulking, radiotherapy and Temozolomide chemotherapy (alkylating agent) ALT rose from 58 to 2220, bilirubin 125, ALP 456 Thought acute hepatitis, Temozolomide stopped LFTs remained abnormal - bilirubin 450 and ALP 999, ALT 2310 Proceeded to liver biopsy
56 Little inflammation, perivenular pigment Scant portal infiltrate, with eosinophils
57 Bile plugs in canalicula & hepatocytes Ongoing duct injury
58 IHC CK 7
59 Case 6 Profound bilirubinostasis, with cholestatic rosettes, feathery degenration Little necroinflammation ; ceroid within Kupffer cells Extensive ductopenia, without ductular reaction Vanishing bile duct syndrome Died with liver failure
60
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62 Conclusions Diagnosis of chronic biliary disease can be subtle and challenging Ancillary stains are necessary Full clinical, serological and radiological correlation is crucial Evolving reasons for biopsy in the diagnosis of PBC and PSC VBD syndromes may be life-threatening
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