The pathogenesis of liver cirrhosis and fibrosis
-
Upload
abbazarami-bukar -
Category
Science
-
view
695 -
download
0
Transcript of The pathogenesis of liver cirrhosis and fibrosis
THE PATHOGENESIS OF LIVER CIRRHOSIS/FIBROSIS
Presenter Dr Bukar Zarami Abba.
Histopathology Dept. University of Maiduguri Teaching Hospital Borno State, Nigeria.
17/January/2013
Outline
• Introduction• Epidemiology• Brief Anatomy• Classification • Pathogenesis • Morphology• Clinical features• Summary/conclusion
Introduction • Liver disease has steadily gained recognition as a major health
problem • Principally because of the world-wide distribution of viral hepatitis,
the ubiquity of cirrhosis of the liver, and HCC. • Recently from fatty liver dx. asso with obesity• Hepatic stellate cell activation represents a critical events in fibrosis• Symptoms such as fever, jaundice, portal HT, and encephalopathy,
are striking phenomena that may bring the patient to the physician.• As pathway of fibrinogenesis are incresingly clarified the key
challenge will be translating new advances into the dev. Of antifibrotic therapies
Liver cirrhosis is a chronic non-neoplastic disease characterized by
1. Diffuse involvement of the liver2. Complete loss and disruption of the
architecture of the liver3. Extensive bridging fibrous septae/fibrosis4. Regenerating parenchymal nodules
Epidemiology • Cirrhosis and chronic liver disease were the 10th leading cause of
death for men and the 12th for women in the United States in 2001
• killing about 27,000 people/yr and additional 10,000 death due to PLCC
• Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis;
• Alcoholic cirrhosis has a worse prognosis than primary billiary cirrhosis and cirrhosis due to hepatitis.
• PBC occurs in middle age with male to female ration 1:9• Childhood cirrhosis common among 6mon- 3yrs in South East Asia
and in the Middle-East
Disability-adjusted life year for cirrhosis of the liver per 100,000 inhabitants in 2004. <50 50-100 100-200 200-300 300-400 400-500 500-600 600-700 700-800 800-900 900-1000 >1000
Preamble Normal adult liver wt 1400-1600g Consist of 2.5% of the body wt The liver has dual blood supply 60-70% via PV and 30-40% HA The branches travels in a parallel and ramified into 17-20 order
branches The micro-architecture of the liver is base on lobular and acini model In the acini model the haepatocytes near the terminal hepatic vn
form the distal apices of triangular acinus The sinusoids are line by fenestrated endothelial cells Deep to the endothelial cells is the space of Disse into which
protrude abundant microvilli of hepatocytes and non parenchymal cells
Microscopic anatomy of the liver
Normal liver
Classification Two major forms of cirrhosis are recognized based on
the size of the regenerative nodules formed, with a cut off point at 3 mm.
The Micronodular form shows uniform small nodules generally less than 3 mm. It is associated with:
• Alcoholic Hepatitis• Haemachromatosis• Drugs• Chronic biliary disease
Macro nodular cirrhosis, the nodules are generally larger than 3 mm.
• This is the form predominantly found in• Chronic viral hepatitis • Autoimmune• It is also found with all other causes of micronodular
cirrhosis if the illness is of sufficiently long duration.Mixed nodularity with variably sized nodules.
Western World
Classification base on aetiology• Alcoholic liver disease 60-70%• Viral hepatitis 10%• Biliary disease 5-10%• Primary hemochromatosis 5%• Cryptogenic cirrhosis 10-15%• Wilson’s, 1AT def rare
Our Environment
• HBV infection (chronic) –high prevalence presumed
• HCV,HDV (chronic)- high prevalence presumed• Alcohol• Cryptogenic• Hereditary, immunologic, metabolic-
alpha antitrypsin deficiency, Primary haemochromatosis, Wilsons disease, galactosaemia, primary biliary cirrhosis
Natural history of liver disease
Pathogenesis • Irrespective of the aetiology, cirrhosis in general is initiated by
hepatocellular necrosis• Replacement of BM collagen type iv and vi by fibrillary collagen type I and
iii• This lead to capillarization with quantitative and qualitative ECM change• ECM regulates cellular activity and availability of growth factors
– Decorin and biglycan binds TGF-B– Fibronectin and laminin binds TNF-alpha– Collagen binds PDGF, HGF, IL-2
• Binding of the survival factors to ECM prevents apoptosis in damage liver and proteolysis
• ECM can modulate the activation of & proliferation of HSC, angiogenesis GF & MMP
• HSC activation represents a critical event in the fibrosis
• This cell become the primary source of ECM in liver upon injury
• This is modulated by immune signaling that is influence by genetic and environmental factors
• The most studied is the adhesion bw ADAMS disintergrin and MMP
• In liver fibrosis two ADAM molecules are identified ADAMTS-13 and ADAMTS-1 which are expressed by HSC & endothelia cell respectively
• Sources of ECM– HSC– Bone marrow derive cells– Epithelial mesenchymal transition– Portal fibroblast
CYTOKINES AND SIGNALING PATHWAYS
Inflammatory cytokines play a key role in fibrosis, given that persistent inflammation precedes fibrosis. Following liver injury, several cell types can
secrete inflammatory cytokines; Cell types include; KCs, hepatocytes, HSCs,
natural killer (NK)cells, lymphocytes, and dendritic cells.
Ligand + receptor = transduction of extracellular signals into the cell =modulation of changes in gene expression.
Common form of ligand-receptor interaction=dimerization/trimerization of receptor molecules Receptors with intrinsic tyrosine kinase Receptors lacking intrinsic tyrosine kinase activity . Seven transmembrane G-protein-coupled receptors (GPCRs). Steroid
hormone receptors.
Activated hepatic stellate cell
Hepatic fibrosis
REGULATION OF GENEEXPRESSION
• Transcriptional Regulation of gene expression in eukaryote cells is a complex, precise, and cell-specific process.
• Recent advances have highlighted the impact of post-translational modifications, including phosphorylation, SUMOylation, prenylation, acetylation, and glucosylation,
• which can regulate a range of effects in transcriptional activity
• Transcription factors can promote or block the recruitment of RNA polymerase binding to a specific DNA sequence
• Changes in genes expression can also occur without modification in DNA sequences through at least three distinct epigenetic processes:– histone deacetylation– DNA methylation, and – silencing by noncoding microRNAs (miRNAs).
• Activation of immune cells through the secretion of proinflammatory and fibrogenic molecules.
• Cytokines and extracellular matrix components also play an important role in initiating fibrosis and perpetuating HSC activation.
Resolution of fibrosis
Morphology of Cirrhosis• In general the liver is enlarged, firm & even hard.• It may however be normal or reduced in size.• Fibrosis of the liver depends on the aetiology• Chx viral hepatitis B&C are the major causes of bridging
fibrosis xterized by interface fibrosis-porto-central• Pericentral or pericellular fibrosis are found in alcohol related
dx (chinken wire pattern)• Biliary cirrosis incorperates the proliferation of bile ductules &
periductal myofibroblast and forms porto-portal fibrosis• Centro-central fibrosis result from condition that alter venous
outflow
Macro-nodular cirrhosis
Alcoholic cirrhosis
MASSON TRICHROME STAIN
A- autoimm hepatitis,B-chx HCV, C-alcoholic hp(chinken wire pattern), D-non alcoholic steatosis E-biliary
cirrhosis
Complications
• Portal hypertension– Pre-sinusoidal-portal vn thrombosis, schistosomiasis and
massive splenomegaly– Sinusoidal-cirrhosis, chx granulomatous dx & hyperplasia– Post-sinusoidal-hepatic vn occlusion(Budd-chiari
syndrome), CCF constrictive pericarditis and hepatic vn outflow obstruction
• Congestive splenomegaly.• Spontaneous bacteria peritonitis• Bleeding varices.
• Metabolic complication– Altered ostrogen metabolism– Spider telangietasia– Palmar erythema– Gynaecomastia/hypogonadism– Abnormal pv bleeding
• Accumulation of NH3-abnormal neurotransmitter- encephalitis and coma• Hypo-albuminarmia-ascitis• Nail changes. Muehrcke's lines- paired horizontal bands separated by normal color
resulting from hypoalbuminemia• Terry's nails- proximal two-thirds of the nail plate appears white with distal one-
third red, also due to hypoalbuminemia• Clubbing - angle between the nail plate and proximal nail fold > 180 degrees• Decrease clotting faactors (75/1210)• Hepatocellular carcinoma.
Summary Hepatic fibrosis is the liver’s wound-healing response to any type
of acute or chronic liver injury. Perpetuation of the fibrotic reaction can lead to end-stage liver
disease, cirrhosis, and HCC whose incidence is increasing worldwide.
Because they produce ECM following activation by liver injury, HSCs are the key effectors of the fibrogenic process.
However, other cellular sources implicated in hepatic scar production were recently identified. Hepatic fibrogenesis is a complex, tightly regulated process in
which genetic determinants and the immune system make important contributions.
Conclusion • The fibrotic response to chronic liver injury depends on both resident and recruited cell types.• There have been major advances in characterizing the
cellular and molecular biology, fibrogenic pathways, and genetic determinants of fibrosis progression and regression.
• The current task is to translate these findings into the development of effective and targeted antifibrotic therapies that will modify the natural history of chronic fibrosing disease.
THANKS