Cirrhosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2];Kalsang Dolma, M.B.B.S.[3]

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. Early disruption of the normal hepatic matrix results in its replacement by scar tissue, which in turn has deleterious effects on cell function.

Pathophysiology

  • Cirrhosis is often preceded by hepatitis and fatty liver (steatosis). If the cause is removed at this stage, the changes are still fully reversible.
  • The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. The development of fibrosis requires several months, or even years, of ongoing injury.
  • The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
  • The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets.
  • Portal hypertension is responsible for the most severe complications of cirrhosis.

Genetics

  • Certain TERT (Telomerase reverese transcriptase)gene variants resulting in reduced telomerase activity has been found to be a risk factor for sporadic cirrhosis[6]
  • An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis[7]
  • Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis[8]
  • Genes are involved in the pathogenesis of portal hypertension include the following:
Gene OMIM number Chromosome Function Gene expression in portal hypertension Notes
Deoxyguanosine kinase (DGUOK) 601465 2p13.1 DNA replication Point mutation Mutation leads to:[9]

Homozygous missense mutation leads to:[10]

Adenosine deaminase (ADA) 608958 20q13.12 Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway Reduced[11] Some roles in modulating tissue response to IL-13

The main effects of IL-13 are:[12]

Phospholipase A2 (PL2G10) 603603 16p13.12 Catalyzing the release of fatty acids from phospholipids Reduced[11] Identifier of PL2G10 expression:
Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) 601270 19p13.12 Catalyzing the omega-hydroxylation of leukotriene B4 (LTB4) Increased[11] -
Glutathione peroxidase 3 (GPX3) 138321 5q33.1 Reduction of glutathione which reduce:[13] Increased[11] Protects various organs against oxidative stress:[14]
Leukotriene B4 (LTB4) 601531 14q12 Include:[15] Mutated Increase blood flow to target tissue (esp. heart) about 4 times more.[16]
Prostaglandin E receptor 2 (PTGER2) 176804 14q22.1 Various biological activities in diverse tissues Reduced[11] -
Endothelin (EDN1) 131240 6p24.1 Vasoconstriction[17] Increased The most powerful vasoconstrictor known[18]
Endothelin receptor type A (EDNRA) 131243 4q31.22-q31.23 Vasoconstriction through binding to endothelin Reduced[11] Directly related to hypertension in patients[17]
Natriuretic peptide receptor 3 (NPR3) 108962 5p13.3 Maintenance of: Increased[11] Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3[19]
Cluster of differentiation 44 (CD44) 107269 11p13 Reduced[11]
Transforming growth factor (TGF)-β 190180 19q13.2 Reduced[11] Hyper-expressed in African-American hypertensive patients[24]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) 607577 8p21.3 Increasing phosphatase activity in intracellular membrane-bound nucleosides Reduced[11] -
ATP-binding cassette, subfamily C, member 1 (ABCC1) 158343 16p13.11 Multi-drug resistance in small cell lung cancer[25] Reduced -

Associated Conditions

 
 
 
 
 
 
 
 
 
 
Portal Hypertension
associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological disorders
 
Infections
 
Medication and toxins
 
Genetic disorders
 
Prothrombotic conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Common variable immunodeficiency syndrome[26]
• Connective tissue diseases[27]
• Crohn’s disease[28]
• Solid organ transplant
•• Renal transplantation[29]
•• Liver transplantation[30]
• Hashimoto's thyroiditis[31]
• Autoimmune disease[32]
 
• Bacterial intestinal infections
• Recurrent E.coli infection[33]
• Human immunodeficiency virus (HIV) infection[34]
• Antiretroviral therapy[35]
 
• Thiopurine derivatives
•• Didanosine
•• Azathioprine[36]
•• Cis-thioguanine[37]
• Arsenicals[38]
• Vitamin A[39]
 
• Adams-Olivier syndrome[40]
• Turner syndrome[41]
• Phosphomannose isomerase deficiency[42]
• Familial cases[43]
 
• Inherited thrombophilias [44]
• Myeloproliferative neoplasm[44]
• Antiphospholipid syndrome[44]
• Sickle cell disease[45]
 
 

Gross Pathology

Macroscopically, 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.

Gross Pathology

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[46]
Macronodular cirrhosis[47]

Splenomegaly

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

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[48]

Esophageal Varices

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

Esophageal varices[49]

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

  • Cirrhosis: Gross, external view of micronodular cirrhosis

    Cirrhosis: Gross, external view of micronodular cirrhosis

  • Cirrhosis: Gross, cut section of previous one (an excellent example)

    Cirrhosis: Gross, cut section of previous one (an excellent example)

  • Cirrhosis: Gross, close-up image

    Cirrhosis: Gross, close-up image

  • Macronodular cirrhosis and hepatoma

    Macronodular cirrhosis and hepatoma

  • Cirrhosis: Gross, close-up, natural color (an excellent example)

    Cirrhosis: Gross, close-up, natural color (an excellent example)

  • Cirrhosis: Gross, close-up (an excellent example)

    Cirrhosis: Gross, close-up (an excellent example)

  • Cirrhosis: Gross, close-up view

    Cirrhosis: Gross, close-up view

  • Micronodular cirrhosis: Gross, external view (an excellent example)

    Micronodular cirrhosis: Gross, external view (an excellent example)

  • Micronodular cirrhosis: Gross, close-up image

    Micronodular cirrhosis: Gross, close-up image

  • Micronodular cirrhosis: Gross (an excellent example)

    Micronodular cirrhosis: Gross (an excellent example)

  • Macronodular cirrhosis: Gross, natural color (perfect color for cirrhosis), close-up, an excellent example

    Macronodular cirrhosis: Gross, natural color (perfect color for cirrhosis), close-up, an excellent example

  • Cirrhosis with portocaval shunt: Gross, severe cirrhosis with extensive liver necrosis due to thrombosis of portocaval shunt (well shown)

    Cirrhosis with portocaval shunt: Gross, severe cirrhosis with extensive liver necrosis due to thrombosis of portocaval shunt (well shown)

  • Endstage cirrhosis: Gross, natural color, close-up (an excellent example)

    Endstage cirrhosis: Gross, natural color, close-up (an excellent example)

  • Endstage cirrhosis: Gross, natural color, close-up view is an excellent example for nodules of yellow-orange liver tissue and broad irregular bands of fibrosis

    Endstage cirrhosis: Gross, natural color, close-up view is an excellent example for nodules of yellow-orange liver tissue and broad irregular bands of fibrosis

  • Endstage cirrhosis: Gross, natural color, close-up cut surface, very well shown nodules of yellow and necrotic opaque liver tissue with broad and irregular bands of fibrosis (an excellent example)

    Endstage cirrhosis: Gross, natural color, close-up cut surface, very well shown nodules of yellow and necrotic opaque liver tissue with broad and irregular bands of fibrosis (an excellent example)

  • Macronodular cirrhosis: Gross, natural color, external view of liver and very enlarged spleen (liver has variable size nodules up to about 2 cm)

    Macronodular cirrhosis: Gross, natural color, external view of liver and very enlarged spleen (liver has variable size nodules up to about 2 cm)

  • Macronodular cirrhosis: Gross, natural color, cut surface, large irregular bands of fibrosis with variable size liver cell nodules up to about 8 mm and all necrotic appears to be an end stage liver disease.

    Macronodular cirrhosis: Gross, natural color, cut surface, large irregular bands of fibrosis with variable size liver cell nodules up to about 8 mm and all necrotic appears to be an end stage liver disease.

  • Macronodular cirrhosis: Gross, natural color view of frontal sections of liver and spleen showing a contracted macronodular liver and an enlarged spleen as large as the liver

    Macronodular cirrhosis: Gross, natural color view of frontal sections of liver and spleen showing a contracted macronodular liver and an enlarged spleen as large as the liver

  • Macronodular cirrhosis: Gross, natural color slab of liver

    Macronodular cirrhosis: Gross, natural color slab of liver

  • Fatty change and early cirrhosis: Gross, natural color, rather close-up image showing typical fatty color, and in lighting at lower right of micrography micronodularity is evident (quite good example)

    Fatty change and early cirrhosis: Gross, natural color, rather close-up image showing typical fatty color, and in lighting at lower right of micrography micronodularity is evident (quite good example)

  • Cirrhosis with portal vein thrombosis: Gross, natural color, sectioned liver with portal vein exposed and filled with red thrombus. A good example of end stage cirrhosis.

    Cirrhosis with portal vein thrombosis: Gross, natural color, sectioned liver with portal vein exposed and filled with red thrombus. A good example of end stage cirrhosis.

  • Endstage cirrhosis with lobular necrosis: Gross, natural color, very close-up view (an excellent example of alcoholic cirrhosis)

    Endstage cirrhosis with lobular necrosis: Gross, natural color, very close-up view (an excellent example of alcoholic cirrhosis)

  • Micronodular cirrhosis: Gross, natural color view of whole liver through capsule with obvious cirrhosis (note to quite large liver)

    Micronodular cirrhosis: Gross, natural color view of whole liver through capsule with obvious cirrhosis (note to quite large liver)

  • Micronodular cirrhosis: Gross, natural color, view of whole liver showing external surface typical cirrhotic liver (history of alcoholism)

    Micronodular cirrhosis: Gross, natural color, view of whole liver showing external surface typical cirrhotic liver (history of alcoholism)

  • Lung: Idiopathic Interstitial Fibrosis: Gross, natural color, an excellent photo of lung cirrhosis (close-up view)

    Lung: Idiopathic Interstitial Fibrosis: Gross, natural color, an excellent photo of lung cirrhosis (close-up view)

  • Endstage cirrhosis: Gross, natural color, slice of liver. Portal vein is opened to show size and patency.

    Endstage cirrhosis: Gross, natural color, slice of liver. Portal vein is opened to show size and patency.

  • Endstage cirrhosis: Gross, natural color, severe cirrhosis with bile stasis

    Endstage cirrhosis: Gross, natural color, severe cirrhosis with bile stasis

  • Portal Vein Thrombosis with cirrhosis: Gross, close-up, micronodular cirrhosis with portal vein thrombosis

    Portal Vein Thrombosis with cirrhosis: Gross, close-up, micronodular cirrhosis with portal vein thrombosis

  • Lung: Hematite: Gross, natural color, external view of "pulmonary cirrhosis" with typical hematite color

    Lung: Hematite: Gross, natural color, external view of "pulmonary cirrhosis" with typical hematite color

  • Gross, natural color of liver and stomach view from external surfaces, micronodular cirrhosis and hemorrhagic gastritis (as the surgeon would see these in natural color)

    Gross, natural color of liver and stomach view from external surfaces, micronodular cirrhosis and hemorrhagic gastritis (as the surgeon would see these in natural color)

Microscopic Pathology

Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages). If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These 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, as the so called "bile lakes".[50]

Microscopic Pathology

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[51]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[52]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[53]

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 Librepathology.org[54]

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 Librepathology.org[55]

Chronic active hepatitis - Cirrhosis

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Micronodular cirrhosis

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Primary biliary cirrhosis

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References

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  2. ↑ 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)
  3. ↑ 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)
  4. ↑ 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)
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  6. ↑ 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)
  7. ↑ 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)
  8. ↑ 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)
  9. ↑ Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N (2001). "The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA". Nat. Genet. 29 (3): 337–41. doi:10.1038/ng746. PMID 11687800.
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  34. ↑ Siramolpiwat S, Seijo S, Miquel R, Berzigotti A, Garcia-Criado A, Darnell A, Turon F, Hernandez-Gea V, Bosch J, Garcia-Pagán JC (2014). "Idiopathic portal hypertension: natural history and long-term outcome". Hepatology. 59 (6): 2276–85. doi:10.1002/hep.26904. PMID 24155091.
  35. ↑ Maida I, Garcia-Gasco P, Sotgiu G, Rios MJ, Vispo ME, Martin-Carbonero L, Barreiro P, Mura MS, Babudieri S, Albertos S, Garcia-Samaniego J, Soriano V (2008). "Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome". Antivir. Ther. (Lond.). 13 (1): 103–7. PMID 18389904.
  36. ↑ Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, Cadiot G, Bouhnik Y, De Vos M, Boureille A, Duclos B, Seksik P, Mary JY, Colombel JF (2007). "Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine". Gut. 56 (10): 1404–9. doi:10.1136/gut.2006.114363. PMC 2000290. PMID 17504943.
  37. ↑ Calabrese E, Hanauer SB (2011). "Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease". J Crohns Colitis. 5 (1): 48–53. doi:10.1016/j.crohns.2010.08.007. PMID 21272804.
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  40. ↑ Girard M, Amiel J, Fabre M, Pariente D, Lyonnet S, Jacquemin E (2005). "Adams-Oliver syndrome and hepatoportal sclerosis: occasional association or common mechanism?". Am. J. Med. Genet. A. 135 (2): 186–9. doi:10.1002/ajmg.a.30724. PMID 15832360.
  41. ↑ Roulot D (2013). "Liver involvement in Turner syndrome". Liver Int. 33 (1): 24–30. doi:10.1111/liv.12007. PMID 23121401.
  42. ↑ de Lonlay P, Seta N (2009). "The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib". Biochim. Biophys. Acta. 1792 (9): 841–3. doi:10.1016/j.bbadis.2008.11.012. PMID 19101627.
  43. ↑ Sarin SK, Mehra NK, Agarwal A, Malhotra V, Anand BS, Taneja V (1987). "Familial aggregation in noncirrhotic portal fibrosis: a report of four families". Am. J. Gastroenterol. 82 (11): 1130–3. PMID 3499813.
  44. ↑ 44.0 44.1 44.2 Bayan K, Tüzün Y, Yilmaz S, Canoruc N, Dursun M (2009). "Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension". J. Thromb. Thrombolysis. 28 (1): 57–62. doi:10.1007/s11239-008-0244-8. PMID 18685811.
  45. ↑ Kumar S, Joshi R, Jain AP (2007). "Portal hypertension associated with sickle cell disease". Indian J Gastroenterol. 26 (2): 94. PMID 17558079.
  46. ↑ <CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)>
  47. ↑ "www.meddean.luc.edu".
  48. ↑ Amadalvarez - Own work, <"https://creativecommons.org/licenses/by-sa/4.0" title="Creative Commons Attribution-Share Alike 4.0">CC BY-SA 4.0, <"https://commons.wikimedia.org/w/index.php?curid=49669333">Link
  49. ↑ <http://wellcomeimages.org/indexplus/obf_images/29/b4/13f38971164f946a97f9d32ddd93.jpg>Gallery: <"http://wellcomeimages.org/indexplus/image/L0074357.html"><"http://creativecommons.org/licenses/by/4.0> CC BY 4.0, <"https://commons.wikimedia.org/w/index.php?curid=36297209">
  50. ↑ Pathology atlas, "cirrhosis".
  51. ↑ Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.
  52. ↑ "File:Cirrhosis high mag.jpg - Libre Pathology".
  53. ↑ "Esophageal varices - Libre Pathology".
  54. ↑ "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  55. ↑ "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".

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