Update from the Gnomes: liver fibrosis - Virtual Pathology · 2008-02-07 · S100A4- PBC S100A4-...
Transcript of Update from the Gnomes: liver fibrosis - Virtual Pathology · 2008-02-07 · S100A4- PBC S100A4-...
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Update from the Gnomes: liverfibrosis
Alastair D Burt
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Liver fibrosis
Changing patterns over time
Importance of the ductular reaction
Multiple hits in fibrosis
Summary of morphological patterns offibrosis
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Newcastle B
Middle aged male
> 90kg and type 2 DM: on metformin
Hypertensive: 204/110
Alcohol excess ? Duration and amount
Said to be abstinent for at least 6 months preTx
OLT
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Transplant assessment biopsy
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EXPLANT
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Newcastle B
Time zero biopsy showed minimal post perfusioninjury only
Initial post OLT course unremarkable apart frommoderate rejection at day 7
Increasing BMI: weight gain of 23kg
Random blood alcohol negative
Developed abnormal LFTs (10 months post OLT):ALT 116/ALP 293
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NCL B1
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NCL B1
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Newcastle B
Period of weight loss; stabilised at 104kg;associated with improvement of LFTs
Then further weight gain: only partially explainedby oedema BMI = 43
Enjoyed ‘very occasional glass of wine’ and ‘onelight meal a day’
Evidence of low grade encephalopathy: re-biopsied
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Follow up biopsy
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(Central) sclerosing hyalinenecrosis
Coined by Edmondson et al (1963)
Part of spectrum of ASH
May be associated with portal hypertension inpre-cirrhotic stage
Large, tender livers (Karasawa & Chedid,1976)
Not a typical feature of NASH
Described in Bloom syndrome; DDI-inducedinjury
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Ductular reaction
New ductular structures atinterface
Attempt to bypassobstruction to bile flow
May resemble ductal plate
Generally accompanied byinflammation
Role of metaplasia;proliferation; recruitment
Driver for portal fibrosis
Importance of epithelial-mesenchymal transition (EMT)?
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EMT occurs in experimental renalfibrosis and can be inhibited by BMP-7
Kalluri & Neilson (2003)
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S100A4- PBC
S100A4- PSC
S100A4/pSmad2/3
• S100A4 is expressed by individual epithelial cells within ductules
• S100A4 is expressed in biliary epithelium in the presence of CD8+ T cells
• Expression of S100A4 in epithelial cells associated with nuclear pSmad2/3
Evidence for EMT in chronicinflammatory liver diseases
S100A4- PSC
S100A4/CD8- PBC S100A4- PSC
Robertson et al, Hepatology 2007; Lab Invest 2008 (in press)
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Robertson et al, Hepatology, 2007
Biliary EMT in post-transplant recurrence of primarybiliary cirrhosis
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S100A4 Cytokeratin 19
S100A4 and CK-19 in epithelium inthe ductular reaction
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control 1ng/ml TGF-β 10ng/ml TGF-β
S100A4
α-SMA
Human intrahepatic biliaryepithelial cells: EMT induced by TGFβ
Robertson et al, Lab Invest, 2008 (in press)
• Accompanied bynuclear pSmad 2/3
• Partial inhibition byBMP-7 and HGF
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Liver injury followingLiver injury followingmultiple traumamultiple traumaSevere trauma, hypotension, mult blood
transfusions, acute renal failure
25 days in ICU
Ventilator-dependent, dialysis, woundinfections, sepsis, pneumonia, open abdomen,mult antibiotics, TPN
Jaundice; cholecystectomy, day 16
Liver biopsy (? day 16-23)
Acknowledgement: Dr Zac Goodman; AFIP
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SMA
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CK7 SMA
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Cholestasis with acute cholangitisand ductular reaction, secondary tosepsis ± other factors
Zone 3 fibrosis (stellate cellactivation) secondary to cholestasis± ischemia
Zone 1 fibrosis (portalmyofibroblast activation) secondaryto ductular reaction
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Patterns of hepatic fibrosis
Localised Abscess
Inflammatorypseudotumour
Intra and peri-tumoralincluding FNH
Trauma
Generalised Portal tracts/zone 1
Hepatic veins/zone 3
Perisinusoidal
Septal
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Patterns of liver fibrosis
Portal Expansive
Periductal
Peri or intravascular
Periportal Interface hepatitis-
associated
Ductular reaction-associated
Spikes
Perinodular
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Patterns of liver fibrosis
Portal Expansive
Periductal
Peri or intravascular
Periportal Interface hepatitis-
associated
Ductular reaction-associated
Spikes
Perinodular
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Patterns of liver fibrosis
Portal Expansive
Periductal
Peri or intravascular
Periportal Interface hepatitis-
associated
Ductular reaction-associated
Spikes
Perinodular
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Patterns of liver fibrosis
Perisinusoidal Diffuse
Zonal
Focal
Pericellular Diffuse
Zonal
Focal
Perivenular ‘Typical’
Sclerosing hyaline necrosis
Intravenular
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Patterns of liver fibrosis
Perisinusoidal Diffuse
Zonal
Focal
Pericellular Diffuse
Zonal
Focal
Perivenular ‘Typical’
Sclerosing hyaline necrosis
Intravenular
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Patterns of liver fibrosis
Intra or peri-lesional
Granulomatous
Glissons capsule
Developmentalabnormality
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Patterns of liver fibrosis
Intra or peri-lesional
Granulomatous
Glissons capsule
Developmentalabnormality
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Patterns of liver fibrosis
Intra or peri-lesional
Granulomatous
Glisson’s capsule
Developmentalabnormality
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Patterns of cirrhosis
Micronodular
Macronodular
Mixed
Incomplete septal
Should we stage cirrhosis?
Laennec scoring: 4A, B and C