Liver diseases associated with inflammatory bowel ... 2019/01/14 ¢  Liver diseases...

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Transcript of Liver diseases associated with inflammatory bowel ... 2019/01/14 ¢  Liver diseases...

  • Liver diseases associated with

    inflammatory bowel disease

    David Adams

    Centre for Liver Research University of Birmingham and NIHR Biomedical Research Centre.

    http://www.birminghamhealthpartners.co.uk/index.htm http://www.birminghamhealthpartners.co.uk/index.htm

  • Extraintestinal Manifestations of inflammatory bowel

    disease

    Joints

    •Type 1 and 2 Arthropathy •Orchard, Wordsworth and Jewell

    •Ankylosing spondylitis

    Liver

    •Primary sclerosing cholangitis

    •Autoimmune hepatitis

    Eye

    •Uveitis

    •Iritis

    •Episcleritis

    Skin

    •Erythema Nodosum

    •Pyoderma Gangrenosum

    Lung

    • Bronchiectasis

    • Bronchiolitis

    • Interstitial lung disease

    Broome U et al. Gut 1996

    Chapman,R.W. Gut 1991

  • Diseases

    associated with

    active bowel

    disease

    Pyoderma gangrenosum

    Pyoderma gangrenosum

    Erythema nodosum

    Episcleritis

  • Arthropathies

    associated with IBDParallel IBD activity

    Type 1 Pauciarticular

    Ankylosing spondylitis

    Independent of IBD

    activity

    Type 2 Polyarticular

    Orchard & Jewell Gastro 1999

  • Autoimmune liver disease and IBD

    PSC or autoimmune hepatitis • 3-10% of patients with IBD • >80% PSC patients have microscopic IBD

    Broome et al 1995; Loftus et al 2005; Jorgensen 2012

    PSC

    T cell mediated destruction of hepatocytes

    AIHPSC

    • 15% risk of cholangiocarcinoma and CRC

    • 36% die or progress to liver transplantation

    • No effective treatment Goode et al Hepatology 2018

  • The colitis of PSC has distinct features disease and runs a

    course that is independent of liver disease

    •PSC can develop after colectomy for UC

    •UC can develop after liver transplant for PSC

    Pan-colonic inflammation

    High risk of colon cancer

    Backwash ileitis

    Right-sided

    predominance Mild

    inflammation

    Rectal sparing Loftus et al Gut 2005;

    Jorgensen KK 2011 IBD

    Marelli 2011 Gut

    Boonstra K IBD 2012

  • IBD PSC

    Do mucosal lymphocytes drive liver disease ?

    Hypothesis:

    Gut activated lymphocytes in IBD enter the liver and contribute to

    liver inflammation in PSC.

  • Trichinella spiralis new born larvae (NBL) and

    the hepato-enteric immune response

    Liver tolerance to

    new borne larvae

    Effector CD4 cells Effector CD4 cells No effector CD4 cells

    IL-10 deficient

    Severe Hepatitis to

    new borne larvae

    NBL

    NBL NBL

    Liver tolerance to

    new borne larvae

    Bliss,SK JI 2007

    IL-10 deficient

    UNDER THE RIGHT CONDITIONS T CELLS ACTIVATED IN THE GUT CAN

    CAUSE LIVER DISEASE

  • In the absence regulatory T cells dysfunctional immune

    regulation leads to immune mediated gut and liver disease

    IL2Ra-/- mice develop autoimmune cholangiopathy and colitis

    Willerford et al. Immunity 1995

    Wakabayashi et al. Hepatology 2006

    GWAS studies in PSC suggest defects in immune

    regulatory genes including IL2RA

    Melum et al Nat Gen 2011

  • Mesenteric lymph node Intestinal mucosal vessels

    CCL25

    CCR9

    a4b7

    MAdCAM-1

    Gut- tropic T-cell

    Stagg et al Eur J Immunol 2002

    Mora, Eksteen et al Science 2006

    KEY:

    MAdCAM-1:

    Mucosal Addressin Cell Adhesion

    Molecule-1

    VAP-1: Vascular Adhesion

    Protein-1

    Intestinal specific lymphocyte recruitment

    Skin lymph node Skin vessels

    CCL17 CCl28

    CCR4 CCR10

    CLA

    E-selectin

    Gut- tropic T-cell

  • Mesenteric lymph node

    Intestinal mucosal vessels

    Hepatic sinusoids

    CCL25

    CCR9

    a4b7

    MAdCAM-1

    Gut- tropic T-cell

    Trivedi et al. J. Autoimmunity 2013

    Enterohepatic lymphocyte recirculation

    PSC

    CCL25 MAdCAM-1

    Eksteen et al J Exp Med 2004 Liaskou et al Gastro 2014

    MADCAM-1 and CCL25 are detected in the PSC liver

    0 20 40 60 80 100

    CD LPL CD PBL NL LIL N PBL

    PBC LIL PSC PBL

    PSC LIL

    20% of T cells in the liver have a gut phenotype

    Bile duct

    CCR9+CD3+ CD28-

  • Mesenteric lymph node

    Intestinal mucosal vessels

    Hepatic sinusoids

    CCL25

    CCR9

    a4b7

    MAdCAM-1

    Gut- tropic T-cell

    Trivedi et al. J. Autoimmunity 2013

    KEY:

    MAdCAM-1:

    Mucosal Addressin Cell Adhesion

    Molecule-1

    VAP-1: Vascular Adhesion

    Protein-1

    CCL25

    MAdCAM-1

    Enterohepatic lymphocyte recirculation

    PSC

    VAP-1

    What induces the liver to express gut homing

    molecules in AIH/PSC?

    VASCULAR ADHESION PROTEIN-1

  • VAP-1

    (SSAO)

    RGD motif

    Endothelium

    Lymphocyte

    Amine

    Aldehyde

    NH3

    H2O2

    ?

    VAP-1:Ligand

    interaction

    VAP-1 is an endothelial adhesion molecule which recruits

    effector cells to the liver AND an amine oxidase.

    Amines from

    food and wine

    and bacteria

    Salmi Science 1991; McNab Gastro 1996; Smith JEM 1998 Jalkanen and Salmi EMBOJ 2001

    Weston et al J Clin Invest 2015

  • VAP-1 expression & enzyme activity is increased in

    PSC liver

    Palak J Trivedi et al. Gut 2018

  • RGD motif

    Endothelium

    Lymphocyte

    Amine

    Aldehyde

    NH3

    H2O2

    ?

    NFkB Activation

    VAP-1:Ligand

    interaction

    The enzyme activity of VAP-1 activates liver endothelium

    TRANSCRIPTION OF

    CHEMOKINES AND ADHESION

    MOLECULES

    Lalor Hepatology 2007; Liaskou Hepatology 2011

    MADCAM-1

  • Methylamine feeding of VAP-1 transgenic mice

    induces increased expression of endothelial

    adhesion molecules including MADCAM-1

    Liaskou et al Hepatology 2011

    Lia Liaskou

  • Mesenteric lymph node

    Intestinal mucosal vessels

    Hepatic sinusoids

    CCL25

    CCR9

    a4b7

    MAdCAM-1

    Gut- tropic T-cell

    Trivedi et al. J. Autoimmunity 2013

    CCL25

    MAdCAM-1

    Enterohepatic lymphocyte recirculation

    PSC

    VAP-1

    What activates VAP-1 leading to expression of gut

    homing molecules in the liver?

    VASCULAR ADHESION PROTEIN-1

    MAdCAM-1

  • Ethylamine

    0 2000 4000 6000 8000 0

    5

    10

    15

    Concentration (mmol)

    V e

    lo c ity

    ( n

    m o

    l H 2 O

    2 /m

    in )

    Phenethylamine

    0 500 1000 1500 2000 0

    5

    10

    15

    Concentration (mmol)

    V e

    lo c ity

    ( n

    m o

    l H 2 O

    2 /m

    in )

    Dopamine

    0 100 200 300 400 0

    20

    40

    60

    80

    100

    Concentration (mmol)

    V e

    lo c ity

    ( n

    m o

    l H 2 O

    2 /m

    in )

    Methylamine

    0 500 1000 1500 2000 0

    5

    10

    15

    20

    Concentration (mmol)

    V e

    lo ci

    ty ( n

    m o

    l H 2 O

    2 /m

    in )

    Cysteamine

    0 50 100 150 200 0

    20

    40

    60

    80

    Concentration (mmol)

    V e

    lo ci

    ty ( n

    m o

    l H 2 O

    2 /m

    in )

    Benzylamine

    0 200 400 600 0

    5

    10

    15

    Concentration (mmol)

    V e

    lo ci

    ty ( n

    m o

    l H 2 O

    2 /m

    in )

    What are the natural amine substrates that

    activate VAP-1?

    Kcat/Km: 2.7e+6 Kcat/Km: 4.5e+6 Kcat/Km: 5.1e+7

    Kcat/Km: 3.8e+7 Kcat/Km: 5.4e+7 Kcat/Km: 2.6e+7

    Trivedi et al. Gut 2018

    Cysteamine

  • Cysteamine induces MADCAM-1 and increases mucosal lymphocyte adhesion to liver endothelium

    Trivedi et al. Gut 2018

    Adhesion of mucosal lymphocytes Expression of MADCAM-1

    **

    MA = Methyl amine

    CA = Cysteamine

  • Cysteamine and mucosal inflammation

    Colonic epithelium generates cysteamine via vanin-1

    • Vanin-1 overexpression = increased cysteamine & colitis

    – Cysteamine depletion abrogates colitis – Berruyer et al JEM 2006, Martin et al. 2004 J. Clin. Inv.

    Cysteamine released by proteobacteria/firmicutes

  • Changes in the enteric microbiome in liver

    disease

    PSC-IBD versus IBD & controls:

    – Reduced Prevotella & Roseburia

    – virtual absence of Bacteroides

    compared with IBD and controls.

    – Increases in

    – Proteobacteria Escherichia,

    – Firmicutes Clostridia, Veillonella

    – Quarashi et al Gut 2017.

    • PSC:

    – Firmicutes Veillonella increased – Kummen et al Gut 2016

    Cysteamine released by proteobacteri