1. Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to multifocal bile duct strictures. 2. PSC is diagnosed based on cholangiography showing characteristic bile duct changes along with elevated cholestatic liver enzymes and exclusion of secondary causes. 3. There is no established medical treatment for PSC, but ursodeoxycholic acid and immunosuppressants have been used to limited benefit. Endoscopic retrograde cholangiography can help relieve symptoms from dominant strictures.

1. Dr/ Mohammed Hussien
Assistant Lecturer of Gastroentrology & Hepatology
Kafrelsheikh University

2. Is a chronic, progressive cholestatic liver disease characterized by
inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading
to the formation of multifocal bile duct strictures. PSC is likely an immune
mediated, in the majority of patients PSC are associated with inflammatory bowel
disease (IBD),it may overlap other immune mediated liver diseases.
Maggs JR.,etal 2008).)
Small duct PSC is a disease variant which is characterized
by typical cholestatic and histological features of PSC
but normal bile ducts on cholangiography.
What is Primary sclerosing cholangitis (PSC)

3. Epidemiology
• The prevalence and incidence of PSC varies in different
regions of the world.
• The prevalence of PSC in ulcerative colitis has been estimated
to be ~5%.
• The prevalence of IBD among European populations with PSC
is estimated to be 50%.
• Gender : Approximately 60%–70% of patients with PSC and
UC are men, and age at diagnosis is usually 30–40 years
(Boonstra K , van Erpecum KJ , van Nieuwkerk KM et al.,2012)

4. :
Pathogenesis

6. Diagnosis of PSC
A diagnosis of PSC is made in patients with
• Cholestatic biochemical profile
• Cholangiography (e.g., magnetic resonance cholangiography
[MRC], endoscopic retrograde cholangiography [ERC],
percutaneous transhepatic cholangiography)--- shows
characteristic bile duct changes with multifocal strictures and
segmental dilatations.
• Secondary causes of sclerosing cholangitis have been
excluded.
Patients who present with clinical, biochemical and histological
features compatible with PSC, but have a normal cholangiogram, are
classified as small duct PSC.

7. • History and assessment of signs and symptoms.
• Serum biochemical tests & Autoantibodies.
• Magnetic resonance cholangiography (MRC).
• Endoscopic retrograde cholangiography (ERC).
• Liver biopsy in selected patients.
• Measuring serum immunoglobulin G4 (IgG4) levels.
Diagnosis/Evaluation

8. Signs and Symptoms
 44% asymptomatic but most develop symptoms over time.
 Pruritis, jaundice, pain and fatigue are common symptoms.
 Later on develop symptoms of cirrhosis and portal
hypertension.
 Rectal bleeding should lead to consideration of IBD as well as
bleeding from portal hypertension.
(Bjornsson E etal.,2008).

9. Biochemical Tests
• A cholestatic profile with elevation of ALP level, Gamma-
glutamyl transferase will be elevate and the aminotransferases
are often elevated.
• Hypergammaglobulinemia IgM levels are found to be
increased in ~50% of patients .
• Elevations of serum levels of IgG4 in ~10% of patients with
PSC and may represent a distinct subset .
• Elevated IgG4 levels tend to have a more rapidly progressive
disease. patients with IgG4-associated disease and PSC do
appear to respond to corticosteroids.
(All patients with PSC should be tested at least once for elevated serum IgG4 level

10. Autoantibodies
A wide range of autoanti-bodies can be detected in the serum of
patients with PSC
indicating an altered state of immune responsiveness or
immune regulation.
Serum Autoantibodies in Primary Sclerosing Cholangitis
• Anti-neutrophil cytoplasmic antibody---- 50%–80%
• Anti-nuclear antibody ----7%–77%
• Anti-smooth muscle antibody ----13%–20%
• Anti-endothelial cell antibody ----35%
• Anti-cardiolipin antibody -----4%–66%
• Thyroperoxidase -----7%–16%
• Thyroglobulin------ 4%
• Rheumatoid factor ------15%
( Portmann B etal., 2012 ).

11. Imaging
*Ultrasound, computed tomography or magnetic
resonance imaging will be performed in the patient with
persistent cholestatic liver tests to exclude biliary obstruction.
*MRCP is noninvasive, less expensive than ERCP, and
has no associated risk of pancreatitis .MRCP, however, does
not allow sampling of strictures for brush cytology or biopsy,
nor does it allow therapeutic interventions.
*ERCP had been the diagnostic procedure of choice.
.
Imaging of the biliary tract is the most important initial step.

13. Liver Biopsy
• is now seldom done to establish the diagnosis of
PSC
• Unexplained cholestastic liver tests; Small duct
PSC liver biopsy is necessary to confirm this
diagnosis .
• The characteristic feature of liver biopsy,
a periductal concentric “onion skin” fibrosis.
(Gossard AA etal., 2005).

15. Differential diagnosis of primary sclerosing cholangitis
• Secondary sclerosing cholangitis.
• Cholangiocarcinoma.
• IgG4-associated cholangitis.
• Histiocytosis X.
• Autoimmune hepatitis.
• HIV syndrome.
• Bile duct strictures.
• Cholendocholithiasis.
• Primary biliary cirrhosis.
• Papillary tumors.

16. Multidisciplinary team in Management
of Primary sclerosing Cholangitis

17. MEDICAL TREATMENT
• Ursodeoxycholic acid (UDCA)
• Immunosuppressive and other Agents
 ENDOSCOPIC MANAGEMENT
• ERCP with balloon dilatation
Surgical Management
• Biliary reconstruction
• LIVER TRANSPLANTATION
SPECIAL SITUATIONS
• PSC AND IBD
• Risk of Colonic Malignancy
• HEPATOBILIARY MALIGNANCIES AND GALLBLADDER DISEASE
• PSC-AIH Overlap Syndrome
• PSC in Children
• Immunoglobulin G4-Associated Cholangitis
• Fertility and Pregnancy in PSC
GENERAL MANAGEMENT
• The management of pruritus
• The Mangament of Portal Hypertension
• Metabolic Bone Disease
• FAT-Soluble Vitamin Deficiencies
Multidisciplinary
Management

18. Ursodeoxycholic acid (UDCA)
• In doses -------->28mg/kg/day.
• Many practitioners are using a dose of ~20
mg/kg/day.
• Although data from well-controlled clinical trials
are lacking.
 At this time, there is no established medical
treatment for patients with PSC.
( Angulo P etal., 2000)

19. Immunosuppressive and other Agents
Other treatments that have been tested without any obvious
proven clinical benefit or improvement of liver biochemistries
include:
• Azathioprine.
• Budesonide.
• Methotrexate.
• Metronidazole.
• Mycophenolate mofetil .
• Nicotine.
• Pentoxifylline .
• Prednisolone.
• Tacrolimus.
• Vancomycin.
( Angulo P etal., 2000).

20. 1 . ERCP with balloon dilatation is recommended for PSC patients with dominant
stricture and pruritus, and/or cholangitis, to relieve symptoms.
2 . PSC with a dominant stricture seen on imaging should have an ERCP with
cytology, biopsies, and fluorescence in-situ hybridization (FISH), to exclude
diagnosis of cholangiocarcinoma.
3 . Antibiotic prophylaxis to prevent post-ERCP cholangitis.
( Preoperative antibiotics followed by a 3- to 5-day course post ERCP have been advised,
using quinolones or cephalosporins ).
4 . Routine stenting after dilation of a dominant stricture is not required,
whereas short-term stenting may be required in patients with severe stricture.
ENDOSCOPIC MANAGEMENT
(Merion RM etal., 2005).

21. • Biliary reconstruction by biliary-enteric
drainage allows prolonged clinical improvement, with
resolution of jaundice and cholangitis, but has
significant risk of cholangitis and increased rates of
mortality .
• Post-operative scarring also increases the difficulty of
liver transplantation.
• Surgical drainage procedures have largely been
discontinued in favor of transplantation due to the
superior outcomes of liver transplantation .
Surgical Management

22. • Liver transplantation, when possible, is recommended
over medical therapy or surgical drainage in PSC
patients with decompensated cirrhosis, to prolong
survival.
• Patients should be referred for liver transplantation
when their Model for End-Stage Liver Disease (MELD)
score exceeds 14.
LIVER TRANSPLANTATION

23. • In specific clinical circumstances, patients with PSC may be offered
additional MELD points, to improve their priority for receiving a donor organ
for liver transplantation.
• MELD exception points can be approved by the United Network for Organ
Sharing Regional Review Board for the following.
indications:
1 . Recurrent episodes of cholangitis, with >2 episodes
of bacteremia or >1 episode of sepsis .
2 . Cholangiocarcinoma <3 cm in diameter, without
evidence of metastasis, undergoing treatment through
an institutional review board-approved clinical trial.
3 . Intractable pruritus.

24. • Recurrence of PSC after liver transplantation
Affecting as many as 20% of patients at 5 years after
transplant .
• The majority of patients tolerate recurrent disease
without significant morbidity or mortality, but
progressive disease can occur in as many as one- third
of patients with recurrent PSC.
( Angulo P etal., 2000)

25. The prevalence of IBD in PSC is much higher than previously
thought and recent reviews have stated that up to 80% of patients
with PSC have IBD
SPECIAL SITUATIONS
● Extensive colitis (with right-sided predominance of inflammatory
activity)
● Rectal sparing
● Backwash ileitis
● Mild or quiescent course
● Increased risk of colorectal neoplasia
● Increased risk of pouchitis in patients undergoing proctocolectomy
with IPAA
● Increased risk of peristomal varices in patients undergoing
proctocolectomy with ileostomy
Characteristics of Inflammatory Bowel Disease
Associated with Primary Sclerosing Cholangitis
PSC AND IBD

26. Recommendations
1 . Annual colon surveillance preferably with chromoendoscopy
is recommended in PSC patients with colitis beginning at
the time of PSC diagnosis.
2 . A full colonoscopy with biopsies is recommended in patients
with PSC regardless of the presence of symptoms to assess
for associated colitis at time of PSC diagnosis.
3 . Some advocate repeating the exam every 3–5 years in those
without prior evidence of colitis.

27. • The risk of colorectal dysplasia and cancer is significantly higher
(approximately four- to five fold) among patients with PSC and
• IBD compared with those with IBD without PSC.
• 5-Acetylsalicylic acid may also reduce the risk of colonic
malignancy
• .
***The mechanism for increased risk of colon cancer in
PSC–IBD is unknown, but exposure of the colonic mucosa
to toxic bile acids, namely secondary bile acids that may
promote carcinogenesis such as deoxycholic acid, So
(low-dose UDCA ) may be effective
Risk of Colonic Malignancy

28. • Consider screening for cholangiocarcinoma with regular
cross-sectional imaging with ultrasound or MR and serial CA 19-9 every
6–12 months.
• Cholecystectomy should be performed for patients with PSC and
gallbladder polyps >8 mm, to prevent the development of gallbladder
adenocarcinoma.
HEPATOBILIARY MALIGNANCIES AND GALLBLADDER DISEASE
( Merion RM etal., 2005).

29. .

30. *The prevalence of autoimmune hepatitis in patients with
PSC is ~10%.
*Patients with autoimmune hepatitis and PSC overlap
syndrome tend to be younger than 25 years of age.
Recommendations
1 . Further testing for autoimmune hepatitis is recommended for patients
with PSC <25 years of age or those with higher than-expected levels of
aminotransferases usually 5× upper limit of normal.
2 . MRCP is recommended for patients <25 years of age with
autoimmune hepatitis, who have elevated serum ALP usually
greater than 2× the upper limit of normal.
(Kashyap R etal.,2010)
PSC-AIH Overlap Syndrome

31. • PSC appears to be much less common among children than
adults (prevalence 20% lower than in adults ).
• PSC in children is more often associated with higher serum
aminotransferase levels and concomitant autoimmune
hepatitis, leading to the use of the term “Autoimmune
sclerosing cholangitis”.
• Cholangiocarcinoma appears to be rare & Current guidelines
do routine surveillance for cholangiocarcinoma.
(Gregorio GV ,etal.,2001)
PSC in Children

32. • IgG4-associated pancreatitis and cholangitis in
patients who present with sclerosing cholangitis & less
likely to have IBD .
• IgG4-associated autoimmune pancreatitis is
characterized by strictures in the pancreatic duct,
elevated IgG4 levels and response to
immunosuppressive therapy.
This condition may be associated with biliary
strictures and elevated plasma IgG4 levels, and liver
biopsy may reveal a lymphoplasmacytic infiltrate.
Immunoglobulin G4-Associated Cholangitis

33. • The pruritus may be so intense that early delivery may
occur by induction.
• No deterioration of liver function during or after
pregnancy has been reported, and outcome has been
satisfactory for both patients and children.
• Treatment of PSC during pregnancy with UDCA(10-15
mg/kg) has been promising, and no adverse effects in
patients or newborns have been noted.
• Regarding the effect of pregnancy on the disease course
of IBD in general, pregnancy did not influence disease
phenotype or resection rates, but was associated with a
reduction in number of flares in the years afterwards.
Fertility and Pregnancy in PSC
(Lindor KD etal.,2009)

34. The management of pruritus
• Local skin treatment should be performed with
emollients and/or antihistamines in patients with PSC
and mild pruritus to reduce symptoms
• Bile acid sequestrants such as cholestyramine should be
taken (prescribed) in patients with PSC and moderate
pruritus to reduce symptoms. Second-line treatment
such as rifampin and naltrexone can be considered if
cholestyramine is ineffective or poorly tolerated

35. The Mangament of Portal Hypertension
• Recommend screening for varices in patients with
signs of advanced disease with platelet counts <150×10
3 /dl. 4 .
• Tips (transjugular portosystemic shunt).
• Management of Ascites & Encephalopathy.
• Surgical Portosystemic Collateral ( should avoided in
patient child B & C ).
• IBD associated with PSC may require proctocolectomy
and peristomal varices develop in 25% of patients (can
be avoided by ileal pouch–anal anastomosis in place of
an ileal stoma).
(Herlong HF etal.,2001)

36. Metabolic Bone Disease
• Patients with PSC should undergo bone mineral density (BMD)
screening at diagnosis with dual energy X-ray absorption at
diagnosis and repeated at 2- to 4-year intervals.
• Fat-soluble vitamin defi ciencies can occur in late stages of PSC
• when patient becomes jaundiced. Levels of vitamins A, E, and D
• should be assessed in patients with advanced disease
(Angulo etal.,2001)

37. Measure IgG4 levels in all patients at diagnosis
Assess for varices in patients with platelet count below 150 x 103 /dl or cirrhosis.
Assess bone density every 2–4 years with dual energy x-ray absorptiometry.
‫ز‬Assess for fat soluble vitamin deficiency in patients with advanced disease/jaundice
.
Monitor liver biochemistries every 3–4 months for signs of strictures, tumors, or
symptoms of autoimmune hepatitis.
Consider screening every 6–12 months for cholangiocarcinoma with cross-sectional
imaging (ultrasound or MRI) and CA 19–9.
Provide colonscopic screening annually in patients with co-existent inflammatory
bowel disease
In patients with deterioration and a dominant stricture perform ERCP with
peri-procedure antibiotics and consider balloon dilation, with stent if needed.
Refer for liver transplantation if MELD score exceeds 14 and consider for cases
suspicious for complicating cholangiocarcinoma.

38. Prognosis
The estimated 10-year survival
for patients with PSC is
approximately 65% in a
population based study