From primary sclerosing cholangitis to c From primary sclerosing cholangitis to cholangiocarcinoma...

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Transcript of From primary sclerosing cholangitis to c From primary sclerosing cholangitis to cholangiocarcinoma...

  • From primary sclerosing

    cholangitis to cholangiocarcinoma

    L.Kupcinskas Kaunas university of medicine, Kaunas, Lithuania

    5th EAGE Postgraduate school, Prague, May 8- 9th,

    2009

  • The hallmarks of cancer

    Mantovani A; Nature 2009; 457, 36-37

    Cancer can be defined

    by six hallmarks,

    including uncontrollable

    growth, immortality and

    the ability to invade

    other tissues

    Increasing evidence

    suggests that a seventh

    feature should make this

    list — inflammation.

  • Link between chronic gastrointestinal

    inflammation and cancer

    • H.pylori gastritis gastric cancer

    • IBD colorectal cancer

    • Gliutenic enteropathy lymphoma

    • Chronic pancreatitis pancreatic cancer

    • Chronic hepatitis B,C HCC

    • PSC cholangiocarcinoma

  • Primary sclerosing cholangitis: definition

    and course

    Biliary obliteration

    Biliary cirrhosis

    Cirrhosis complications:

    Variceal bleeding,

    Ascitis

    SPB

    Liver failure,

    HRS

    Biliary inflammation

    Cholangiocarcinoma

    Death

    8-14 %

  • PSC epidemiology:

    • prevalence of 10/100,000 in Northern European

    • annual incidence 1.01 per 100,000 in men, and 0.84 in women.

    • inflammatory bowel disease (IBD), mostly ulcerative colitis (UC) was present in about 70 %.

    • more prevalent in patients with pancolitis than in those with distal colitis (5.5% versus 0.5 %)

    • in UC patients PSC presented in 7 % of cases

    • patients with PSC have a five year survival of 88% and a median survival of 11.9 years from the time of diagnosis

    Silveira MG, Lindor KD. Can J Gastroenterol. 2008; 22(8):689-98.

  • Etiology and pathogenesis: PSC as a

    genetic disease

    Pros:

    • Increased prevalence of PSC among first-degree

    relatives

    • Association with certain MHC- and non-MHC- alleles

    Cons:

    • Association with HLA-haplotypes is only weak

    • Studies on non-HLA polymorphisms are not reproducible or contradictory

    Weismüller TJ, et al, J Hepatol. 2008; 48 Suppl 1:S38-57

  • Etiology and pathogenesis: PSC as an

    autoimmune disease

    Pros:

    • Increased incidence of co-existing autoimmune diseases

    • Presence of autoantibodies like pANCA

    Cons: • No response on immunosuppressive treatment

    • Male predominance

    • Antibodies are not specific and do not correlate with clinical parameters

  • Etiology and pathogenesis: PSC as

    inflammatory reaction on infectious agents

    Pros:

    • Co-expression of VAP-1 and MadCAM-1 in the gut and the liver of patients with PSC and IBD allows an enterohepatic lymphocyte circulation

    • In a rat model small intestinal bacterial overgrowth lead to biliary strictures

    • Helicobacter species can be found in 24–75% of PSC livers

    Cons:

    • In PSC without IBD enterohepatic lymphocyte circulation is not a conclusive concept

    • No evidence of significant bacteraemia in UC

    • No evidence of small intestinal bacterial overgrowth or disturbed intestinal permeability in PSC

    • Helicobacter species are not found more often in livers of PSC patients than in non-cholestatic liver diseases

    Weismüller TJ, et al, J Hepatol. 2008; 48 Suppl 1:S38-57

  • Etiology and pathogenesis: PSC as a

    cholangiopathy

    Pros:

    • Knockout of the Mdr2 gene which encodes a canalicular

    phospholipid transporter in mice, results in a sclerosing

    cholangitis

    • Biliary epithelial cells that are activated by serum autoantibodies produce cytokines and trigger inflammation

    Cons:

    • In human PSC patients a significant variation of the

    corresponding MDR3-gene could not be found

  • PSC is a multifactorial disorder, developing in individuals with

    a genetic predisposition when exposed to the appropriate

    environmental (microflora?) stimulus

  • Ductal involvement at the time of

    diagnosis PSC

    • Intrahepatic & extrahepatic - 69%

    • Intrahepatic 25%

    • Extrahepatic 4%

  • Clinical variants of PCH

    • “Classic” large-ducts – 90%

    • “Small-ducts” –

    normal cholangiogram – 5-15 %

    • IgG4-related cholangitis:

    associated with autoimmune pancreatitis,

    more favorable prognosis

    • Overlap with autoimmune hepatitis, especially in children (till 49%)

  • “Small-duct” PSH- a distinct clinical

    entity?

    • Typical cholestatic enzyme pattern

    • Normal cholangiogram

    • Do not progress to “large duct” PSH

    • Do not progress to cholangiocarcinoma

    Silveira MG et al, Can J Gastroenterol. 2008; 22(8):689-98.

  • Survival free of LT was significantly longer in patients

    with small-duct in comparison to “classic” large-duct PSC

    Bjornson E et al. Gastroenterology, 2008 Apr;134(4):975-80.

    hazard ratio, 3.04; 95% CI: 1.82–5.06; P < 0.0001

  • Follow-up cholangiogram after 8 weeks of corticosteroid

    therapy - complete resolution of strictures in

    IgG4-related sclerosing colangitis

    Small A et al. Nature Gastroenterol&Hepatol 2008; 5 (12), 707-12

  • Diagnostic algorithm for PSC

    Jeans J et al Liver Transplantation, 2008; 14; 736-746

  • MR cholangiogram or ERCP?

    • Because it is less invasive, MRCP is primarily used for diagnosing PSC

    • ERCP is preferred if dilated bile ducts demonstrate a need for direct

    intervention.

  • Primary sclerosing cholangitis. Liver biopsy

    Portal tract with

    moderately dense

    inflammatory infiltrate

    (mainly lymphocytes,

    some eosinophils);

    and concentric,

    lamellated, periductal

    (‘onion skin’) fibrosis

    around the

    interlobular bile duct

    (center). (H&E)

  • Staging of histological findings in

    PSC (Liudwig, 1981)

    • Stage 1 - portal hepatitis, degeneration of

    bile ducts with inflammatory cell infiltrate

    • Stage 2 - extension of disease to periportal

    area with prominent bile ductopenia

    • Stage 3 - septal fibrosis and necrosis

    • Stage 4 - frank cirrhosis

  • PSC: treatment

    Ursodeoxycholic acid (UDCA):

    • a choleretic effect,

    • cytoprotective effect,

    • immunomodulatory effect,

    The traditional Chinese drug ‘Yutan’,

    a powder preparation derived from

    the dried bile of adult bears, has

    been used in the treatment of

    hepatobiliary disorders for 3000

    years.

  • PSC: treatment

    • Standard dose of UDCA (15 mg/kg/day) has shown some efficacy in

    providing symptomatic relief, improving biochemical abnormalities,

    and stabilizing hepatic inflammation, however, do not change

    mortality and need for LT

    • High dose UDCA (20-30 mg/kg/day) like immunosupresants,

    antibiotics (metronidasole, vancomicine) and other agents should be

    used only as part of a clinical trials

    • Supplementation with calcium and fat soluble vitamins,

    • Patients with a dominant stricture should undergo endoscopic therapy

    (dilatation or stenting),

    • biliary reconstructive procedures could be applied in selected patients

    with predominantly extrahepatic damage,

    • LT for end stage liver disease

  • Is high-dose ursodeoxycholic acid (17-23

    mg/kg/d) effective for the treatment of patients

    with primary sclerosing cholangitis?

    Olsson R et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year

    multicenter, randomized, controlled study. Gastroenterology (2005) 129: 1464–1472

  • Treatment with minocycline (100 mg twice daily, 1 year)

    is related with significant improvement of AlkPhosph

    and PSC Mayo risk score (a pilot study)

    Variable Baseline Post-treatment P

    Alkaline phosphatase, U/l (nr, 45– 142)

    330 (189– 1040) 265 (108–737) 0.04

    AST, U/l (nr, 8–48) 72 (32–202) 70 (24–174) 0.06

    Total bilirubin, mg/dl (nr, 0.1–1.0) 0.9 (0.3–2.3) 0.6 (0.4–1.9) 0.11

    Direct bilirubin, mg/dl (nr, 0.0–0.3) 0.3 (0.1–0.9) 0.2 (0.1–0.4) 0.11

    Prothrombin time, s (nr, 8.3–10.8) 9.0 (8.4–10.6) 8.9 (8.0–10.4) 0.38

    Albumin, g/dl (nr, 3.5–5.0) 4.0 (3.6–4.4) 4.0 (3.6–4.3) 0.73

    Mayo risk score 0.55 (-0.65–

    0.91) 0.02 (-0.89–

    1.65) 0.05

    Silveira MG et al.. Am. J. Gastroenterol. 2009, 104, 83–88

  • PSC: treatment

    • Standard dose of UDCA (15 mg/kg/day) has shown some efficacy in

    providing symptomatic relief, improving biochemical abnormalities,

    and stabilizing h