patterns of liver fibrosis and their clinical significance · patterns of liver fibrosis and their...
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Nottingham 2006
Patterns of liver fibrosis and their clinical significance
Alastair D BurtProfessor of Pathology and Dean of Clinical Medicine
University of Newcastle upon Tyne
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Collapse of reticulin framework or dynamic process ? Popper 1960s
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Hepatic fibrosis
� Consequence of repair process following chronic liver injury with resultant net accumulation of extracellular matrix proteins with abnormal distribution: dynamic process involves increased production and decreased turnover of matrix
� Effects not only space occupying but influence gene transcription, cellular proliferation etc: via integrinsand non-integrin ECM receptors
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Hepatic stellate cells: principal effectors in liver fibrogenesis
� Found within the space of Disse� Pericyte-like with long cytoplasmic processes:
?contractile� Principal site of storage of vitamin A (fat-storing
cells)� ? Origin
� Mesencyhmal� Neural crest� Bone marrow� (Epithelial-mesenchymal transition)
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Injury
Cytokines
HSC response to injury
Quiescent Activated
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•Fibrosis may be reversible: animal models and anti-viral trials
•HSC apoptosis important as is changing profile of MMPs/TIMPs
HSC apoptosis in CCL4 injury
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Second layer cells and myofibroblasts
Other possible effectors:
•Bile duct epithelium• Hepatocytes• EMT• Endothelium• ‘Fibrocytes’• Other portal tract fibroblasts
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Assessment of fibrosis� Histochemistry
� Silver impregnation: type III/fibronectin and type I� Trichrome stains/Van Gieson� Picro Sirius Red� Orcein/Victoria Blue
� Immunohistochemistry� Collagen subtypes� Elastin� Activated HSCs (α SMA)
� Quantitative� Semi-quantitative scoring� Elution of Picro Sirius Red� Image analysis
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PBC: which stage?
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Oh yes it does!!
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Sampling variability of liver fibrosis in chronic hepatitis C
� Surgical specimens of livers from patients with HCV� Image analysis and METAVIR: overall reference
value� Virtual biopsies of increasing length� 15mm biopsies categorised correctly in 55%;
increased to 65% with 25mm� Concluded that at least 25mm required for accurate
semi-quantitative assessment of fibrosis
Bedossa et al, 2003
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Surrogate markers of hepatic fibrosis
� Forns score: based on age, GGT, platelets, cholesterol
� FIBROTEST: apoA1, haptoglobin, α2-MG, GGT, bilirubin
� Effective at identifying patients with mild fibrosis
� Large percentage within indeterminate range
� ? Enhanced by incorporating ECM markers
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Patterns of hepatic fibrosis
� Localised� Abscess� Inflammatory
pseudotumour� Intra and peritumoral� Trauma
� Generalised� Portal tracts/zone 1� Hepatic veins/zone 3 � Perisinusoidal
� Septal� Others………..
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Portal tracts/zone 1 and fibrosis� Portal tract fibrosis
� Increased density and fibrous enlargement of PTs� Biliary diseases; chronic hepatitides; NASH; ?? ALD
� Pipe stem fibrosis� Schistosomiasis
� Hepatoportal fibrosis� Idiopathic non-cirrhotic hypertension
� Periportal fibrosis� Fibrous spurs extending from PTs� May be associated with interface hepatitis
� Periductal fibrosis� Sclerosing cholangitis (primary or secondary)
� Periductular fibrosis� Accompanies ductular reaction: cholestatic diseases and chronic
hepatitides
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Hepatoportal sclerosis
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Progressive fibrosis in autoimmune biliarydisease
� Progressive periportalfibrosis is associated with and may be driven by the so-called ductular reaction
� Portal-portal fibrous linkage ensues leading to a monolobular form of cirrhosis
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Hepatic veins/zone 3 and fibrosis
� Perivenular fibrosis� Alcoholic liver disease
� NASH� Veno-occlusive disease
� Centrilobular fibrosis (? distinct)� Alcoholic liver disease
(‘central sclerosing hyaline necrosis’)
� NASH
� Ischaemic injury (chronic venous outflow obstruction)
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Ischaemic fibrosis
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Pericellular/perisinusoidalfibrosis
� Zone 3 predominance� Chicken wire appearance: alcoholic liver
disease/NASH
� Diffuse� Diabetes type 1� Similar appearance with amyloidosis and light
chain disease� Congenital syphilis
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Septal fibrosis
� Portal-portal septa� Link adjacent portal tracts� Chronic cholestatic diseases (‘biliary fibrosis’); chronic
hepatitides� Central-central septa
� Scarring stage of confluent necrosis/central-central bridging necrosis
� Portal-central septa� Scarring of portal-central bridging necrosis
� Active septa� Prominent inflammatory infiltrate and ongoing necrosis
� Passive septa � Post-necrotic collapse
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NEWCASTLE A: POST TREATMENT BIOPSY
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Other fibrosis
� Glisson’s capsule fibrosis
� Granulomas� Sarcoidosis
� Mineral oil granulomas
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Other fibrosis
� Developmental abnormalities� Congential hepatic
fibrosis� Mesenchymal
hamartoma
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Patterns of cirrhosis
� Micronodular
� Macronodular� Mixed
� Incomplete septal
� Should we stage cirrhosis?� Laennec scoring: 4A, B and C
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Fatty liver disease
Alastair D BurtUniversity of Newcastle upon Tyne