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