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

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 1996 – developed severe attack of UC requiring hospital admission / iv steroids / blood transfusion - symptoms settled on treatment Abnormal LFT’s noted - Asymptomatic

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

Primary Sclerosing Cholangitis Risk factors  Male gender  Environmental factors eg. Non-smoker (cp PBC)  IBD  Genetic predisposition

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 ERCP South Wales,Sweden) PSC -70-80% have assoc IBD  PSC -occurs in 5-10% of Total UC  -underestimate? MRC P

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 MRCP *Bungay et al; GUT 2008 UC with Dysplasia /cancer : 12% have PSC

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

Current gene status in IBD/PSC 2013 BCL2 Found only in PSC pts with 11 Found in PSC with IBD-Macrophage stim and without IBD – proteins: BCL 211- encodes regulate innate immune Bim – major effect on response to bacterial FUT2 immune tolerance ligands Effects constitution of biome

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) 

Etiopathogenesis of PSC? ?

Etiopathogenesis of PSC? Current evidence suggests PSC/IBD is genotypically and phenotypically distinct from UC or Crohn’s without PSC ? PSC/IBD separate,distinct disease

Pathogenesis of PSC 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) “Complex genetic disease” Toxic Bile 

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”

Management of PSC Case 1 Nov 2005 – referred to Oxford co fatigue ;itch ;rigors ;pale stools on examination : no signs of liver disease no hepatosplenomegaly liver function tests: Alb – 41 Bili – 18 AST – 29 Alk Phos – 1851 Admitted for investigation

Management of PSC Case 1 differential diagnosis?  dominant stricture  biliary sludge  worsening disease  cholangiocarcinoma  hepatocellular carcinoma

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

Management of PSC Case 1 Nov 2005 – repeat ERCP .sphincterotomy- “ no dominant stricture” . guidewire/cytology brush “no malignant cells seen”

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

Management of PSC Case 1 Abdominal CT Scan CT- Two nodules CT needle biopsy

Management of PSC Case 1 Liver Histology 1 ( March 2005 )

Management of PSC Case 2 (March 2005) On Review;”biliary dysplasia”

Management of PSC Case 1 Liver Histology 2 (C.T guided) [ Dec 2005] “biliary cirrhosis” - no dysplasia

Management of PSC Case 1-Biliary Dysplasia* Biliary dysplasia is ▫ definite entity Antedated ▫ cholangiocarcinoma by 2 years in 25%PSC pts who eventually develop cholangioca Relationship with ▫ colonic dysplasia? *Fleming et al;J Hepatol 2001:34:360-4

Management of PSC Case 1 Dec 2005 – What to do next?

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

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

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

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

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

• 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

Cholangiocarcinoma in PSC - prognosis in 72 pts- Bergqvist et al;J Hepatol 2002

Survival post transplant for PSC Nordic experience *Brandsaeter B et al, J Hepatol 2004

Management of PSC Case 2 Dr RW Chapman, Oxford,UK

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”

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

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

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”

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

Management of PSC Case 2 – Mr MK Abdominal CT scan Jan 2001 Dilated IH Ducts

Management of PSC Case 2 -ERCP Jan 2001 Biliary cytology: negative

Management of PSC Case 2-MK : ERCP Jan 2001

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

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”

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