Management of PSC Case 1 Dr RW Chapman Oxford, UK Management of - - PowerPoint PPT Presentation

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Management of PSC Case 1 Dr RW Chapman Oxford, UK Management of - - PowerPoint PPT Presentation

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Management of PSC Case 1 Dr RW Chapman Oxford, UK Management of PSC Case 1 Mrs A.O. 45 yr old Secretary Caucasian PMH 1977 - developed total ulcerative colitis at 12 - treated with salazopyrine 1 gm bd - colitis quiescent until 1991

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SLIDE 1

Management of PSC

Case 1

Dr RW Chapman Oxford, UK

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SLIDE 2

Management of PSC

Case 1

Mrs A.O. – 45 yr old Secretary – Caucasian PMH 1977 - developed total ulcerative colitis at 12

  • treated with salazopyrine 1 gm bd
  • colitis quiescent until 1991

1996– developed severe attack of UC requiring hospital admission / iv steroids / blood transfusion

  • symptoms settled on treatment

Abnormal LFT’s noted - Asymptomatic

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SLIDE 3

Management of PSC Case 1

2001 – Abnormal LFT’s AST - 75 IU/l ( NR 15-40 ) AlK Phos - 820 IU/l ( NR 80-250 ) GGT - 552 IU/l ( NR 10-50 ) Alb - 42 g/l Bili - 16 umol/l 2001 – ERCP – “diffuse IH/EH PSC”

  • No treatment
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Primary Sclerosing Cholangitis

Risk factors

 Male gender  Environmental factors eg. Non-smoker

(cp PBC)

 IBD  Genetic predisposition

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PSC and Inflammatory Bowel Disease

PSC -uncommon but increasing prev: 7-9/100,000 pop 20/100,00 pop latest: 25/100,000 (2011) (Olmstead County,USA South Wales,Sweden)

PSC -70-80% have assoc IBD

PSC -occurs in 5-10% of Total UC

  • underestimate?

ERCP MRC P

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SLIDE 6

PSC & Inflammatory Bowel Disease*

Total UC with normal LFT’s

.6/55 (12%) abnormal MRCP

.ALL 10pts DR3 +/pANCA + 4M:6F /Smokers .cp 0/30 age matched controls *Bungay et al; GUT 2008

MRCP UC with Dysplasia /cancer : 12% have PSC

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Clinical Features of UC assoc with PSC “PSC-UC” –

Different clinical phenotype?

 Male predominance [2:1] /different genotype  Total in distribution – but symptomatically mild  Rectal sparing in 23% -cp 5% of UC alone  Backwash Ileitis in 64%-cp 18% of UC alone

  • backwash ileitis assoc with colon ca /dysplasia

 Extra colonic manifestations different (HLA)

  • rheumatoid arthritis,no skin or eye involvement

 Increased rate pouchitis post colectomy

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SLIDE 8

Current gene status in IBD/PSC 2013

Found in PSC with and without IBD – BCL 211- encodes Bim – major effect on immune tolerance

Found only in PSC pts with IBD-Macrophage stim proteins: regulate innate immune response to bacterial

ligands FUT2

Effects constitution of biome

BCL2 11

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SLIDE 9

Genetic Studies in PSC conclusion

 Confirmed Close HLA Association

  • A1 B8 DR3; DR6; DR2

 New genes from immunochip

  • Immune response genes

(shared with other organ specific AI diseases)

  • FUT2;BCL211

Conclusion

PSC is a complex, polygenic , autoimmune disease

Different genetic profile to IBD (some similarities)

Different genetic profile to PBC ( no similarities)

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SLIDE 10

Etiopathogenesis of PSC?

?

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SLIDE 11

Etiopathogenesis of PSC?

?

Current evidence suggests PSC/IBD is genotypically and phenotypically distinct from UC

  • r Crohn’s without PSC

PSC/IBD separate,distinct disease

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SLIDE 12

Possible mechanism

Immune mediated “autoimmune disease”(GWAS)

Specific bacterial Ag’s from the “biome” gain access to the immune system through “leaky”colon

Shared colonic / biliary antigens attacked by gut derived T lymphocytes (inappropriate homing of gut derived T lymphs to liver)

Toxic Bile

Pathogenesis of PSC

“Complex genetic disease”

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SLIDE 13

Management of PSC

Case 1

Dec 2004 – Colitis no problem but developed severe fatigue/itching

  • deterioration in LFT’s-alk phos doubled

alb/bilirubin remained normal Dec 2004 – MRCP & repeat ERCP – “main duct stricture”

  • balloon dilatation of stricture
  • no improvement in itching

March 2005 – liver biopsy “biliary cirrhosis”

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SLIDE 14

Management of PSC Case 1

Nov 2005 – referred to Oxford co fatigue ;itch ;rigors ;pale stools

  • n examination :

no signs of liver disease no hepatosplenomegaly liver function tests: Alb – 41 Bili – 18 AST – 29 Alk Phos – 1851 Admitted for investigation

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Management of PSC Case 1 differential diagnosis?

 dominant stricture  biliary sludge  worsening disease  cholangiocarcinoma  hepatocellular carcinoma

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Management of PSC

Case 1

Nov 2005 Admitted for Investigation Plan : ▫ Tumour markers CEA / CA 19-9/ AFP ▫ Abdo CT Scan (MRCP N/A) ▫ Biliary cytology (DIA & FISH n/a) ▫ ERCP and balloon dilatation ▫ Liver biopsy ▫ Review previous ERCP/liver histology ▫ Colonoscopy

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Management of PSC Case 1

Nov 2005 – repeat ERCP .sphincterotomy- “no

dominant stricture”

. guidewire/cytology brush

“no malignant cells seen”

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SLIDE 18

Management of PSC Case 1

Tumour Markers -

▫ AFP - 3 KU/l ( 0-7 ) ▫ CA 19-9 - 16 U/ml ( 0-33 ) ▫ CEA – 1 ug/l ( 0-4 )

King’s Index *–

▫ CA 19-9 + ( CEA X 40) > 400 indicates

cholangiocarcinoma

*Ramage et al;Gastro 1995

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SLIDE 19

Management of PSC Case 1

Abdominal CT Scan

CT needle biopsy CT- Two nodules

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SLIDE 20

Management of PSC Case 1

Liver Histology 1 ( March 2005 )

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SLIDE 21

Management of PSC Case 2 (March 2005)

On Review;”biliary dysplasia”

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Management of PSC Case 1

Liver Histology 2 (C.T guided) [ Dec 2005]

“biliary cirrhosis”- no dysplasia

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Management of PSC

Case 1-Biliary Dysplasia*

▫

Biliary dysplasia is definite entity

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Antedated cholangiocarcinoma by 2 years in 25%PSC pts who eventually develop cholangioca

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Relationship with colonic dysplasia? *Fleming et al;J Hepatol 2001:34:360-4

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Management of PSC Case 1

Dec 2005 – What to do next?

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Management of PSC Case 1 Indications for liver transplantation in PSC

 Hepatic decompensation  Worsening fatigue/itching  Progressive jaundice  Recurrent cholangitis  Biliary dysplasia (?)

timing of transplant v.difficult

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SLIDE 26

Management of PSC Case 1

Indications for liver transplantation in PSC

 Hepatic decompensation -no  Worsening fatigue/itching -yes  Progressive jaundice -no  Recurrent cholangitis-yes  Biliary dysplasia (?)-yes

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SLIDE 27

Management of PSC Case 1

Dec 2005

  • Started on urso [20 mg/kg body wt]
  • referred for liver transplantation

[ symptomatic, cirrhotic, biliary dysplasia] March 20006

  • not listed

“synthetic liver function – normal”

  • LFT’s improved on urso
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SLIDE 28

Management of PSC Case 1

treatment options for proven cholangiocarcinoma

 Chemotherapy

  • no proven therapy

 Radiotherapy/brachytherapy/PDT

  • no proven therapy

 Liver transplantation  Palliative Care -biliary stenting

NB Mayo Protocol

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SLIDE 29

Management of PSC

Case 1

March – Dec 2011

  • recurrent rigors/cholangitis

fatigue/itching

  • treated with low dose cipro

Jan 2012

  • listed for transplant

June 2012

  • operation “cholangiocarcinoma”

small focus-transplanted

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SLIDE 30
  • Management of PSC / IBD

 October 2012 : “flare up of colitis”

(despite immunosuppression)

 September 2013

  • alive and well

Problem- colonic dysplasia (low grade) on yearly colonoscopy and dye spray

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Cholangiocarcinoma in PSC

  • prognosis in 72 pts-

Bergqvist et al;J Hepatol 2002

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Survival post transplant for PSC Nordic experience

*Brandsaeter B et al, J Hepatol 2004

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Management of PSC Case 2

Dr RW Chapman, Oxford,UK

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Management of PSC Case 2

Mr MK;45yr engineer,asian

  • 1972-developed total UC at 17yr;no further attacks
  • 1997-acute pancreatitis
  • 1998-rigors/cholestatic LFT’s

ERCP –strictures in CBD & sludge/stones in situ

  • treated by sphincterotomy

Abdo CT-peripancreatic lymph nodes biopsy:”reactive changes”

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Management of PSC Case 2

 June 2000- recurrent cholangitis

liver biopsy- “PSC” ERCP- main duct stricture

  • stent inserted

 Oct 2000- stent removed

“pus oozing from CBD”

 Nov 2000- recurrent fevers despite

prophylactic antibiotics

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Management of PSC Case 2

Dec 2000 – referred to Oxford c.o. RUQ abdo pain itching for 6/12 rec rigors/fevers weight loss 15 kg drugs-urso 450mg bd

salazopyrine 1gm cephradine/metro

  • on examination

liver enlarged 3 cms

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SLIDE 38

Management of PSC

Case 2-Mr MK

Jan 2001 -admitted for assessment Blood results: Hb 13.2g/dl alb 39g/L bili 12 umol/L ast 105 IU/L alk phos 921 IU/L ggt 399 IU/L PT 13 secs Colonoscopy:”Quiescent UC “ Liver Biopsy :”Stage 3 PSC-no dysplasia”

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SLIDE 39

Management of PSC Case 2-Mr MK

Tumour Markers CEA - 19 (0-4) CA 19-9 -7 (0-33) AFP -2 King’s Index: 7 + (19 x40=760)=767

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SLIDE 40

Management of PSC

Case 2 –Mr MK

Abdominal CT scan

Dilated IH Ducts Jan 2001

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Management of PSC

Case 2 -ERCP

Jan 2001 Biliary cytology: negative

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Management of PSC Case 2-MK : ERCP

Jan 2001

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Management of PSC Case 2 MK

 Suspicion of cholangiocarcinoma  What other tests available in 2006?

  • endoscopic ductal US & biopsy
  • PET Scanning
  • DIA and/or FISHy on biliary

cytology

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Management of PSC Case 2 MK

Feb 2001- rec fevers/itching despite cipro/urso

  • ? cholangioca
  • referred for transplant

May 2001-seen in transplant centre

“liver transplant not indicated - consider surgical resection of dominant stricture”

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SLIDE 45

Management of PSC

Case 2 MK

Sept 2001 –listed for transplant Dec 2001 -at operation: “cholangioca/multiple mets” Jan 2001 -not fit for chemotherapy Mar 2001 -terminal care June 2001 -died

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SLIDE 46
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Management of PSC Case 3

 46 yr old male Financial advisor

 Age 24 developed Total UC

hospitalized Rx Iv steroids

No flare ups since on Mesalasine

 Age 33 developed itching & abn LFT’s

Bili 1.0 ;Alb 40; ALT70;GGT380;ALK phos 980; PT

normal

 Liver biopsy & ERCP :  Diagnosis :PSC – EH & IH bile ducts

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SLIDE 48

Management of PSC

case 3

 1997 age 37 referred to oxford  3 attacks of cholangitis

(RUQ pain,itching,fever jaundice) Treated with cipro / cholestyramine

 Repeat ERCP “Main duct stricture”  Brush cytology “negative”  serum CA19-9 “ <100”  Balloon dilatation :good result

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Management of dominant stenoses in PSC

Dominant stricture

Exclude malignancy

  • CA19-9
  • Cytology
  • IDUS +/-
  • Bile duct

biopsy

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Endoscopic Treatment (balloon dilatation) of Main duct stricture in PSC

Main duct stricture

?who and how often to dilate ?role of stenting

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0.4 0.8 1.2 1.6 2 1 2 3 4 5 6 Dilatations Stents

Number of endoscopic procedures per patient

(Stiehl 2006)

Years

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10 20 30 40 50 60 70 80 90 100 Baluyut, n=63 Stiehl, n=52 Survival Predicted survival

OLT free survival after 5 years after endoscopic treatment of dominant strictures %

+ UDCA

NB Stiehl pts also received UDCA ?Lower Rate of cholangiocarcino ma (4% vs 10%)

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Management of PSC

 1997 -Started on UDCA mod dose  Didn’t tolerate ?why  Still itching RX Rifampicin

Good result itching settled

 Well for 6 years “fatigue” but tennis /golf

yearly colonoscopy “no dysplasia”

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Management of PSC

 2004 made redundant

splenomegaly noted low WBC low platelets upper endoscopy ;small varices Alb 40;bili 1.2 ;alk phos 1000;PT normal

 Severe itching despite cholestyramine / rifampicin  Rifamp increased to 300mg bd

“Still itching”

 Started on Naltrexone /UDCA

Good result itching controlled & tolerated UDCA

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SLIDE 55

Management of PSC case 3

 Jan 2005 court case: worsened fatigue

but ran half marathon!

 Increasing liver spleen size  June 2005 worsening RUQ pain

 Fever sweats ;Bili 4.0

 MRCP: tight hilar stricture  ERCP: Balloon dilated ; cytology neg ;bili 1.6  Colonoscopy :no dysplasia

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Management of PSC Case 3

 Jan 2006 ;RUQ pain  Abdo us

“Gall Bladder Polyp”

What to do next?

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Management of PSC

 March 2006 lap cholecystectomy

Confirmed cirrhosis

 Gall bladder histology:

“Severe Dysplasia/ca in situ”

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Gall bladder histology

High grade dysplasia

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Gallbladder Cancer in PSC

  • case for annual screening*

 102 PSC pts undergone cholecystectomy

[retrospective review]

 Gallbladder mass in 14: 8 malignant adenoca  Favourable survival : 36 month survival 66%  Benign adenomatous polyps in 5/6; dysplasia in

2/5

 Recommend “annual US : early

cholecystectomy for gall bladder polyps” *Buckles DC et al, Am J Gastroenterol 2002;97:1138

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 What to do next?  Patient wants transplant

“can’t live with uncertainty”

 Sept 2006 liver transplant

 “Widespread dysplasia ;no cancer”

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Survival of 72 pts with PSC and cholangiocarcinoma

Bergquist ,,J Hepatol 2002;36:321-7 11 pts transplanted ; 8 unsuspected until surgery

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Survival post transplant for PSC Nordic experience

*Brandsaeter B et al, J Hepatol 2004 ;in press

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