Cirrhosis pathophysiology

Jump to navigation Jump to search

Cirrhosis Microchapters


Patient Information


Historical Perspective




Differentiating Cirrhosis from other Diseases

Epidemiology and Demographics

Risk Factors


Natural History, Complications and Prognosis


Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings


Chest X Ray



Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies


Medical Therapy


Primary Prevention

Secondary Prevention

Tertiary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case studies

Case #1

Cirrhosis pathophysiology On the Web

Most recent articles

cited articles

Review articles

CME Programs

Powerpoint slides


American Roentgen Ray Society Images of Cirrhosis pathophysiology

All Images
Echo & Ultrasound
CT Images

Ongoing Trials at Clinical

US National Guidelines Clearinghouse

NICE Guidance

FDA on Cirrhosis pathophysiology

CDC on Cirrhosis pathophysiology

Cirrhosis pathophysiology in the news

Blogs on Cirrhosis pathophysiology

Directions to Hospitals Treating Cirrhosis

Risk calculators and risk factors for Cirrhosis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]


Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. The pathological hallmark of cirrhosis is the development of scar tissue which leads to replacement of normal liver parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function. When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver. The pathogenesis of cirrhosis involves inflammation, hepatic stellate cell activation, angiogenesis, and fibrogenesis. Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury. Hepatic stellate cells (HSC) which are located in the subendothelial space of Disse, become activated in areas of liver injury and secrete transforming growth factor-beta 1 (TGF-β1), which leads to a fibrotic response and proliferation of connective tissue. Cirrhosis may also lead to hepatic microvascular changes including the formation of intra-hepatic shunts (due to angiogenesis and loss of parenchymal cells) and endothelial dysfunction. Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature, accompanied by regenerative nodule formation. HAYOP


The pathogenesis of cirrhosis is as follows:[1][2][3][4][5][6]

Hepatic stellate cell activation

The role of hepatic stellate cells in the pathogenesis of cirrhosis is described below:

Microvascular changes

Cirrhosis leads to hepatic microvascular changes characterised by:[9]



The role of fibrosis in the pathogenesis of cirrhosis is described below:

Pathogenesis of cirrhosis according to cause

Pathogenesis of cirrhosis based upon the underlying cause is as follows:

Pathophysiology of Cirrhosis due to Alcohol

Mechanisms of alcohol-induced liver damage include:[18][19][20][21]

Pathophysiology of Portal Hypertension due to Cirrhosis

Increased resistance

Hyperdynamic circulation in portal hypertension


Gross Pathology

On gross examination, the liver may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.

  • In the micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm.
  • In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm.
  • The mixed cirrhosis consists of a variety of nodules with different sizes.

On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension.


On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[41]
Macronodular cirrhosis[42]


On gross pathology, diffuse enlargement and congestion of the spleen are characteristic findings of splenomegaly.

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[43]

Esophageal Varices

On gross pathology, prominent, congested, and tortoise veins in the lower parts of esophagus are characteristic findings of esophageal varices.

Esophageal varices[44]

Images of gross pathology of cirrhosis

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

  • Microscopic pathology reveals the four stages of cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis: inflammation and necrosis of portal tracts with lymphocyte infiltration leads to the destruction of the bile ducts
    • Development of biliary stasis and fibrosis
    • Periportal fibrosis progresses to bridging fibrosis
    • Increased proliferation of smaller bile ductules leads to regenerative nodule formation
  • Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa.
  • In these nodules, regenerating hepatocytes are present.
  • Portal tracts, central veins and the radial pattern of hepatocytes are absent.
  • Fibrous septa are present and inflammatory infiltrate composed of lymphocytes and macrophages) are also visible.
  • If the underlying cause is secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended leading to bile stasis.
  • Dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous).
  • Bile retention may be found also in the parenchyma and are referred to as "bile lakes".[45]

Microscopic pathology

The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome.


Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[46]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via[47]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via[48]

Hepatic amyloidosis

The main microscopic histopathological findings in hepatic amyloidosis is amorphous extracellular pink stuff on H&E staining.

Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via[49]

Congestive hepatopathy

The main microscopic histopathological findings in congestive hepatopathy (due to heart failure or Budd-Chiari syndrome) are:

Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via[50]






  1. Arthur MJ, Iredale JP (1994). "Hepatic lipocytes, TIMP-1 and liver fibrosis". J R Coll Physicians Lond. 28 (3): 200–8. PMID 7932316.
  2. Friedman SL (1993). "Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies". N. Engl. J. Med. 328 (25): 1828–35. doi:10.1056/NEJM199306243282508. PMID 8502273.
  3. Iredale JP (1996). "Matrix turnover in fibrogenesis". Hepatogastroenterology. 43 (7): 56–71. PMID 8682489.
  4. Gressner AM (1994). "Perisinusoidal lipocytes and fibrogenesis". Gut. 35 (10): 1331–3. PMC 1374996. PMID 7959178.
  5. Iredale JP (2007). "Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ". J. Clin. Invest. 117 (3): 539–48. doi:10.1172/JCI30542. PMC 1804370. PMID 17332881.
  6. 6.0 6.1 Arthur MJ (2002). "Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C". Gastroenterology. 122 (5): 1525–8. PMID 11984538.
  7. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G (1995). "Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension". Hepatology. 21 (5): 1238–47. PMID 7737629.
  8. Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 2003;327:143-7.Fulltext. PMID 12869458.
  9. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J (2009). "Angiogenesis in liver disease". J. Hepatol. 50 (3): 604–20. doi:10.1016/j.jhep.2008.12.011. PMID 19157625.
  10. Maher JJ, McGuire RF (1990). "Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo". J. Clin. Invest. 86 (5): 1641–8. doi:10.1172/JCI114886. PMC 296914. PMID 2243137. Unknown parameter |month= ignored (help)
  11. Herbst H, Frey A, Heinrichs O; et al. (1997). "Heterogeneity of liver cells expressing procollagen types I and IV in vivo". Histochem. Cell Biol. 107 (5): 399–409. PMID 9208331. Unknown parameter |month= ignored (help)
  12. García-Pagán JC, Gracia-Sancho J, Bosch J (2012). "Functional aspects on the pathophysiology of portal hypertension in cirrhosis". J. Hepatol. 57 (2): 458–61. doi:10.1016/j.jhep.2012.03.007. PMID 22504334.
  13. Lee JS, Semela D, Iredale J, Shah VH (2007). "Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?". Hepatology. 45 (3): 817–25. doi:10.1002/hep.21564. PMID 17326208. Unknown parameter |month= ignored (help)
  14. Rosmorduc O, Housset C (2010). "Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease". Semin. Liver Dis. 30 (3): 258–70. doi:10.1055/s-0030-1255355. PMID 20665378. Unknown parameter |month= ignored (help)
  15. Schuppan D, Afdhal NH (2008). "Liver cirrhosis". Lancet. 371 (9615): 838–51. doi:10.1016/S0140-6736(08)60383-9. PMC 2271178. PMID 18328931.
  16. Desmet VJ, Roskams T (2004). "Cirrhosis reversal: a duel between dogma and myth". J. Hepatol. 40 (5): 860–7. doi:10.1016/j.jhep.2004.03.007. PMID 15094237.
  17. Wanless IR, Nakashima E, Sherman M (2000). "Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis". Arch. Pathol. Lab. Med. 124 (11): 1599–607. doi:10.1043/0003-9985(2000)124<1599:ROHC>2.0.CO;2. PMID 11079009.
  18. Ceni E, Mello T, Galli A (2014). "Pathogenesis of alcoholic liver disease: role of oxidative metabolism". World J. Gastroenterol. 20 (47): 17756–72. doi:10.3748/wjg.v20.i47.17756. PMC 4273126. PMID 25548474.
  19. You M, Crabb DW (2004). "Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver". Am. J. Physiol. Gastrointest. Liver Physiol. 287 (1): G1–6. doi:10.1152/ajpgi.00056.2004. PMID 15194557.
  20. Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR (2005). "Recent advances in alcohol-induced adduct formation". Alcohol. Clin. Exp. Res. 29 (7): 1310–6. PMID 16088993.
  21. Niemelä O (2007). "Acetaldehyde adducts in circulation". Novartis Found. Symp. 285: 183–92, discussion 193–7. PMID 17590995.
  22. Fischer M, You M, Matsumoto M, Crabb DW (2003). "Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice". J. Biol. Chem. 278 (30): 27997–8004. doi:10.1074/jbc.M302140200. PMID 12791698.
  23. You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW (2004). "The role of AMP-activated protein kinase in the action of ethanol in the liver". Gastroenterology. 127 (6): 1798–808. PMID 15578517.
  24. Ji C, Chan C, Kaplowitz N (2006). "Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model". J. Hepatol. 45 (5): 717–24. doi:10.1016/j.jhep.2006.05.009. PMID 16879892.
  25. Greenway CV, Stark RD (1971). "Hepatic vascular bed". Physiol. Rev. 51 (1): 23–65. PMID 5543903.
  26. Schiff, Eugene (2012). Schiff's diseases of the liver. Chichester, West Sussex, UK: John Wiley & Sons. ISBN 9780470654682.
  27. SCHAFFNER F, POPER H (1963). "Capillarization of hepatic sinusoids in man". Gastroenterology. 44: 239–42. PMID 13976646.
  28. Reynolds TB, Hidemura R, Michel H, Peters R (1969). "Portal hypertension without cirrhosis in alcoholic liver disease". Ann. Intern. Med. 70 (3): 497–506. PMID 5775031.
  29. Rubanyi GM (1991). "Endothelium-derived relaxing and contracting factors". J. Cell. Biochem. 46 (1): 27–36. doi:10.1002/jcb.240460106. PMID 1874796.
  30. Epstein, Franklin H.; Vane, John R.; Änggård, Erik E.; Botting, Regina M. (1990). "Regulatory Functions of the Vascular Endothelium". New England Journal of Medicine. 323 (1): 27–36. doi:10.1056/NEJM199007053230106. ISSN 0028-4793.
  31. Rockey DC, Weisiger RA (1996). "Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance". Hepatology. 24 (1): 233–40. doi:10.1002/hep.510240137. PMID 8707268.
  32. Mosca P, Lee FY, Kaumann AJ, Groszmann RJ (1992). "Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium". Am. J. Physiol. 263 (4 Pt 1): G544–50. PMID 1415713.
  33. Colombato LA, Albillos A, Groszmann RJ (1992). "Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats". Hepatology. 15 (2): 323–8. PMID 1735537.
  34. Genecin P, Polio J, Colombato LA, Ferraioli G, Reuben A, Groszmann RJ (1990). "Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats". Am. J. Physiol. 259 (1 Pt 1): G21–5. PMID 2372062.
  35. Casadevall, María; Panés, Julián; Piqué, Josep M.; Marroni, Norma; Bosch, Jaume; Whittle, Brendan J. R. (1993). "Involvement of nitric oxide and prostaglandins in gastric mucosal hyperemia of portal-hypertensive anesthetized rats". Hepatology. 18 (3): 628–634. doi:10.1002/hep.1840180323. ISSN 0270-9139.
  36. Sieber CC, Groszmann RJ (1992). "In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade". Am. J. Physiol. 262 (6 Pt 1): G996–1001. PMID 1616049.
  37. Albillos A, Colombato LA, Lee FY, Groszmann RJ (1993). "Octreotide ameliorates vasodilatation and Na+ retention in portal hypertensive rats". Gastroenterology. 104 (2): 575–9. PMID 8425700.
  38. Calado RT, Brudno J, Mehta P; et al. (2011). "Constitutional telomerase mutations are genetic risk factors for cirrhosis". Hepatology. 53 (5): 1600–7. doi:10.1002/hep.24173. PMC 3082730. PMID 21520173. Unknown parameter |month= ignored (help)
  39. Freed EF, Prieto JL, McCann KL, McStay B, Baserga SJ (2012). "NOL11, Implicated in the Pathogenesis of North American Indian Childhood Cirrhosis, Is Required for Pre-rRNA Transcription and Processing". PLoS Genet. 8 (8): e1002892. doi:10.1371/journal.pgen.1002892. PMC 3420923. PMID 22916032. Unknown parameter |month= ignored (help)
  40. Freed EF, Baserga SJ (2010). "The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis". Nucleic Acids Res. 38 (14): 4798–806. doi:10.1093/nar/gkq185. PMC 2919705. PMID 20385600. Unknown parameter |month= ignored (help)
  41. <CC BY-SA 4.0 (>
  42. "".
  43. Amadalvarez - Own work, <"" title="Creative Commons Attribution-Share Alike 4.0">CC BY-SA 4.0, <"">Link
  44. <>Gallery: <""><"> CC BY 4.0, <"">
  45. Pathology atlas, "cirrhosis".
  46. Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.
  47. "File:Cirrhosis high mag.jpg - Libre Pathology".
  48. "Esophageal varices - Libre Pathology".
  49. "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  50. "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".