Cirrhosis pathophysiology: Difference between revisions

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* [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury.
* [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury.
* The [[Ito cell|stellate cell]], (also known as the [[Ito cell|perisinusoidal cell]] or [[Ito cell]]) is a type of [[cell]] that normally stores [[vitamin A]] and plays a pivotal role in the development of cirrhosis.
* The [[Ito cell|stellate cell]], (also known as the [[Ito cell|perisinusoidal cell]] or [[Ito cell]]) is a type of [[cell]] that normally stores [[vitamin A]] and plays a pivotal role in the development of cirrhosis.
* [[Ito cell|Hepatic stellate cells (HSC)]] are usually located in the subendothelial space of Disse and become activated to a [[myofibroblast]]-like phenotype in areas of [[liver]] injury. This contractile cell (known as a [[myofibroblast]]) obstructs [[blood flow]] in the [[Circulatory system|circulation]].  
* [[Ito cell|Hepatic stellate cells (HSC)]] are usually located in the [[Space of Disse|subendothelial space of Disse]] and become activated to a [[myofibroblast]]-like phenotype in areas of [[liver]] injury. This contractile cell (known as a [[myofibroblast]]) obstructs [[blood flow]] in the [[Circulatory system|circulation]].  
* The [[stellate cell]] secretes [[TGF beta 1|TGF-β<sub>1</sub>]], which leads to a [[Fibrosis|fibrotic]] response and proliferation of [[connective tissue]].
* The [[stellate cell]] secretes [[TGF beta 1|TGF-β<sub>1</sub>]], which leads to a [[Fibrosis|fibrotic]] response and proliferation of [[connective tissue]].
* [[Connective tissue]] proliferation leads to the formation of [[extracellular matrix]] around [[hepatocytes]] and is composed of [[collagen]]s (especially type I, III, IV), [[glycoprotein]] and [[proteoglycan]]s.  
* [[Connective tissue]] proliferation leads to the formation of [[extracellular matrix]] around [[hepatocytes]] and is composed of [[collagen]]s (especially type I, III, IV), [[glycoprotein]] and [[proteoglycan]]s.  

Revision as of 17:26, 26 December 2017

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

Overview

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.

Pathophysiology

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

Hepatic stellate cell activation

Vascular changes

Angiogenesis

Fibrosis

Pathogenesis of cirrhosis according to cause

Pathophysiology of cirrhosis due to alcohol

Pathophysiology of Portal Hypertension

Increased resistance

Hyperdynamic circulation in portal hypertension

Genetics

  • Certain TERT (Telomerase reverese transcriptase) gene variants resulting in reduced telomerase activity have been found to be a risk factor for sporadic cirrhosis[61]
  • An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis[62]
  • Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis[63]
  • Genes involved in the pathogenesis of cirrhosis and 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:[64]

Homozygous missense mutation leads to:[65]

Adenosine deaminase (ADA) 608958 20q13.12 Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway Reduced[66] Some roles in modulating tissue response to IL-13

The main effects of IL-13 are:[67]

Phospholipase A2 (PL2G10) 603603 16p13.12 Catalyzing the release of fatty acids from phospholipids Reduced[66] 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[66] -
Glutathione peroxidase 3 (GPX3) 138321 5q33.1 Reduction of glutathione which reduce:[68] Increased[66] Protects various organs against oxidative stress:[69]
Leukotriene B4 (LTB4) 601531 14q12 Include:[70] Mutated Increase blood flow to target tissue (esp. heart) about 4 times more.[71]
Prostaglandin E receptor 2 (PTGER2) 176804 14q22.1 Various biological activities in diverse tissues Reduced[66] -
Endothelin (EDN1) 131240 6p24.1 Vasoconstriction[72] Increased The most powerful vasoconstrictor known[73]
Endothelin receptor type A (EDNRA) 131243 4q31.22-q31.23 Vasoconstriction through binding to endothelin Reduced[66] Directly related to hypertension in patients[72]
Natriuretic peptide receptor 3 (NPR3) 108962 5p13.3 Maintenance of: Increased[66] Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3[74]
Cluster of differentiation 44 (CD44) 107269 11p13 Reduced[66]
Transforming growth factor (TGF)-β 190180 19q13.2 Reduced[66] Hyper-expressed in African-American hypertensive patients[79]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) 607577 8p21.3 Increasing phosphatase activity in intracellular membrane-bound nucleosides Reduced[66] -
ATP-binding cassette, subfamily C, member 1 (ABCC1) 158343 16p13.11 Multi-drug resistance in small cell lung cancer[80] Reduced -

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.

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[81]
Macronodular cirrhosis[82]

Splenomegaly

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

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[83]

Esophageal Varices

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

Esophageal varices[84]

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".[85]

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[86]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[87]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[88]

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[89]

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[90]

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