Primary Sclerosing Cholangitis (PSC)

Primary Sclerosing
Cholangitis-
Past and Present
Dr. Kailash Raj Makhejani
MBBS. FCPS (GI). Fellowship Transplant Hepatology (UoFT, Canada)
Consultant Hepatologist and Transplant Hepatologist
Assistant Professor, Liver Tranplant Unit
Dow University of Health Sciences, Karachi
drkrm2003@gmail.com ©kailashmakhejani @drkrm2003@gmail.com 1

Disclosure
Statement
• No Relevant Financial Relationship(s) or Non-
Financial Relationship(s)
• I have no relevant financial or non-financial
relationships in the products or services described,
reviewed, evaluated or compared in this
presentation.
©kailashmakhejani @drkrm2003@gmail.com 2

Outline for upcoming 15 to 20 minutes
Introduction Statistics Pathogenesis Clinical Features Phenotypes
Inter-relationship
with socio
economic status
Association with
IBD, Premalignant
& Malignant
Conditions
Diagnosis Treatment
Endoscopic
Treatment and
Complications
Role of
Cholangioscopy
Post Transplant
outcomes and
Transplant free
survival
Medical
management and
what's in pipeline
Role of FMT
Recurrence Post
Transplant

Primary Sclerosing Cholangitis
Williamson KD, Chapman RW. Primary sclerosing cholangitis: a clinical update. Brit Med Bull
2015;114:53--64.
It represents the greatest unmet need in modern hepatology
PSC conforms to the deﬁnition of a rare disease, affecting less than 200,000 individuals in the US and less than 5 per
10,000 inhabitants in the EU (with fewer than 250,000 individuals affected across the EU)
Despite active research during the last decades the etiology is unknown and there is still no standard medical treatment
known to affect the natural history of the disease
Named ‘black box of hepatology’
Its a rare, progressive, cholestatic liver disease
characterized by inflammation, stricturing, and concentric, obliterative fibrosis of the biliary system
leading to biliary cirrhosis, portal hypertension, and hepatic failure

.
.
. .
. .
. .
.
T.H. Karlsen et al. / Digestive and Liver Disease 42 (2010) 390–400
Landmarks in PSC

Biostatistics
Journal of Hepatology 2017 vol. 67 1298–1323
PSC Incidence: North European ancestry > other
Epidemiological
studies report
Prevalence ~ 1 per 10,000
Incidence (Northern Europe/ US): 0.4 - 2.0 per 100,000 per year.
Geographic gradient towards the South and the East
with approximately 10-fold lower prevalence rates
Spain: 0.022/10,000
Singapore: 0.13/10,000
Japan 0.095/10,000
Childhood-centric assessments have found incidence rates of 0.23 and 0.2 per 100,000 per year.

Biostatistics
Trivedi PJ et al, Epidemiology, Natural History, and Outcomes of Primary Sclerosing Cholangitis: A Systematic Review of Population-based Studies. Clin Gastroenterol Hepatol. 2021 Aug

Biostatistics
Mehta TI et al, Global incidence, prevalence and features of primary sclerosing cholangitis: A systematic review and meta-analysis. Liver Int. 2021
17/1003 studies
Spanning three continents
PSC IR: 0.60/100 000 person-years (PY)
(95% CI: 0.37-0.88).
PSC prevalence: 0 – 31.7/100 000
persons
Concurrent IBD: 50%
76% UC, 17% CD, and 8% indeterminate

Mehta TI, et al,Global incidence, prevalence and features of primary sclerosing cholangitis: A systematic review and meta-analysis. Liver Int. 2021
Bimodal Age Distribution

PSC and Liver Transplantation
Fosby B, Melum E, Bjøro K, Bennet W, Rasmussen A, Andersen IM, et al. Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982–2013. Scand J
Gastroenterol 2015;50:797–808. https://doi.org/ 10.3109/00365521.2015.1036359.
Organ Donation and Transplantation Activity Report 2017 / 18. NHSBT 2018
Although rare, PSC now accounts for 10–15% of all liver transplant activity in European liver transplant
programmes
Is one of lead indication for transplantation in Nordic countries
Remains the fifth most common indication for liver transplantation in the USA and a leading indication in several
other countries, likely owning to the nebulous role of pharmacological therapy in this disease
Several studies indicate the incidence of PSC is increasing. Whilst this may be partly attributable to the
application of magnetic resonance cholangiography (MRC) rather than ERC, the clinical features of newly
diagnosed patients appear stable over time, which indicates an earlier diagnosis may not explain the increase.

Pathogenesis
• The pathogenesis is poorly understood,
but following factors are involved
(Epi-)genetic factors
Innate
and
adaptive
immunity
Toxic effects of
hydrophobic bile
acids
Intestinal
dysbiosis
Lindor KD, Kowdley KV, Harrison ME. ACG clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol 2015;110:646-659.
Karlsen TH, Folseraas T, Thorburn D, et al. Primary sclerosing cholangitis: a comprehensive review. J Hepatol 2017;67:1298-1323.
•An immunologically mediated process is supported by known associations with
human leukocyte antigens
Genome-wide association studies have identiﬁed 23 genome-wide signiﬁcant (p
≤10 –8 ) risk loci that positions autoimmune processes central to the pathogenesis
of PSC
Another theory involves bacterial translocation to the biliary tree based on an
animal model of bacterial overgrowth and link with ulcerative colitis.
Certain gene mutations including cystic fibrosis transmembrane receptor (CFTR)
mutations have also been associated with the development of PSC

Gut-Liver Axis
Fibrosis
Integrated overview of the pathophysiology of primary sclerosing cholangitis
(PSC)

Natural history in primary sclerosing cholangitis (PSC)

PSC Phenotypes
Sarkar S, Bowlus CL. Primary Sclerosing Cholangitis: Multiple Phenotypes, Multiple Approaches. Clin Liver Dis. 2016 Feb;20(1):67-77. doi: 10.1016/j.cld.2015.08.005. Epub 2015 Oct 6. PMID: 26593291;

Clinical Presentation
Prokopič, M., Beuers, U. Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol
It can present as isolated imaging abnormalities, biochemical changes, cholangiocarcinoma,
or end-stage complications such as cirrhosis.

PSC & PBC
Journal of Clinical and Translational Hepatology 2020 vol. 8 | 336–346

PSC & IBD
Trivedi PJ et al, Epidemiology, Natural History, and Outcomes of Primary Sclerosing Cholangitis: A Systematic Review of Population-based Studies. Clin Gastroenterol Hepatol. 2021 Aug
30:S1542-3565(21)00919-8.

Lifetime incidence of various cancers associated with primary sclerosing cholangitis and their respective risks compared with the general
population.
Fung BM, Lindor KD, Tabibian JH. Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies. World J Gastroenterol 2019; 25(6): 659-671
PSC & Cancers

The algorithmic approach
Hepatology International (2021) 15:6–20
Algorithmic approach to diagnosis of PSC
The algorithmic approach to the patient with cholestasis

Images
ERCP Image MRCP Image

Algorithm for the management of suspected primary sclerosing cholangitis.
Michael Huw Chapman et al. Gut 2019;68:1356-1378
Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Chapman MH, Thorburn D, Hirschfield GM, et al British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut 2019;68:1356-1378.
Clinical scores are an emerging theme, but no single method has been recommended at
present
Prognostic scores used for PSC

Prognostic Scores in use

Transplant free survival

Current Therapeutic approaches

Medications under evaluation in randomized, placebo-controlled
trials for the treatment of PSC
Prokopič M, Beuers U. Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol Int. 2021 Feb;15(1):6-20. doi: 10.1007/s12072-020-10118-x. Epub 2020 Dec 30. PMID: 33377990;
PMCID: PMC7886831.

• Nor-Ursodeoxycholic acid (nor-UDCA) a more potent inducer of bile flow than UDCA
• been tested in a phase II study in PSC patients and was found to have a good safety profile and treatment with nor-UDCA
was associated with reduced ALP levels in a dose dependent manner, up to 26% in the group given the highest dose. Phase
III trial is ongoing.
• Obethicolic acid (OCA), the selective farnesoid X receptor agonist marketed for PBC,
• has also been tried in a phase II trial in PSC.
• Treatment with OCA was associated with a significant reduction in ALP in patient receiving 5-10 mg OCA vs. placebo but not
significantly in those receiving 1.5-3.0 mg.
• Antibiotics, in particular vancomycin, have shown positive effects on ALP in PSC patients,
both children and adults. As with other medical therapy phase III clinical trials are still
lacking.
• Results of liver transplantation are favorable but recurrence can be of clinical relevance
particularly in patients transplanted before the age of 40.

Endoscopic management of PSC
Barkin JA, et al. Annals of Hepatology 2017; 16 (6): 842-850

EASL/AASLD
Summary points of the EASL and AASLD practice guidelines on primary sclerosing cholangitis (PSC)
T.H. Karlsen et al. / Digestive and Liver Disease 42 (2010)
390–400

Fung BM, Lindor KD, Tabibian JH. Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies. World J Gastroenterol 2019; 25(6): 659-671
Overview of cancer surveillance in patients
with primary sclerosing cholangitis,
beginning at time of primary sclerosing
cholangitis diagnosis.
This overview is based on
recommendations from the American
Association for the Study of Liver Disease
practice guidelines
Cancer surveillance & PSC

Fung BM, Lindor KD, Tabibian JH. Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies. World J
Gastroenterol 2019; 25(6): 659-671
Suggested cholangiocarcinoma
surveillance in patients with primary
sclerosing cholangitis.
Cancer surveillance & PSC

EMERGING MODALITIES FOR EVALUATION OF BILIARY STRICTURES
• Several new technologies are currently being investigated
• Probe-based confocal laser endomicroscopy (CLE)
• For evaluation of PSC-associated strictures and differentiating from non-PSC strictures
• Data still limited but Heif, et al shows 100% sensitivity, 61.1% specificity
• Positronemission tomography (PET) scanning
• Complimentary use of PET scanning with brush cytology for early identification of high-grade dysplasia and
cholangiocarcinoma in those with dominant strictures was advocated by Sangfelt, et al. who showed improved
performance when adding PET scanning compared to brush cytology alone.
• Additional studies revealed some potential utility of PET scanning in diagnosis of cholangiocarcinoma, with potential
benefit compared to traditional CT or MRI.
• Widespread feasibility and performance of PET scanning in this area remain to be seen.

EMERGING MODALITIES FOR EVALUATION OF BILIARY STRICTURES
• Intraductal ultrasound
• Intraductal ultrasound for evaluation of strictures was proposed approximately 10 years ago
with some promising initial data with sensitivity of up to 86% for identification of
malignancy but has not caught on in routine clinical practice to date.
• In the future, much like of FISH, or next generation DNA sequencing in the evaluation of
pancreatic cyst fluid, additional genetic and molecular markers may be developed to improve
identification of cholangiocarcinoma in PSC.

PSC & Liver Transplantation
• Liver transplantation
• Life-threatening complications of cirrhosis
• Recurrent cholangitis
• Cholangiocarcinoma in conjunction with neoadjuvant chemotherapy (for selected patients)
• On a prognostic level
• Serum ALP >/= 2.4 times the ULN are at increased risk of LT
• Post-LT survival for PSC is excellent
• 1-year = 93.4%
• 3-year = 89.7%
• 5-year = 87.4%,
• 10-year = 83.2%

Recurrent PSC
• Rates of rPSC are reported to occur in 20% to 25% of patients over 10 years
• Diagnosis is often challenging and exclusion of other causes of biliary strictures must be ruled out
• Hepatic artery thrombosis,
• Anastomotic strictures,
• Non-anastomotic strictures occurring less than 90 days post-LT,
• Donor-recipient ABO incompatibility,
• Chronic ductopenic rejection
• Diagnostic criteria of rPSC include a
• Diagnosis of PSC prior to LT
• Cholangiographic appearance of non-anastomotic intrahepatic and/or extrahepatic bile duct strictures
with irregularities and beading occurring more than 90 days post-LT
• Some advocate the use of a diagnostic liver biopsy demonstrating concentric fibrous cholangitis and/or
fibro-obliterative lesions to make a diagnosis of rPSC although this is less well-accepted

Recurrent PSC
• Risk factors for rPSC
• Still unclear that why it recurs
• IBD is risk factor
• Decreased frequency of rPSC following colectomy prior to LT
• Presence of UC post-LT is associated with the development of rPSC
• In those without a prior history of UC, development of de novo colitis increases the risk
• These studies underscore the importance of colonic disease post-LT and suggest that the
management with either prophylactic colectomy or the treatment of IBD is protective against the
development of rPSC.

Recurrent PSC
• Occurrence of ACR post-LT is a risk factor
• Studies from North America and Netherlands show increased rPSC with more episodes of ACR
• link of rPSC with rejection may be inflammation of the biliary epithelium that occurs in acute cellular rejection
leading to damage of the bile ducts
• There is possibility that increased use of immune suppression and immune reconstitution may influence the development of rPSC
• Donor-recipient cytomegalovirus mismatch
• Graft quality including increased donor age and extended donor criteria grafts
• Higher MELD
• Higher INR
• Use of MMF and cyclosporine
Chen C, Ke R, Yang F, et al. Risk factors for recurrent autoimmune liver diseases after liver transplantation: a meta-analysis. Medicine 2020;99:e20205

Recurrent PSC
Mack CL, Adams D, Assis DN, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice
Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020;72:671-

In a nutshell

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Primary Sclerosing Cholangitis (PSC)

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