Cirrhosis of Liver - Etiopathogenesis Chronic Liver Disease by Karun Bhattarai MBBS(Batch 2018) BPKIHS, Nepal Includes: Etiology of Liver Damage, Spectrum of Alcoholic Liver Damage Pathogenesis of Liver Injury Liver Cirrhosis

1. Etiopathogenesis
of
Cirrhosis of Liver
Karun Bhattarai
MBBS(Batch 2018)
BPKIHS, Nepal

2. Natural History of Chronic Liver Disease
Persisted Liver
Insult
Chronic Liver
Disease
Compensated
Cirrhosis
Decompensated
Cirrhosis
Or Death
Ascites
Jaundice
Encephalopathy
Variceal Hemorrhage

3. Cirrhosis
• An advanced stage liver disease which is defined histopathologically!
• Marked by the diffuse transformation of the entire liver parenchyma
into regenerative nodules surrounded by fibrous bands and variable
degrees of vascular (often portosystemic) shunting.(1)

4. Post Necrotic Cirrhosis
Chronic
Hepatitis B/ C Virus
Toxins from
Alcohol
Autoimmune Hepatitis
(PBC, PSC)
Hemochromatosis,
Wilson’s Disease,
α1 AT deficiency
Chronic RHF,
Veno-occlusive disease
Etiology and Spectrum: Chronic Liver diseases!
???

5. Spectrum of Alcoholic Liver Disease

6. Impaired
Fatty acid oxidation and
lipoprotein secretion
Ethanol
Acetaldehyde
Acetate
NAD+
NADH + H+
NAD+
NADH + H+
Ethanol Dehydrogenase
MEOS (iCYP 2E1)
Peroxisomal Catalase
Aldehyde Dehydrogenase
Production
of ROS
Lipid
Peroxidation of
Hepatocyte
Cell membrane
MethionineGlutathione
Increased Gut
Permeability; LPS
from Normal flora
Inhibts

7. Hepatic Steatosis
• Deposition of lipid droplets within Hepatocyte; which coalesces into
large droplets distending the Hepatocyte and push the nucleus aside.
GrossMicroscopy

8. Steato-Hepatitis
• Seen Microscopically,
a) Accumulation of lipids, water and protein(ubiquitin) causes swelling of
either single or scattered foci of cells. Ballooning of Hepatocytes
b) Tangled Intermediate filaments(clumped, amorphous, eosinophilic)
within hepatocytes are known as Mallory-Denk Bodies. (can be
observed in NAFLD, Wilsons Disease, HCC and so forth.)
c) Neutrophils permeate the hepatic lobule and accumulate around
degenerating Hepatocytes.

10. Activation of Kupffer cells and Endothelial
cells of Hepatocytes leading Steato-fibrosis(2).

11. Role of APC and Lymphocytes to release mediators (2).
Antigens in the Liver are
taken up by APC like Kupffer
cells, Dendritic cells
NK cells and CD8+ T Cells
Pro-inflammatory Cytokines
like TNF-α, IL-1, IL-6
Antigen
Presenting Cell
Lymphocytes

12. Activation of Hepatic Stellate cells
Inflammatory cytokines(
TNFa, Lymphotoxins, IL-
1B) from
Chronic Inflammation
Cytokines and
chemokines from Kupffer
cells, Endothelial cells,
Hepatocytes and Bile
duct epithelial cells
Disruption of ECM
Direct Stimulation by
Toxins
Activation of
Hepatic Stellate Cells

13. Normal Vs Activated HSC(3)

14. Role of Activated Hepatic Stellate Cells in
Fibrosis
• Endothelin 1 causes the contraction of activated HSC and releases
Transforming Growth Factor β (TGF- β)
• Chemotaxis of which is promoted by Platelet Derived Growth
Factor(PDGF) and Monocyte Chemotatic Protein-1 (MCP-1)

16. Is Fibrosis IRREVERSIBLE???
• Is evident in :
a) Successful treatment of Chronic Hepatitis C
b) Treatment of Patient of Hemochromatosis
c) Abstinence of alcohol
The underlying insults that has
caused the cirrhosis has been
removed
Cessation of stellate cell
activation
Scars Condenses, being more
dense and thin
Metalloproteinases breaks
apart fibrous scars

18. Natural History of Fibrosis Progression and
Regression(4)
• ---------------------------
• Foxit Reader
• ---------------------------
• The selected area has been copied to the clipboard.
• ---------------------------
• Do not show this message again
• ---------------------------
• OK
• ---------------------------

19. (5) (6)

20. Regenerative Hyperplastic Nodules
a. Regenerative nodules form in response to necrosis, altered
circulation, or other stimuli
b. may be monoacinar(single terminal portal tract) or multiacinar(
multiple portal tract
according to size
micronodules (<3 mm) or macronodules (≥3 mm).

22. Morphology of Cirrhosis
• Characterised by:
1.Bridging fibrous septa:
2.Parenchymal nodules:
Regenerative nodules surrounded by fibrosis
< 3mm = Micronodular cirrhosis (alcoholic cirrhosis)
> 3mm = Macronodular cirrhosis (Viral Hepatitis)
3.Disruption of the architecture of the entire liver
Vasculature affected in particular with formation of abnormal
interconnections between vascular inflow and hepatic vein outflow

23. (7)

24. References:
1. Vinay Kumar, Abul K. Abbas, Jon C. Aster. n.d. ROBBINS AND COTRAN PATHOLOGIC BASIS OF
DISEASE. Vol. 2. 2 vols. Elsevier Inc.
2. Carlson, Gary. n.d. Gary Carlson ILLUSTRATION. Accessed 01 09, 2020.
http://www.gcarlson.com/immunological-block.
3. Romulo Celli, Xuchen Zhang. 2014. "Pathology of Alcoholic Liver Disease." Journal of Clinical and
Translational Hepatology (Xia & He Publishing ) 2 (2): 103-109. doi:10.14218/JCTH.2014.00010.
4. Wanless IR, et al: Regression of Human Cirrhosis: Morphologic Features and
the
Genesis of Incomplete Septal Cirrhosis, Arch Pathol Lab Med Vol. 124, page
1606, 2000.)
5. Campana L, Iredale JP. Regression of liver fibrosis. InSeminars in liver disease 2017 Mar (Vol. 58, No.
01, pp. 001-010). Thieme Medical Publishers.
6. Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. Journal of hepatology. 2012
May 1;56(5):1171-80.
7. Tsuchida T, Friedman SL. Nature Reviews Gastroenterology & Hepatology. 14:397-411.
doi:10.1038/nrgastro.2017.38

25. Thank You
World Liver Day
April 19