Post on 20-Dec-2021
Jonathan Potts PhD MRCPConsultant Hepatologist & HPB Endoscopist
jonathan.potts@nhs.net @PBEndoscopist
Hepato Pernambuco
13th July 2021
Sheila Sherlock Liver Centre, Royal Free & UCL Institute Of Liver & Digestive Health
Primary Sclerosing CholangitisOptimal management
OutlineOptimal PSC management
• Overview of PSC
- definition, diagnosis & natural history
• Current treatments
- Symptomatic, disease modifying
- ERCP
- Liver transplantation
• Patient experience in PSC
- symptom burden, psychological impact, unmet need
• Therapies under evaluation
• General management
• Cancer surveillance
PSC: Definition and prevalence
1. Karlsen TH, et al. J Hepatol 2017;67:1298–323;
ESGE/EASL CPG Endoscopy in PSC. J Hepatol 2017;66:1265–81
Image © Kari C Toverud CMI 2017
Chronic bile duct disease
• Multifocal bile duct strictures and progressive liver disease1
• IBD coexists in 70%
• Prevalence 1–16/100,000
• Regional differences across Europe
• More common in men
IBD phenotype
• Pan-UC with right-sided predominance
• Subtle ileal inflammation and rectal sparing are common
• Often more quiescent course
• Pouchitis more common
• Increased and unpredictable risk of biliary and colonic malignancy
Macroscopic bowel and bile duct pathology in PSC1
‘Backwash’
ileitis
Colonic
cancer
Pancolitis with
right-sided
predominance
Rectal sparing
Cholangiocarcinoma
Multifocal bile duct
strictures and dilatations
Diagnosis of PSC
- Unexplained cholestatic biochemistry
- Characteristic cholangiography
(MRCP superseded ERCP)
- multifocal strictures & segmental dilatations
- Secondary sclerosing cholangitis and other cholestatic disorders excluded.
EASL Cholestatic Liver Disease Guidelines J Hepatol 2009
PSC: Differential Diagnosis
PSC: Natural History
IPSCSG phenotype paper – 7,121 patients / 37 centres / 1980-2010
Male 65.5%, mean age of diagnosis 38 years, 70% with concomitant IBD
Weissmuller, Trivedi et al. Gastroenterology 2017
36.4%
Median survival 14.5 years
Event rate 5.1 per 100 patient years
Boonstra et al. Hepatology 2013
Medical managementTherapeutic Efficacy of UDCA in PSC
Beuers
(n=14)
Stiehl
(n=20)
Lindor
(n=105)
Mitchell
(n=26)
Olsson
(n=219)
Lindor
(n=150)
Dose
(mg/kg/d)
13-15 10-12 13-15 20 17-23 28-30
LFTs + + + + 0 +
Histology (+) (+) 0 +
ERCP/MRCP 0 0 -
Survival 0 0 -
Placebo Controlled Trials
Medical Management: UDCA• Early studies: biochemical improvement with 10-15mg/kg
• No improvement in outcomes/LT-free survival
• High dose (25-30mg/kg) terminated prematurely due to
increased incidence of SAEs, LT or death in UDCA group
• Stopping: associated with deterioration in biochemistry,
• no data on outcomes
Lindor 2009
Medical Management: immunosuppression
• No benefit in PSC from:
pred/aza/budesonide/CYA/methotrexate/MMF/anti-TNF
• PSC/AIH overlap:
• Compatible transaminases, IgG elevation & auto-abs
• Biopsy advised
• Treat dominant disease as per classical AIH
• AIH may evolve into PSC
• PSC with elevated IgG4 vs IgG4-SC1
• ?distinct, more aggressive clinical phenotype
• IgG4:1 ratio may help distinguish
• Immunosuppressant response not defined
1. Manganis WJG 2020
ERCP for Dominant Strictures in PSC:
What are the benefits?
Baluyut GIE 2001
63 PSC pts underwent
repeat therapeutic ERCP for
DS, median FU 34 mo
Gluck J Clin Gastroenterol 2008
106 PSC pts (84 with DS)
underwent 317 therapeutic
ERCPs, Mean FU 8 years
5-year survival:
Observed 83%
Predicted 65% p=0.03
4-year survival:
Observed 83%
Predicted 71% p=0.02
DILSTENT Study
Design: Prospective RCT of ERCP in PSC, 100 pts without
prior sphincterotomy, 9 European centres
Results: Stopped after interim analysis (65 patients)
recu
rre
nce fre
e p
ate
ncy o
f th
e s
tric
ture
Treatment-related AEs
17/65 (26%):
Pancreatitis 10/17
Cholangitis (4/17)
Stent (42%) v Dilatation (10%)
(OR=6.4, 95% CI 1.6–25.4).
Ponsioen et al. Gastroenterology 2018
2019 BSG guidelines on ERCP in PSC
Role of MDM: ERCP only after expert multidisciplinary
discussion (Strong recommendation / moderate evidence)
Antibiotic Prophylaxis for ERCP advised
(Strong recommendation / moderate evidence)
Role of Imaging: MRCP/liver MR +/- contrast CT to
evaluate (Strong recommendation / moderate evidence)
Tissue Sampling: Sampling of Dominant strictures
mandatory (Strong recommendation & evidence)
Choice of ERCP intervention: biliary dilatation preferred
to stenting (Strong recommendation / moderate evidence)
BSG 2019
Immune targets
Anti-fibrotics
Bile acid therapy
PSC: Targets for Treatment
PSC: Trials of New TherapiesBile Acid Manipulation
• Nor-URSO (Falk) – phase 3
• n=161, 12wks; 4wk f/u, dose dependent ALP
• Obeticholic Acid (FXR agonist; Intercept) – phase 2
• n=76, 24 wks, OCA 5-10mg ALP
• GS-9674 (non-steroidal FXR ag; Gilead) – phase 2
• n=52, 12 wks, dose dependent ALP
• NGM-282 (FGF19 analogue NGM Bio) – phase 2
• n=62, 12 wks, ALP, fibrosis biomarkers
Immune Modulation
• VAP-1 inhibitor (BTT1023; Birmingham) – phase 2
• Vedoluzimab (Takeda) – phase 2
• No biochemical signal in retrospective series
PSC: Symptoms & Patient Experience
Patient Survey: March 16
Most difficult part of living
with PSC (n = 340)
PSC: symptomatic & general management
Fatigue & Depression: Seek & treat alternative causes
Strong recommendation/low evidence
Pruritus:Cholestyramine (1st line) / Rifampicin/Naltrexone (2nd)
Weak recommendation/low evidence
Bone Disease: Osteoporosis assessment / treatment in all
Strong recommendation/moderate evidence
Nutrition: Empiric supplementation of fat-soluble vitamins
weak recommendation/moderate evidence
Other considerations:
Pregnancy
Support groups
BSG 2019
PSC: HPB Malignancy
IPSCSG phenotype paper (n=7,121)
Weissmuller & Trivedi Gastroenterology 2017
10.9%
21.6%
Cholangiocarcinoma
82% of malignancies
38% detected within 1st
year of diagnosis
Weissmuller, Trivedi et al. Gastroenterology 2017
PSC Management: CholangiocarcinomaRole of Ca 19-9: Routine measurement not advised
Weak recommendation / moderate evidence
Suspected CCA: specialist cancer MDT review essential
Strong recommendation / moderate evidence
Work-up: Contrast cross sectional imaging preferred
diagnostic/staging investigation
Confirmatory histology:
ERCP brush +/- FISH
Cholangioscopy
EUS-guided biopsy
Percutaneous bx
Strong recommendation / high evidence
BSG 2019
Investigation of suspected cholangioca
BSG 2019
PSC Management: Cancer Surveillance
Gallbladder Cancer: Annual surveillance ultrasonography
Intervention for polyps guided by cancer MDT
Weak recommendation / low evidence
HCC: surveillance as per cirrhosis guidelines
Weak recommendation / Low evidence
Colon Cancer: PSC-IBD annual surveillance colonoscopy
5 yearly / symptom lead if no IBD
Weak recommendation / very low evidence
BSG 2019
PSC: an excellent indication for OLTx
Risk adjusted transplant survival for adult
first elective transplantation; 2000-11
60
70
80
90
100
0 1 2 3 4 5
% 5 year survival HBV 86.9 PBC 83.0 PSC 79.5
33.9
26.9
25.1
21.6
21.1
15.4
12.4
5.8
0
10
20
30
40
Primarybiliary
cirrhosis
Sclerosingcholangitis
Cryptogeniccirrhosis
Autoimmunecirrhosis
Posthepatitis Bcirrhosis
Alcoholiccirrhosis
Posthepatitis Ccirrhosis
Cancer
Life
exp
ecta
ncy (
ye
ars
)
Primary liver disease
Overall 3.2 years lost
after OLT compared with
matched UK population
(26.0 v 29.2 years)
PSC: when to consider transplantation?
Journal of Hepatology 2017 vol. 67 j 1298–1323
Mayo PSC risk score: http://www.psc-literature.org/mrscalc.htm
UK-PSC risk score: http://www.uk-psc.com/resources/the-uk-psc-risk-scores/
OLT in PSC: Specific challenges
Referral
Assessment
&
Listing
TransplantPost-
transplant care
Patient Selection
Graft
Selection
Biliary
Anastomosis
Recurrent
PSC
Management of IBD
?transplantation for perihilar CCA
53% 5 year survival in Mayo series with neoadjuvant chemorad
Algorithm for PSC management
BSG 2019
The challenges of PSC in 2021….
Rare disease
• Few patients in mixed
GI practice
Unfavourable natural history
• <50% transplant free survival at 10 yrs
Patient experience
• Symptom burden
• Psychological impact
Lack of effective medical
therapy
• ‘Surgical’ management of
advanced disease
Complex disease
• Several phenotypes
• IBD Association (70%)
Young male patient
population
• Median age of
diagnosis <40yo
Weissmuller et al. Gastroenterology 2017
Boonstra et al. Hepatology 2013
Cancer risk
• Cholangiocarcinoma (>20% 20yr)
• Colorectal (10x higher risk than UC)
Thank you!
Questions?
Thanks to the RFH Team:Professor Doug Thorburn, Dr Aileen Marshall & Dr Beverley Kok
Dr Neil Halliday
Prof Alberto Quaglia, Dr Tu Vinh Luong, Dr Jen Watkins
Dr Neil Davies, Dr Dominic Yu, Dr Nick Woodward, Dr Anthie Papadopoulou
Transplant co-ordinators and research nursing staff