This document summarizes the pathogenesis of liver cirrhosis and fibrosis. It begins with an introduction to liver disease as a major health problem worldwide. It then discusses the epidemiology of cirrhosis, noting its 10th and 12th leading causes of death in the US. The document outlines the classification of cirrhosis based on nodule size, and describes the key events in the pathogenesis of fibrosis, including hepatic stellate cell activation and cytokine signaling pathways. Morphological features of cirrhosis seen on microscopy and complications like portal hypertension are also summarized. The document concludes by stating hepatic fibrogenesis involves both resident and recruited cell types, and advances may help develop effective antifibrotic therapies.

1. THE PATHOGENESIS OF LIVER
CIRRHOSIS/FIBROSIS
Presenter
Dr Bukar Zarami Abba.
Histopathology Dept. University of Maiduguri Teaching
Hospital Borno State, Nigeria.
17/January/2013

2. Outline
• Introduction
• Epidemiology
• Brief Anatomy
• Classification
• Pathogenesis
• Morphology
• Clinical features
• Summary/conclusion

3. 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

4.  Liver cirrhosis is a chronic non-neoplastic
disease characterized by
1. Diffuse involvement of the liver
2. Complete loss and disruption of the
architecture of the liver
3. Extensive bridging fibrous septae/fibrosis
4. Regenerating parenchymal nodules

5. 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

6. 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

7. 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

8. Microscopic anatomy of the liver

9. Normal liver

11. 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

12.  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.

13. 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

14. 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

15. Natural history of liver disease

16. 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

17. • 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

18. • 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

19. • Sources of ECM
– HSC
– Bone marrow derive cells
– Epithelial mesenchymal transition
– Portal fibroblast

21. 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.

22. 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.

23. Activated hepatic stellate cell

24. Hepatic fibrosis

25. REGULATION OF GENE
EXPRESSION
• 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

27. • 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.

29. Resolution of fibrosis

30. 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

31. Macro-nodular cirrhosis

32. Alcoholic cirrhosis

34. MASSON TRICHROME STAIN

35. A- autoimm hepatitis,B-chx HCV, C-alcoholic hp(chinken
wire pattern), D-non alcoholic steatosis E-biliary
cirrhosis

36. 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.

37. • 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.

38. 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.

39. 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.

40. THANKS