Primary Sclerosing Cholangitis diagnosis, surveillance, and management.

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1 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

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

3 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:

4 Making the diagnosis

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

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

7 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 n=17 USA n=4 UK n=7 Japan 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 CCA, and no steroids for presumed PSC, based on interpretation of ERC alone Despite high specificity for diagnosing IgG4-SC using ERC, sensitivity was uniformly low even among physicians with large experience. Kalaitzakis E at Clin Gastroenterol Hepatol 2011;9:

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

9 Elevated Serum IgG4 Concentration in Patients with Primary Sclerosing Cholangitis Mendes DF et al Am J Gastroenterol 2006;101: 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.

10 IgG4+plasma cell infiltrates in liver explants with PSC Zhang L et al. Am J Surg Pathol 2010;34: consecutive OLTs for PSC 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.

11 Natural history of PSC 65% 10 year survival from diagnosis Mean time to death or transplantation 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

12 Elastography in PSC Corpechot C et al Gastroenterology. 2014;146(4): pts with PSC and liver biopsy Liver stiffness measurement (LSM) using vibrationcontrolled 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.

13 Cancer in PSC Site of cancer observed expected standard incidence ratio colon/rect Hepatobiliary [inc CCA;HCC;GB cancer] pancreas Incidence ratio for first cancer n = 604 Bergquist et al, J Hepatol 2002;36:

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

15 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

16 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

17 Chapman MH, Webster GJ et al Eur J Gastroenterol Hepatol. 2012;24(9): Bile Duct Carcinomas in PSC Author / Centre No. of patients Observation time (years) Cancer (%) Wiesner (1989), Mayo Farrant (1991), KCH Broome (1996), Sweden Stiehl (2002), Heidelberg Chapman (2011), UCLH

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

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

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

21 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

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

23 Pathological sampling in biliary strictures Hartman DJ Clin Gastroenterol Hepatol 2012:10; 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

24 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 Normal pcle 98% 67% Biliary cytology 45% 100% CCA Meining A et al. Gastrointest Endosc 2011:74;961-8

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

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

27 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

28 Randomised double-blind controlled trial of high-dose UDCA for PSC Lindor FD et al. Hepatology 2009;50: 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

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

30 UDCA in PSC Conclusions High dose UDCA should not be used in PSC Intermediate doses may improve biochemistry, but not disease course In adults with PSC we recommend against the use of UDCA.. But: Improves LFTs Role in paediatric PSC Patient preference!! AASLD guideline 2010

31 Steroids for IgG4+ PSC? Oxford Group 26/186 (14%) had elevated serum IgG4 7/26 received trial of steroids 5/7 (71%) had objective response to steroids (reversible changes on MRCP in 1 pt) 3/5 (60%) relapsed on stopping steroids Mayo Group 18 IgG4+ PSC pts treated with steroids Culver EL, Williamson KD, Chapman RW /10 jaundiced pts had steroid response Adverse events in 39% (eg DM) 50% relapse rate Bjornsson E, Chari S et al Am J Ther 2011

32 Bone protection Bone densitometry at diagnosis, and then every 2-3 years Osteoporosisin 4-10% of patients with PSC Osteopaenia (T score 1 to 2.5): Calcium 1-1.5g, and vit D 1000 IU daily Osteoporosis (T score > -2.5): Calcium + Vit D, plus bisphoshonates (give parenterally if known varices/portal hypertension)

33 Endoscopic Balloon dilatation v stenting for dominant (benign) PSC strictures? Move away from stent alone DILSTENT 2 European multicentre trial (coordinated by AMC) Patients with PSC + dominant stricture, and no intervention for 4/12 Randomised to balloon dilatation v balloon + short term stenting

34 Colonoscopic surveillance Significant proportion of right sided lesions No clear definitive data on when to start, extent of disease.. Consensus guidelines for yearly colonoscopy in patients with colitis and PSC Suggested commence colonoscopic surveillance as soon as diagnosis of PSC made

35 Colonoscopic surveillance in PSC Diagnosis of PSC Colonoscopy with surveillance biopsies at diagnosis No IBD IBD Reassess for IBD/polyps/CRC Repeat colonoscopy in 5 years CRC screening Annual colonoscopy. Continue after OLT Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Gastroenterology Sep;145(3):

36 Surveillance for HPB cancer in PSC Annual gallbladder U/S (cholecystectomy if polyps any size) No clear role for surveillance for CCA (? 6-12 monthly CA19.9, US, MRCP) In cirrhotics, 6 monthly US + AFP (endoscopic variceal assessment in cirrhotics)

37 End-stage PSC Surgery/Transplantation OLT is only treatment that improves outcome in advanced disease(meld > 12) > 80% 5 year survival post-olt for PSC Timing of referral difficult (suggest early rather than later) Main reason for death prior to OLT is CCA. Recurrence of PSC in graft in 20-25% at 10 years Cholangiocarcinoma: Local resection rarely feasible in PSC, but may cure 80% recurrence of CCA in PSC patients transplanted 65% 5 year survival in highly selected patients transplanted for CCA, following chemotx + radiotherapy (ext + intrabiliary)

38 Summary Diagnosis of PSC may be made non-invasively, but be aware of other causes Disease progression unpredictable, but malignancy a major cause of death Advances in investigation of dominant biliary strictures No established role for medical therapy Surveillance for HPB and colonic malignancy is vital Transplantation highly effective, but recurrence in graft may occur