diagnosis, surveillance, and management. Dr George Webster - PowerPoint PPT Presentation

HKASLD 27 th Annual Scientific Meeting 2014 Primary Sclerosing Cholangitis – diagnosis, surveillance, and management. Dr George Webster University College London and Royal Free Hospitals London UK george.webster@uclh.nhs.uk

Overview • Making the diagnosis • Investigation • Management • Surveillance: • HPB • Colon • Other • Future developments

Definition • PSC is a chronic, cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to the formation of multifocal bile duct strictures. • Diagnosis made in patients with cholestatic LFTs, charecteristic cholangiographic changes (MRC, ERC, PTC), and no suspicion of secondary causes of SC AASLD Guideline Chapman et al Hepatology 2010;51:661-679

Making the diagnosis

Causes of sclerosing cholangitis • • Eosinophilic CholangioCa cholangitis • PSC • Histiocytosis X • Gallbladder Ca • Stone disease • Mirrizzi ’ s Syn • Parasites (Clonorchis, • IgG4-SC Ascaris) • Ischaemic • HIV • Post-surgical • Intra-arterial • Peridochal chemotherapy varices/cavernoma • Hilar nodes • Sarcoidosis

Cholangiographic differentiation of IgG4-SC, PSC, CCA IgG4 -SC CCA IgG4-SC PSC IgG4-SC PSC

Use of ERCP to differentiate PSC, IgG4-SC, CCA • Multicentre study: UK (UCH), USA (Mayo clinic), and Japan • 48 good-quality ERCs (20 IgG4-SC, 10 PSC, 10 CCA, 8 duplicates) sent to 17 physicians from these centres • Physicians noted the presence or absence of key ERC features and ranked diagnostic possibilities All USA UK Japan n=17 n=4 n=7 n=6 Sensitivity 45%(36-54%) 51% (25-78%) 42% (25-59%) 44% (24-64%) Specificity 88% (83-93%) 88% (68-100%) 86% (77-95%) 90% (82-98%) • Low sensitivity risks inappropriate surgery for presumed Despite high specificity for diagnosing IgG4-SC using ERC, sensitivity was uniformly low even among CCA, and no steroids for presumed PSC, based on physicians with large experience. interpretation of ERC alone Kalaitzakis E at Clin Gastroenterol Hepatol 2011;9:800-03.

Similarities and differences between IgG4-SC and PSC PSC IgG4-SC M:F 2:1 8:1 ≈ 65 Age at diagnosis (years) 25-45 Associated with IBD +++ + Associated pancreatic dis. +/- +++ Associated cholangioca. +++ - Other organ involvement - +++ Cholangiographic findings Beading. Band- Segmental and distal like strictures bile duct strictures. ≈ 70% Elevated serum IgG4 7-9% IgG4+ plasma cell infiltrate +/- ++ Response to steroids - ++

Elevated Serum IgG4 Concentration in Patients with Primary Sclerosing Cholangitis Mendes DF et al Am J Gastroenterol 2006;101:2070 – 2075  127 PSC patients  Raised serum IgG4 in 9% (compared with 1% of PBC p=0.017)  Significantly higher Bn, ALP, PSC Mayo score, and lower rate of IBD.  Shorter time to OLT if IgG4 raised.

IgG4+plasma cell infiltrates in liver explants with PSC Zhang L et al. Am J Surg Pathol 2010;34:88-94. • 99 consecutive OLTs for PSC 1996-2005 • H+E and IgG4+ immunostaining of liver • 23 (23.2%) liver explants showed increased (>10/HPF) IgG4+ periductal plasma cell infiltrate, with close correlation with lymphoplasmacytic inflammation. Dense periductal fibrosis in all. • IgG4 positivity correlated with shorter duration of PSC before OLT (5.3 ± 4.6yrs vs 8.5 ± 6.2yrs p=0.03), and higher risk of recurrence.

Natural history of PSC  65% 10 year survival from diagnosis  Mean time to death or transplantation 10-18 years  In those not transplanted, death due to:  cholangiocarcinoma (58%)  liver failure (30%)  variceal bleeding (9%).  Better prognosis with small duct PSC (v low risk CCA), but 23% develop large duct PSC.  Child-Pugh and Mayo score poorly predict prognosis in individual patients

Elastography in PSC Corpechot C et al Gastroenterology. 2014;146(4):970-9 • 73 pts with PSC and liver biopsy • Liver stiffness measurement (LSM) using vibration- controlled transient elastography (VCTE). • Diagnostic accuracy for severe fibrosis and cirrhosis were 0.83 and 0.88, respectively. • LSM better than FIB-4 score, and Mayo risk score in differentiating patients with significant or severe fibrosis from those without. • VCTE differentiates severe from non-severe liver fibrosis • Baseline measurements of LSM and longitudinal changes are prognostic factors for PSC.

Cancer in PSC standard Site of cancer observed expected incidence ratio colon/rect 12 1.2 10.3 Hepatobiliary 53 0.3 160.6 [inc CCA;HCC;GB cancer] pancreas 5 0.3 9.7 Incidence ratio for first Bergquist et al, J Hepatol 2002;36:321-327 cancer n = 604

Cumulative risk of developing colorectal dysplasia/cancer Disease 10 20 30 duration years years years UC alone 2% 5% 10% UC/PSC 9% 31% 50% Broome et al,Hepatology 1995

Dominant strictures in PSC  <1.5mm diameter stricture in CBD, < 1mm hepatic duct  Usually associated with rise in LFTs  45-58% of patients with PSC  Majority of strictures benign, but excluding malignancy is paramount

Dominant strictures in PSC UCL Experience • 128 patients with PSC (64% male, mean age 49 years) • Mean 9.8 years FU. • Eighty patients (62.5%) with dominant biliary strictures • Endoscopic interventions: stenting alone (46%); dilatation alone (20%); dilatation and stenting (17%) • The mean survival of those with dominant strictures (13.7 years), compared those without dominant strictures (23 years) • Difference due to 26% risk of CCA in patients with dominant strictures • 50% of CCAs presented within 4 months of PSC diagnosis. Chapman MH, Webster GJ et al Eur J Gastroenterol Hepatol. 2012;24:1051-8

Bile Duct Carcinomas in PSC Observation No. of Cancer Author / Centre time (years) patients (%) Wiesner (1989), Mayo 19 6 174 Farrant (1991), KCH 6 5.8 126 Broome (1996), Sweden 8 5.2 305 Stiehl (2002), Heidelberg 3 5.0 106 Chapman (2011), UCLH 16 8.9 128 Chapman MH, Webster GJ et al Eur J Gastroenterol Hepatol. 2012;24(9):1051-8

How do we investigate biliary stricturing? • Pancreatic protocol CT • MRI/MRCP • Serum CA19-9 • ERCP + brush cytology • Perc Bx (for unresectable cases) • EUS

CA19.9 in detection of cholangiocarcinoma in PSC King ’ s Index CA 19-9 + (CEA x 40) >400 =cholangioca 90% spec; 60% sens A=PSC/cholangio • Ramage et al, Gastro 1995 B=PSC/transplant C=PSC

Diagnosis of biliary tract strictures Routine cytology • Specificity 90% for diagnosis of malignancy • Low sensitivity (20-40%) • Need for better diagnostic tests

Cholangioscopy for PSC strictures • Direct endoscopic examination of biliary strictures likely better than cholangiography (cf colonoscopy v enema) • 53 PSC pts with dominant strictures (12 confirmed malignant on eventual histology/cytology) Cholangioscopy ERCP Sensitivity 92% 66% Specificity 93% 51% Accuracy 93% 55% Tischendorf Endoscopy 2006;38: 665-9

Spyglass cholangioscopy for biliary strictures in sclerosing cholangitis • Diagnosing malignancy in PSC particularly challenging • UK + Swedish experience Sclerosing Non-SC single P value cholangitis (SC) stricture controls (n=54) (n=54) Sensitivity 50% 55% ns Specificity 100% 97% ns Accuracy 88% 80% ns Cholangitis 11% 1.9% P<0.005

Pathological sampling in biliary strictures Hartman DJ Clin Gastroenterol Hepatol 2012:10;1042-6 • Fluoroscopic v cholangioscopic (Spybite) biopsies • 89 patients with indeterminate strictures • Sufficient samples in 94.4% • More tissue from intraductal biospies (more Bx fragments p=0.018, larger Bx size 0.001) Specificity Sensitivity Accuracy Fluoro. Bx 100% 76% 88% Spybite Bx 100% 57% 78% • “ More biopsies, and larger bites, may improve sensitivity of Spybite biopsies ”

Probe based confocal laser endomicroscopy (pCLE) • 1mm probe passed down duodenoscope or cholangioscope • Real-time visualisation of cell-to-cell borders, single-cell CHF-B260 structures, mucosal inflammation, and vessel structures. • Flurescein is given IV 1-2 min prior to image acquisition n Sensitivity Specificity pCLE 98% 67% Normal Biliary cytology 45% 100% Meining A et al. Gastrointest Endosc 2011:74;961-8 CCA

High definition cholangioscopy - The future (remembering enema v colonoscopy) NBI

Management • Medical • Endoscopic (dominant strictures) • Cancer surveillance • HPB • Colonic • Surgery/Transplantation

Medical treatment for PSC • No role for immunosuppression demonstrated (except in PSC/AIH overlap) • Intermediate dose UDCA (15-20mg/kg/day) improves biochemistry and histology, but not clinical outcome • Possible reduction in colonic (and biliary) neoplasia, but most studies retrospective

“ Randomised double-blind controlled trial of high-dose UDCA for PSC ” Lindor FD et al. Hepatology 2009;50:808-14  150 patients with PSC (ALP >1.5ULN; Liver Bx; characteristic cholangiogram)  Stratified by stage, varices, Mayo score  UDCA 28-30mg/kg/day v placebo  Endpoints:  Progression to cirrhosis  Development of varices  CholangioCa  Transplant  Death

Results  Significant improvement in ALP + AST in UDCA group at 12, 24, 36 mths UDCA Placebo End-point 52 27 reached n= Death 4 2 Transplant 11 4 Varices 15 5  UDCA posed > x2 risk of death/OLT compared with placebo