PSC: Diagnosis, natural history,

pharmacological and endoscopic

treatmentAnnarosa Floreani

Dept. of Surgical and Gastroenterological Sciences

University of Padova - Italy

Primary sclerosing cholangitis

Diagnosis

Natural history

Pharmacological and

endoscopic treatment

PSC variants

AIH

~ 10% “AIH-like” adult PSC

PSC/AIH overlap syndrome

~ AIH 10% in adult PSC

~ AIH 25% in children

Small-duct PSC

~ 10% of total PSC

- separate entity vs “early PSC”?

IgG4 associated cholangitis (IAC)

~ 10% of PSC patients (?)

- pancreatic involvement

Diagnosis of PSC/AIH overlap by use of the modified

AIH score

AIH

~ 10% “AIH-like” adult PSC

Author Country N. of PSC

pts

% with

overlap

van Buuren, 2000 Netherlands 113 8%

Kaya M, 2000 USA 211 1.4%

Floreani, 2005

2010

Italy 41

79

17%

12.6%

Al-Chalaby, 2008 UK 211 6.1%

IgG4-associated PSC

Ghazale A et al, Gastroenterology 2009

Clinical profile

older (mean age 62 yrs)

men (85%)

presenting with obstructive

jaundice (77%)

associated with AIP (92%)

abundant IgG4 infiltrate in

biopsy duct specimens (88%)

Normalization of liver

enzymes with steroids (61%)

Cholestatic biochemical profile

No biliary dilation

at ultrasound

Diagnostic of

large duct

PSC

ERCP

Diagnosis (AASLD guidelines)

Non diagnostic

MRCP

Normal

Liver biopsy for

diagnosis of Small

Duct PSC

Normal Diagnostic of

large duct

PSC

Diagnosis

AIH

~ 10% “AIH-like” adult PSC

Is made in patients with a cholestatic profile

when cholangiography shows characteristic

bile duct changes with multifocal strictures and

segmental dilatations

MRC

OR

ERC

OR

Percutaneous

Transhepatic

cholangiography

Meta-analysis of diagnostic performance of MRC

AIH

~ 10% “AIH-like” adult PSCParameter Estimate

Sensitivity 0.86 (0.80, 0.90)

Specificity 0.94 (0.86, 0.98)

Positive LR 15.3 (6.2, 38.1)

Negative LR 0.15 (0.11, 0.21)

Diagnostic score 5 (4, 6)

DOR 101 (38, 268)

6 manuscripts with 456 patients

Dave M et al, Radiology 2010

ERCP

Bangarulingam SY et al, AJG 2008

Diagnosis

PSC (n=168)

Non-PSC (n=981)

The incidence of cholangitis was

higher in the PSC group (4% vs 0.2%,

P<0.0002) despite routine use of

antibiotics

Intra- and Extrahepatic ducts:

Ductal dilation

Ductal stenosis

Skip dilation

Intrahepatic ducts:

Beading

Pruning

Mural irregularities

CTC Cholangiographic features

Cholangio-TC vs cholangio-MR

Macchi, Floreani et al, Digest Liver Dis 2004

Diagnosis of PSC with CholangioMR

47%23%

15%0% 15%

Diagnosis of PSC with CholangioCT

77%

15%8% 0%0%

Present

Probably

present

Equivocal

Probably

absent

Absent

PSC was identified in 12 cases with CTC and 10 cases with MRC (test 2; p<0.05)

In the presence of an abnormal

cholangiogram, not required to establish a

diagnosis of large duct PSC

Essential in suspected small duct PSC

and overlap syndromes

Periductal “onion-skin” fibrosis may be

also observed in secondary SC

Role of liver biopsy

Diagnosis

AASLD guidelines Hepatology 2010AISF guidelines 2001

Diagnosis

138PSC

30No hepatic biopsy

108Hepatic biopsy

29Biopsy BEFORE

Cholangiography

79Biopsy AFTER

Cholangiography

1Management

changed

78No management

changed

OverlapPSC/AIH

1complication1,3%

Burak et al. Am J Gastroenterol 2003

Kasper et al, Pathol Res Pract 2010

PBC PSC Obstruction DILD

CK7

Biliary cytokeratin expression in non-

neoplastic bile duct disease

Olsson, Gastroenterology 1991; Loftus, Gut 2005Broome, Semin Liver Dis 2006; Mendes F, AJG 2007; Floreani et al, unpublished

PSC

PSC+IBD

IBD in PSC: 48-86%

IBD

IBD+PSC

PSC in IBD: 2.4-7.5%

PSC and IBD

IBD in PSC

AIH

~ 10% “AIH-like” adult PSC

Most often classified as UC

Rectal sparing (Loftus EV at al, Gut 2005)

Extensive 90% (Chapman R et al, Gut 1980; Schrumpf E et al,

Scand J Gastroenterol 1989; Broomè U et al, Semin Liver Dis 2006)

Mild course; right > left colon (Loftus EV et al, Gut 2005;

Lundqvist K et al, Dis Colon Rectum 1997)

High frequency of pouchitis (50-75%)

risk of cancer (right site)

risk of pauchitis in patients undergoing

proctocolectomy (Kartheuser AH eta al, Mayo Clin Proc 1996;

Penna C et al, Gut 1996)

Primary Sclerosing Cholangitis

Diagnosis

Natural history

Pharmacological and

endoscopic treatment

PSC modeled as a chronic liver disease

•Dominant stricture

•Cholangitis

•Cirrhosis

•Portal hypertension

•ESLD

•Cholangiocarcinoma

•IBD

•Colon cancer

Pre-symptomatic

Symptomatic

Irreversible damage

Birth Death

Outcomes variables in PSC challenges

AIH

~ 10% “AIH-like” adult PSC

Undefined basis of disease heterogeneity

Unpredictable events (Cholangiocarcinoma)

Management of IBD, pauchitis and colorectal

cancer

Lack of efficient therapy

MELD vs dysplasia/pruritus/fatigue/recurrent

cholangitis

from: WR Kim, Hepatology 2006

100

80

60

40

20

0 5 10 15

Death or OLTx

Death

8 yrs

14 yrs

Duration (yearsi)

Su

rviv

al

Progressive disease!

Natural history

Kim WR, et al. Mayo Clin Proc 2000;75:688-694

Mayo Clinic(n=174)

King’s College (n=126)

Multicenter (n=126)

Swedish (n=305)

Age Age Age Age

Bilirubin Hepatomegaly Bilirubin Bilirubin

AST Histologic Stage Histologic Stage Histologic Stage

Variceal bleeding

Splenomegaly Splenomegaly

AlbuminAlkaline

phosphatase

New !!

Prognostic models in PSC

We recommend against the use of

prognostic models for predicting clinical

outcomes as no consensus exists

regarding optimal model (1B).

AASLD Guidelines 2010

Validation of a cholangiographic prognostic model

Ponsioen CY et al, Endoscopy 2010

Estimated transplant-free survival can be appreciated by drawing a vertical line

from the total points SUMIHEHD score

Age

Points

Classification

Points

Total points

1-yrs survival

5-yr survival

10-yr survival

20 50 604030

C2

0 8

C3

15

C4

35 4025 30

47 29

200

70

98

94

5 10

96

89 82

90

72

15

6376859094

3.3132847

0.22.09.2

637684

244259

0 2 5 8 11 14

Changes over a 20-year period in the clinical

presentation of PSC in Sweden

N. 246 pts diagnosed between 1984 and 2004

Bergquist A et al, Scand J Gastroenterol 2007

Variables significantly correlated with survival

AIH

~ 10% “AIH-like” adult PSC Symptomatic vs asymptomatic pts

Dominant strictures

Small duct variant

AIH/PSC overlap variant

IgG4 variant

Variability disease course

Broomè 1996

Asymptomatic better prognosis

Tishendorf 2007

In PSC with dominant stenosis, IBD is associated

with an increase in carcinomas

N=171 pts with a prospective follow-up of 20 years

Rudolph G et al. J Hepatol 2010

Dominant stricture = stenosis with a diameter <1.5 mm in the common bile duct

or <1 mm in the hepatic duct

Small-duct PSC

Bjornsson et al, Gut 2002

N=33 vs n=260 with large

duct PSC [Oxford and Oslo]

Median follow-up: 106 vs

105 months

Bjornsson et al, Gastroenterology 2008

N=83 vs n=166 with large

duct PSC [Europe and USA]

Median follow-up: 11 yrs

Long term AIH/PSC overlap syndrome

AIH

~ 10% “AIH-like” adult PSC

Luth S. et al, J Clin Gastroenterol 2009

n=16 patients with a median observation period of 12

years; at the end 75% suffered from cirrhosis

AIH/PSC (# 10) Classical PSC (# 69) p

Mean age 23.4 ± 8.5 33 ± 13.8 <0.05

Male:female ratio 5:5 37:32 n.s.

AST (U/L) 177.3 ± 52.8 77 ± 37.3 <0.0001

ALT (U/L) 299.5 ± 25.2 111 ± 145.5 <0.01

ALP (U/L) 270.2 ± 179.6 216 ± 204.9 0.976 n.s.

GGT (U/L) 285.9 ± 374.2 216 ± 204.9 0.371 n.s.

Tot bilirubin (mg/dL) 1.5 ± 1.1 2 ± 6 0.811 n.s.

Albumin (g/dL) 4.1 ± 0.3 4.1 ± 0.4 0.791 n.s.

PT (%) 88.9 ± 8.2 91 ± 16.5 0.4745 n.s.

IgG (g/L) 24.7 ± 4.1 16 ± 3 <0.0001

IgA (g/L) 2 ± 1 1.2 ± 0.9 <0.05

IgM (g/L) 3.4 ± 1.4 2 ± 1.1 0.176 n.s.

HCV + 0 (0%) 4 (5%) n.s.

IBD 2 (20%) 32 (46.4%) <0.01

Clinical features at presentation

Antoniazzi S et al, Monotematica AISF 2010

300250200150100500

1,0

0,8

0,6

0,4

0,2

0,0

CU

MU

LA

TIV

E S

UR

VIV

AL

FOLLOW-UP (months)

• Global median survival 272.7 (CI 95%: 219.9-325.4)• Cumulative probability of survival at 240 months: PSC 73.6%

AIH/PSC 87.5%

AIH/PSCPSC

Kaplan-Meier survival curves

Antoniazzi S et al, Monotematica AISF 2010

Patients with high IgG4 levels have a more

severe course

Mendes FD et al, AJG 2006

Prevalence and predictors of esophageal

varices

Zein CO, et al, Hepatology 2004

283 pts with PSC treated for 8 consecutive years; 102

(36%) had esophageal varices

Predictors of varices:

PLT count <150 x 103/dl

Albumin <3.3 g/dl

Advanced histological stage (3-4)

Algorithm for screening and surveillance of

varices in PSC

Treepprasertsuk S et al, Hepatology 2010

Long standing UC in PSC patients is a predisposing condition for the

development of colon cancer (Broome U et al, Hepatology 1995; Kornfeld D

et al, Gut 1997, Brentnall TA, et al, Gastroenterology 1996)

Development of colon cancer pre-OLTx

Colo-rectal cancer in PSC without

IBD:

10 years: 2%

20 years: 2%

Colo-rectal cancer in PSC + IBD:

10 years 14%

20 years: 31%

Claessen M et al, J Hepatol 2009

from: Broome, Semin Liver Dis 2006

Presence of IBD at diagnosis of PSC?

Therapy with

UDCA, 5-ASA

Yearly Colonscopy

Consider

colectomy

Dysplasia

SI NO

No Dysplasia

Continue yearly

follow-up

Ileum-colonscopy with

multiple biopsies

IBDNO IBD

New colonscopy if

suspected IBD

PSC, IBD e colon cancer

Development of colangiocarcinoma

CCC in PSC

10 years: 9%

20 years: 9%

Claessen M et al, J Hepatol 2009

Diagnostic accuracy of Ca 19-9 for CCA

Author N.pts Cut-offSensitivy

%

Specificity

%

PPV

(%)PNV (%)

Lindberg et al. 2002 28 100 67 89 91 63

Siqueira et al 2002 44 180 67 98 - -

Chalasani et al. 2000 27 100 75 80 - -

Patel et al. 2007 36 100 53 - - -

Kim et al 2004 152 37 73 63 - -

Bjornsson et al. 1999 18 37(200) 63 (38) 50 (81) 16 (38) 90 (91)

Ramage et al. 1995 15 100 60 91 - -

Buffet et al 1996 14 40 92 72 84 85

Nichols et al. 1993 9 100 89 86 - -

Kuusela et al 1991 14 37 76 74 - -

Ker et al 1989 18 37 61 72 - -

Charatcharoenwitthaya

et al 2008

23 (in PSC) 20 78 67 23 96

AISF Guidelines for CCC

Markers tumorali

Insulin-like Growth Factor I

Alvaro D et al, Ann Int Med 2007

73 pazienti con ittero ostruttivo sottoposti

a ERCP:

29 colangioCC

19 ca. del pancreas

25 colestasi benigna

Surveillance for colangiocarcinoma

Charatcharoenwitthaya et al. Hepatology 2008

FOLLOW UP

Dynamic FDG-PET is useful for detection of CC in PSC

patients listed for liver tranplantation

Prytz H et al, Hepatology 2006

N=24 pts within 2 weeks after listing for OLTx and with no evidence of

malignancy on CT, MRI, US

3 patients were diagnosed with CC by PET

Colangite Sclerosante Primitiva

Diagnosis

Natural history

Pharmacological and

endoscopic treatment

Therapeutic goals

Cure PSC

Improve QoL: relieve symptoms

Prevent disease progression

Prevent hepatobiliary cancer

Prevent colon cancer in PSC/IBD

Strenght of recommendation

Strong (1): quality of the evidence, presumed patient’s important outcomes, and cost

Weak (2): Less certainty, higher cost or resource consumption

Quality of evidence

High (A): Further research is unlikely to change confidence in the estimate of the clinical effect

Moderate (B): Further research may change confidence in the estimate of the clinical effect

Low (C): Further research is very likely to impact confidence on the estimate of clinical effect

Grading of recommendation and quality of evidence

UDCA and PSC: meta-analysis of RCTs

Shi J et al, Hepatol Res 2009

8 RCT including 465 pts

UDCA significantly improved liver biochemistry,

but had no effect on pruritus and fatigue

UDCA had no significant effect on the incidence

of death, liver transplantation, and death and/or

liver transplantation

UDCA showed a significant difference in the

incidence of histological deterioration (p<0.05) and

a trend in improving cholangiographic changes

Low dose UDCA* vs mod dose UDCA**

Survival free of liver tranplantation

*Lindor et al, NEJM 1997 **Olsson J Hepatol 2004

Death/Tranplantation:

7.2% UDCA vs 10.9% placebo (ns)

Summary on high dose-UDCA in PSC

Cullen et al, 2008 Lindor, Hepatology 2009

High dose UDCA trial

*Lindor et al, Hepatology 2009In adult patients with PSC, we recommend against the use

of UDCA (1A). AASLD Guidelines 2010

Pardi DS et al. Gastroenterology 2003; 124: 889

Bruce Y et al, Ann Int Med 2001; 134: 89

UDCA as a chemopreventive agent in colon cancer

RIFA UDCA

CYP3A4

Bilirubin-Glucuronide

6a-Hydroxy Bile Salts Bile Salts

K+

Observed effects of RIFA and UDCA on

hepatobiliary transport systems

Hydrophobic Bile Salts

MRP3

MRP4

BSEP

MDR3UGT1A1 MRP2

Phospholipids

Organic Anions

Glutathione

Marschall H-U et al, Gastroenterology 2005

May be beneficial in PSC/AIH in pediatric or

adult patients

Indicated in the subgroup with IgG4-associated

autoimmune cholangitis (IAC)/autoimmune

pancreatitis (AIP)

(Bjornsson E, Hepatology 2007)

Corticosteroids

In adult patients with PSC and overlap syndrome, we

recommend the use of corticosteroids and other

immunosuppressive agents for medical therapy (1C).

AASLD Guidelines 2010

Standard regimen of steroids for AIP

Nishimori I , Otsuki M, Best Pract & Res

Clin Gastroenterol 2009

Tacrolimus (FK506)

1 open study in 10 pts: improvement in LFTs, no assessment of liver

histology (Van Thiel DH, AJG 1995) 2C

Clabidrine

No effect on symptoms, LFTs and cholangiograms (Duchini A, J

Clin Gastroenterol 2000) 2C

Etanercept

1 pilot study in 10 pts for 6 months: no clinical efficacy (Epstein MP,

DDS, 2004) 2C

Pentoxifilline

1 pilot study in 20 pts: no effect (Bharucha AE, AJG 2000) 2C

Immunosuppressive and other agents

Methotrexate

no beneficial effect alone or in combination with UDCA (Knox TA,

Gastroenterology 1994; Lindor KD, AJG 1996) 2B

Azathioprine

no controlled trials, only case reports with conflicting data 2C

Cyclosporin

No improvement in biochemical indices (Javett, Lancet 1971)

Beneficial in a case report in combination with Prednisolone

(Kyokane, Hepatogastroenterology 1994) 2B

Immunosuppressive and other agents

Future prospects

New bile acids

Nuclear receptor agonists

Biologics: Adhesion molecule blockers

Long term antibiotics

Delineation of genetic pathophysiology will

lead to new therapeutic target

24-norUDCA in treatment of sclerosing cholangitis in Mdr2

knockout mice (Fickert P et al, Gastroenterology 2006)

Immunoistochimica con Anti-CK19

Sirius Red

H & E

Side chain structure determines unique physiologic and

therapeutic properties of norUDCA in Mdr2 knockout mice

Halibasich E et al, Hepatology 2009

Metronidazole and UDCA: a randomized placebo-

controlled trial

Farkkila et al, Hepatology 2004

Change in

histology

Stage n(%)

UDCA + placebo

(n=36)

UDCA + MTZ

(n=32)

Improvement

No change

Worsening

5 (14%)

20 (56%)

11(34%) p<0.047

9 (28%) p<0.022

12 (38%) ns

Grade n (%)

Improvement

No change

Worsening

6 (17%)

15 (42%)

15 (41%)

14 (44%) p<0.014

9 (28%) ns

9 (28%) ns

Metronidazole and UDCA: a randomized placebo-

controlled trial

Farkkila et al, Hepatology 2004

n=41 UDCA/placebo vs 39 UDCA/MTZ

Stiehl, Semin Liver Dis 2006AASLD guidelines, 2010

Goal=relieve biliary obstruction

Biliary sphinterotomy and balloon dilatation

with or without stent placement

dilatation up to 18-24 Fr in the common bile duct

dilatation up to 18 Fr in hepatic ducts

Performing brush cytology and/or endoscopic biopsy to exclude a

superimposed malignancy is recommended

Multiple dilatations may be useful

Antibiotic prophylaxis is recommended

Endoscopic management

Brushing

Brush citology

Boberg KM et al, J Hepatol 2006

Sensibilità 100%

Specificità 84%

Valore predittivo positivo 68%

Valore predittivo negativo 100%

Accuratezza 88%

0

20

40

60

80

100

Survival

Predictedsurvival

Baluyut, Gastroint Endosc 2001; Stiehl, J Hepatol 2002; Gluck, J

Clin Gastroenterol 2008

p=0.027

p<0.001

Impact of endoscopic management on survival

P=0.021

Baluyut Stiehl Gluck

Cholangioscopy

Peroral cholangioscopy (POCS) and percutaneous

transhepatic cholangioscopy (PTCS) first developed

in 1970

POCS is significantly superior to ERCP in

distinguishing between malignant and benign

dominant bile duct stenoses

The positive rate of PTCS biopsy for CCA is 96%

Nimura Y, Review HPB 2008

Performance N=40* N=34**

Sensitivity 88% 64%

Specificity 91% 95%

Accuracy 90% 82%

PPV 70% 90%

NPV 97% 79%

IDUS (intraductal ultrasound) for malignant vs

benign stenosis

*Tischendorf JJW et al, Scand J Gastroenterol 2007; **Levy M et al,

AJG 2008

Composite digital

image analysis +

fluorescence in situ

hybridization may

improve the accuracy

Malignant stricture: 1) hypoechoic and infiltrating; 2: a) abnormal morphology

(asymmetry, notching and shelf-like); b) suspicious lymph nodes (hypoechoic,

round, and smooth-border);

Take home messages:

1. PSC is a heterogeneous disease with a natural history which

depends on several variables

2. Full colonoscopy with biopsies in new diagnosis is

mandatory

3. Surveillance for CCA and colo-rectal cancer is

recommended

4. Patients with IBD should be treated according to guidelines

for IBD

5. No strong evidence exists for the use of UDCA

6. Evidence exixsts against high dose UDCA

7. Corticosteroids/immunosuppressant are recommended in

AIH/PSC overlap, and in IgG4-associated PSC