1. Introduction to PSC: From A to Z
David N. Assis, MD
Assistant Professor of Medicine
Yale University

2. I have no disclosures relevant to this presentation.

3. Primary Sclerosing Cholangitis (PSC)
A heterogeneous, idiopathic, inflammatory disorder of the bile ducts, frequently associated with inflammatory bowel disease (IBD) of the colon, resulting in strictures of the intrahepatic and/or extrahepatic bile ducts.

4. What is bile and what does it do?
Bile is made in the liver which has a variety of important functions:
Helps to digest food
Carries waste products from the liver to the intestine
Contains bile acids, which are hormones that help regulate metabolism
Bile flows out of the liver through bile ducts

5. NIH.

6. In PSC… The bile in PSC is more toxic than normal
Increase in harmful bile acids
There is inflammation along the walls of the bile ducts
Caused by bile acids and also immune cells attracted to the bile ducts
Over time, this results in scars (strictures) of the biliary tree

7. Netter’s Gastroenterology. 2nd Edition. 2010.

8. Researchgate.

10. Primary vs. Secondary Sclerosing Cholangitis
Primary if the cause is not known
Secondary if a specific cause is known
Causes of Secondary Sclerosing Cholangitis:
Vascular injury
Cancer
Infectious
Inherited
Iatrogenic (surgical errors)

11. Categories of PSC (Variants)
Large duct PSC
Small duct PSC
PSC – Autoimmune Hepatitis Overlap
Autoimmune sclerosing cholangitis (kids)
IgG4 related sclerosing cholangitis

12. Large Duct PSC Classic form of the disease
Majority of patients have this type
Bile duct strictures can be found by imaging such as MRI or endoscopy (ERCP)
More commonly men
Strongly associated with IBD (80%)
Usually ulcerative colitis
Often causes no symptoms (asymptomatic)
Involves the entire colon

13. Small Duct PSC
The injury is limited to the microscopic bile ducts seen on liver biopsy
10% of all PSC patients
Similar patient population as large duct PSC
Often associated with colitis
Usually does not progress to large duct PSC
May have a better outcome vs. large duct PSC

14. Autoimmune Sclerosing Cholangitis
Found in some children with PSC
More inflammatory than adult PSC
May respond to immune suppressing medications

15. PSC-Autoimmune Hepatitis Overlap
5-10% of patients with PSC
Clinical features of PSC but also inflammation in the liver tissue (autoimmune hepatitis)
May start with one and later develop the other
The hepatitis responds to immune suppressing medications

16. IgG4 related Sclerosing Cholangitis
Rare!
High blood levels of immunoglobulin G4 (IgG4)
IgG4 positive plasma cells seen in the tissue
Associated with autoimmune pancreatitis
Presents with large duct scars (strictures) that
look like typical large duct PSC
Responds very well to steroids and scars
improve

17. Epidemiology of PSC Incidence 1 to 1.5 cases per 100,000 person-years
Prevalence
6 to 16 cases per 100,000 inhabitants
More common in North America & Northern Europe
Men > Women
Any age
Approximately 32,000 Americans have PSC
Definition of Rare Disease in the US: <200,000 patients at any given time.

18. Where does PSC come from?
Multiple mechanisms involved
PSC
Bile Acids
Toxic Injury
Inflammation
Immune System
Self-reacting lymphocytes
Liver-Gut Axis
Altered Microbiome
Colitis
Genetics
HLA

19. Possible causes of PSC
Various genes have been found that can increase the risk of PSC
Variations in the HLA molecule
Presents fragments of protein to the immune system
Abnormal genes account for less than 20% of the overall risk of PSC

20. PSC and Genetic Associations
Integration of Genetics and Environment?
Karlsen et al. J Hepatol 2015;62:S6–S14.

21. Environmental risk factors
Not well understood!
Smoking is protects against ulcerative colitis, and this is also seen in patients who have both PSC and colitis
Two independent studies have suggested a negative association between coffee consumption and PSC.
Lammert et al Clin Gastroenterol Hepatol 2014; 12:

22. Autoimmune PSC is an autoimmune disease
The immune system loses “tolerance to self”
Lymphocytes (white cells) are attracted to bile ducts (why?)
The link with variations in HLA molecule is likely significant

23. Liver-Gut Axis
The liver continuously receives blood coming from the intestines
Carries bacterial products, toxins, nutrition
Abnormalities in the intestine might trigger inflammation in the liver
Abnormal composition of the microbiome (organisms living in the intestines)
Are these bacteria causing PSC or responding to the different cause?

24. Toxic Bile
Increase in toxic bile acids will harm the surface of the bile ducts
Beuers et al Hepatology 2010.

25. Diagnosis of PSC Cholestasis
Difficulty in moving bile out of the liver
Results in inflammation of biliary and liver tests
Alkaline Phosphatase (ALP), Gamma GT (GGT)
Strictures
By ERCP (endoscopic retrograde cholangiopancreatography)
By MRI
Typical liver biopsy findings (only 30%)
Lack of evidence of Secondary Sclerosing Cholangitis

26. Clinical Features of PSC
Early stages
Most (but not all) patients are asymptomatic
Cholestatic tests may be the only indication of disease
Strictures may exist
Little to no scars in the liver itself
Advanced stages
Cholestasis with symptoms
Significant amount of scars in the liver itself (Cirrhosis)
Portal Hypertension (increased pressure in the veins of the abdomen)
Jaundice, weight loss, abdominal pain, ascites (fluid in the abdomen), intestinal bleeding

27. Symptoms of PSC Itching (pruritus) Fatigue Abdominal pain Cholangitis
Mineral bone deficiency

28. Itching (Pruritus) in PSC
Can be devastating! Excoriations
If sudden onset, verify that there is no blockage of the bile ducts
Best medication:
Cholestyramine 4 g 20 minutes before meals
Cannot take other medications with it
Refractory cases: rifampin, naltrexone, selective serotonin reuptake inhibitors, and plasmapheresis.

29. Bacterial Cholangitis
Sudden pain, fever, chills, jaundice
Infection of the biliary ducts, often due to blockage from a stricture
Requires antibiotics and possibly an ERCP to open a blockage

30. Mineral Bone Disease
Lack of normal bile flow in the intestine prevents absorption and processing of vitamins
A, D, E, K
Can contribute to risk of osteoporosis

31. Maintaining Bone Health in PSC
DEXA scan at presentation and every 1-3 years
Regular Exercise
Good nutrition
Minimize/eliminate alcohol intake
Calcium: mg/day
Vitamin D: IU/day
Bisphosphonates in setting of osteoporosis

32. Malignancy Risks in PSC
Cholangiocarcinoma
Cumulative risk of cholangiocarcinoma at 10 years, 20 years, and 30 years of 6%, 14%, and 20%.
Recommendation for yearly imaging
Colorectal adenocarcinoma
Need yearly colonoscopy
Gallbladder carcinoma

33. Drugs for PSC
As of now, there is no proven pharmacotherapy for the treatment of PSC that is able to reduce disease progression or improve mortality.

34. Drug Development Clear need for improvement in outcomes!
Mendes et al. Hepatology 2008;47:

35. Ursodiol
AASLD: In adult patients with PSC, we recommend against the use of UDCA as medical therapy (1A). EASL: The limited data base does not yet allow a specific recommendation for the general use of UDCA in PSC.
Hepatology. 2010;51:
J Hepatol. 2009;51:

36. Procedures in PSC? For blockages with infection or dominant strictures
A narrowing with a diameter of 1.5 mm or less in the common bile duct or 1 mm or less in the hepatic duct
As high as 50% in PSC.

38. Procedures in PSC
Short-term stenting or dilation for dominant strictures can lead to significant improvement in symptoms
However, doing this to prevent symptoms could increase the potential for bacterial cholangitis and the formation of biliary abscesses

39. Liver Transplant
Patients with signs of decompensated cirrhosis (failing liver) need to be evaluated and listed for liver transplant
Deceased Donor transplant
Living Donor transplant
PSC can recur after liver transplant (30%)

40. Summary PSC is a challenging disease
Several categories and association with other diseases (IBD)
Gradual progression in many (but not all) patients
There is an urgent need for new therapies