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

HKASLD 27th 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

• f 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

• 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

Cholangiographic differentiation of IgG4-SC, PSC, CCA

PSC CCA IgG4-SC IgG4-SC PSC IgG4-SC

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%)

Kalaitzakis E at Clin Gastroenterol Hepatol 2011;9:800-03.

• Despite high specificity for diagnosing IgG4-SC using

ERC, sensitivity was uniformly low even among physicians with large experience.

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

Low sensitivity risks inappropriate surgery for presumed CCA, and no steroids for presumed PSC, based on interpretation of ERC alone

Similarities and differences between IgG4-SC and PSC

PSC IgG4-SC M:F 2:1 8:1 Age at diagnosis (years) 25-45 ≈ 65 Associated with IBD +++ + Associated pancreatic dis. +/- +++ Associated cholangioca. +++

• Other organ involvement
• +++

Cholangiographic findings

• Beading. Band-

like strictures Segmental and distal bile duct strictures. Elevated serum IgG4 7-9% ≈ 70% 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%

• f 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.

• 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

Natural history of PSC

• 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.

Elastography in PSC

Corpechot C et al Gastroenterology. 2014;146(4):970-9

Incidence ratio for first cancer n = 604

Site of cancer

• bserved

expected standard incidence ratio colon/rect 12 1.2 10.3

Hepatobiliary

[inc CCA;HCC;GB cancer]

53 0.3 160.6

pancreas 5 0.3 9.7

Bergquist et al, J Hepatol 2002;36:321-327

Cancer in PSC

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

• <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

Dominant strictures in PSC UCL Experience

Chapman MH, Webster GJ et al Eur J Gastroenterol Hepatol. 2012;24:1051-8

• 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.

Bile Duct Carcinomas in PSC

Author / Centre

Wiesner (1989), Mayo Farrant (1991), KCH Broome (1996), Sweden Stiehl (2002), Heidelberg Chapman (2011), UCLH

• No. of

patients Cancer (%)

174 126 305 106 128 19 6 8 3 16

Observation time (years)

6 5.8 5.2 5.0 8.9

Chapman MH, Webster GJ et al Eur J Gastroenterol Hepatol. 2012;24(9):1051-8

• Pancreatic protocol CT
• MRI/MRCP
• Serum CA19-9
• ERCP + brush cytology
• Perc Bx (for unresectable cases)
• EUS

How do we investigate biliary stricturing?

CA19.9 in detection of cholangiocarcinoma in PSC

King’s Index

CA 19-9 + (CEA x 40) >400 =cholangioca 90% spec; 60% sens

• Ramage et al, Gastro 1995

A=PSC/cholangio B=PSC/transplant C=PSC

Diagnosis of biliary tract strictures

Routine cytology

• Specificity 90% for diagnosis
• f 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

Sclerosing cholangitis (SC) (n=54) Non-SC single stricture controls (n=54) P value Sensitivity 50% 55% ns Specificity 100% 97% ns Accuracy 88% 80% ns Cholangitis 11% 1.9% P<0.005

• Diagnosing malignancy in PSC particularly challenging
• UK + Swedish experience

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”

CHF-B260

n Sensitivity Specificity pCLE 98% 67% Biliary cytology 45% 100%

• 1mm probe passed down duodenoscope or cholangioscope
• Real-time visualisation of cell-to-cell borders, single-cell

structures, mucosal inflammation, and vessel structures.

• Flurescein is given IV 1-2 min prior to image acquisition

Probe based confocal laser endomicroscopy (pCLE)

Normal CCA Meining A et al. Gastrointest Endosc 2011:74;961-8

NBI

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

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 reached n= 52 27 Death 4 2 Transplant 11 4 Varices 15 5

• UDCA posed > x2 risk of death/OLT compared with

placebo

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..”

AASLD guideline 2010

But:

• Improves LFTs
• Role in paediatric PSC
• Patient preference!!

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

Culver EL, Williamson KD, Chapman RW 2014

Mayo Group

• 18 IgG4+ PSC pts treated with steroids
• 9/10 jaundiced pts had steroid response
• Adverse events in 39% (eg DM)
• 50% relapse rate

Bjornsson E, Chari S et al Am J Ther 2011

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)

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

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

Colonoscopic surveillance in PSC

Diagnosis of PSC

Colonoscopy with surveillance biopsies at diagnosis 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. 2013 Sep;145(3):521-36.

IBD No IBD

• 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)

Surveillance for HPB cancer in PSC

Surgery/Transplantation

End-stage PSC

• 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)

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