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==Pathophysiology==
==Pathophysiology==
Pathophysiology <ref name="pmid7932316">{{cite journal |vauthors=Arthur MJ, Iredale JP |title=Hepatic lipocytes, TIMP-1 and liver fibrosis |journal=J R Coll Physicians Lond |volume=28 |issue=3 |pages=200–8 |year=1994 |pmid=7932316 |doi= |url=}}</ref><ref name="pmid8502273">{{cite journal |vauthors=Friedman SL |title=Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies |journal=N. Engl. J. Med. |volume=328 |issue=25 |pages=1828–35 |year=1993 |pmid=8502273 |doi=10.1056/NEJM199306243282508 |url=}}</ref><ref name="pmid8682489">{{cite journal |vauthors=Iredale JP |title=Matrix turnover in fibrogenesis |journal=Hepatogastroenterology |volume=43 |issue=7 |pages=56–71 |year=1996 |pmid=8682489 |doi= |url=}}</ref><ref name="pmid7959178">{{cite journal |vauthors=Gressner AM |title=Perisinusoidal lipocytes and fibrogenesis |journal=Gut |volume=35 |issue=10 |pages=1331–3 |year=1994 |pmid=7959178 |pmc=1374996 |doi= |url=}}</ref><ref name="pmid17332881">{{cite journal |vauthors=Iredale JP |title=Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ |journal=J. Clin. Invest. |volume=117 |issue=3 |pages=539–48 |year=2007 |pmid=17332881 |pmc=1804370 |doi=10.1172/JCI30542 |url=}}</ref><ref name="pmid11984538">{{cite journal |vauthors=Arthur MJ |title=Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C |journal=Gastroenterology |volume=122 |issue=5 |pages=1525–8 |year=2002 |pmid=11984538 |doi= |url=}}</ref>
* When an injured issue is replaced by a collagenous scar, it is termed as fibrosis. The development of [[fibrosis]] requires several months, or even years, of ongoing injury.
* 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. If the damage progresses, panlobular cirrhosis may result.
* The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
* Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
* Cirrhosis involves the following steps: <ref name="pmid7737629">{{cite journal |vauthors=Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G |title=Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension |journal=Hepatology |volume=21 |issue=5 |pages=1238–47 |year=1995 |pmid=7737629 |doi= |url=}}</ref>
** Inflammation
** Hepatic stellate cell activation
** Angiogenesis
** Fibrogenesis
* Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
* The [[Ito cell|stellate cell]], a cell type that normally stores [[vitamin A]], plays a pivotal role in the development of cirrhosis.
* Damage to the hepatic [[parenchyma]] leads to activation of the stellate cell, which becomes contractile (called [[myofibroblast]]) and obstructs blood flow in the circulation.
* The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
* 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.
* The [[stellate cell]] secretes [[TGF beta 1|TGF-β<sub>1</sub>]], which leads to a 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.
* Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
* Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
* Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
* The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
* Stellate cell activation leads to disturbance of the balance between [[matrix metalloproteinase]]s and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by [[matrix (biology)|matrix]] breakdown and replacement by connective tissue-secreted matrix.<ref>Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. [[British Medical Journal|BMJ]] 2003;327:143-7.[http://bmj.bmjjournals.com/cgi/content/full/327/7407/143 Fulltext.] PMID 12869458.</ref>
* [[Matrix metalloproteinase]] (MMP) are calcium dependent enzymes that specifically degrade [[collagen]] and non collagenous substrate.
* MMP-2 and stromyelysin-1 are produced by stellate cells.
* MMP-2 degrades collagen and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
* Cirrhosis leads to hepatic microvascular changes characterised by <ref name="pmid19157625">{{cite journal |vauthors=Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J |title=Angiogenesis in liver disease |journal=J. Hepatol. |volume=50 |issue=3 |pages=604–20 |year=2009 |pmid=19157625 |doi=10.1016/j.jhep.2008.12.011 |url=}}</ref>
**  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
** hepatic endothelial dysfunction
* Sinusoidal endothelial cells are also important contributors of early fibrosis. [[Endothelial cell]]s from a normal liver produces collagen, [[laminin]] and [[fibronectin]].<ref>{{cite journal |author=Maher JJ, McGuire RF |title=Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo |journal=J. Clin. Invest. |volume=86 |issue=5 |pages=1641–8 |year=1990 |month=November |pmid=2243137 |pmc=296914 |doi=10.1172/JCI114886 |url=}}</ref><ref>{{cite journal |author=Herbst H, Frey A, Heinrichs O, ''et al.'' |title=Heterogeneity of liver cells expressing procollagen types I and IV in vivo |journal=Histochem. Cell Biol. |volume=107 |issue=5 |pages=399–409 |year=1997 |month=May |pmid=9208331 |doi= |url=}}</ref>
* The endothelial dysfunction is characterised by <ref name="pmid22504334">{{cite journal |vauthors=García-Pagán JC, Gracia-Sancho J, Bosch J |title=Functional aspects on the pathophysiology of portal hypertension in cirrhosis |journal=J. Hepatol. |volume=57 |issue=2 |pages=458–61 |year=2012 |pmid=22504334 |doi=10.1016/j.jhep.2012.03.007 |url=}}</ref>
** insufficient release of vasodilators, such as nitric oxide due to oxidative stress
** increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
* The liver responds to injury with new blood vessel formation. Mediators involved in angiogenesis include:
**Platelet derived growth factor (PDGF)
**[[Vascular endothelial growth factor]] (VEGF)
**[[Nitric oxide]]
**[[Carbon monoxide]]
*[[Angiogenesis]] in cirrhosis results in the production of immature and permeable [[Vascular endothelial growth factor|VEGF]] induced neo-[[Blood vessel|vessels]] that further exacerbate [[liver]] injury. <ref>{{cite journal |author=Lee JS, Semela D, Iredale J, Shah VH |title=Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? |journal=Hepatology |volume=45 |issue=3 |pages=817–25 |year=2007 |month=March |pmid=17326208 |doi=10.1002/hep.21564 |url=}}</ref><ref>{{cite journal |author=Rosmorduc O, Housset C |title=Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease |journal=Semin. Liver Dis. |volume=30 |issue=3 |pages=258–70 |year=2010 |month=August |pmid=20665378 |doi=10.1055/s-0030-1255355 |url=}}</ref>
* Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.<ref name="pmid18328931">{{cite journal |vauthors=Schuppan D, Afdhal NH |title=Liver cirrhosis |journal=Lancet |volume=371 |issue=9615 |pages=838–51 |year=2008 |pmid=18328931 |pmc=2271178 |doi=10.1016/S0140-6736(08)60383-9 |url=}}</ref><ref name="pmid15094237">{{cite journal |vauthors=Desmet VJ, Roskams T |title=Cirrhosis reversal: a duel between dogma and myth |journal=J. Hepatol. |volume=40 |issue=5 |pages=860–7 |year=2004 |pmid=15094237 |doi=10.1016/j.jhep.2004.03.007 |url=}}</ref><ref name="pmid11079009">{{cite journal |vauthors=Wanless IR, Nakashima E, Sherman M |title=Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis |journal=Arch. Pathol. Lab. Med. |volume=124 |issue=11 |pages=1599–607 |year=2000 |pmid=11079009 |doi=10.1043/0003-9985(2000)124<1599:ROHC>2.0.CO;2 |url=}}</ref>
* These mechanisms simultaneously occurring in the liver lead to fibrous tissue band (septa) and regenerative hepatocyte nodule formation, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
* The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
* Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
* The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal [[parenchyma]], leading to blockade of portal blood flow and disturbance of normal liver function.
* Due to portal hypertension, the [[spleen]] becomes congested, which leads to [[hypersplenism]] and increased [[platelet]] sequestration.
* Pathogenesis of cirrhosis based upon its individual cause is as follows:
** '''[[Alcoholic liver disease]]''':  [[Alcohol]] seems to injure the [[liver]] by blocking the normal metabolism of [[protein]], [[fat]]s, and [[carbohydrate]]s. Patients may also have concurrent [[alcoholic hepatitis]] with [[fever]], [[hepatomegaly]], [[jaundice]], and anorexia. Liver damage due to alcoholic hepatitis may progress to cirrhosis.
** '''Chronic hepatitis C''':  Infection with the [[hepatitis C]] virus causes inflammation of and low grade damage to the [[liver]] that over several decades can lead to cirrhosis.
** '''[[Non-alcoholic fatty liver disease|Non-alcoholic steatohepatitis]]''' (NASH):  In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with [[diabetes]], [[protein malnutrition]], [[obesity]], [[coronary artery disease]], and treatment with [[corticosteroid]] medications.
** '''[[Primary sclerosing cholangitis]]:'''  PSC is a progressive cholestatic disorder presenting with [[pruritus]], [[steatorrhea]], fat soluble vitamin deficiencies, and [[metabolic bone disease]].
*** There is a strong association with [[inflammatory bowel disease]] (IBD), especially [[ulcerative colitis]].
** '''[[Autoimmune hepatitis]]''':  Immunologic damage to the liver leads to [[inflammation]], scarring and cirrhosis.


* The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal [[parenchyma]], leading to blockade of portal blood flow and disturbance of normal liver function.
* The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal [[parenchyma]], leading to blockade of portal blood flow and disturbance of normal liver function.

Revision as of 18:49, 20 December 2017

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

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

Pathophysiology [1][2][3][4][5][6]

  • When an injured issue is replaced by a collagenous scar, it is termed as fibrosis. The development of fibrosis requires several months, or even years, of ongoing injury.
  • 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. If the damage progresses, panlobular cirrhosis may result.
  • The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
  • Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
  • Cirrhosis involves the following steps: [7]
    • Inflammation
    • Hepatic stellate cell activation
    • Angiogenesis
    • Fibrogenesis
  • Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
  • The stellate cell, a cell type that normally stores vitamin A, plays a pivotal role in the development of cirrhosis.
  • Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation.
  • The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
  • 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.
  • The stellate cell secretes TGF-β1, which leads to a fibrotic response and proliferation of connective tissue.
  • Connective tissue proliferation leads to the formation of extracellular matrix around hepatocytes and is composed of collagens (especially type I, III, IV), glycoprotein and proteoglycans.
  • Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
  • Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
  • Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
  • The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
  • Stellate cell activation leads to disturbance of the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by matrix breakdown and replacement by connective tissue-secreted matrix.[8]
  • Matrix metalloproteinase (MMP) are calcium dependent enzymes that specifically degrade collagen and non collagenous substrate.
  • MMP-2 and stromyelysin-1 are produced by stellate cells.
  • MMP-2 degrades collagen and stromelysin-1 degrades proteoglycan and glycoprotein.
  • Cirrhosis leads to hepatic microvascular changes characterised by [9]
    •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
    • hepatic endothelial dysfunction
  • Sinusoidal endothelial cells are also important contributors of early fibrosis. Endothelial cells from a normal liver produces collagen, laminin and fibronectin.[10][11]
  • The endothelial dysfunction is characterised by [12]
    • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
    • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
  • The liver responds to injury with new blood vessel formation. Mediators involved in angiogenesis include:
  • Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that further exacerbate liver injury. [13][14]
  • Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.[15][16][17]
  • These mechanisms simultaneously occurring in the liver lead to fibrous tissue band (septa) and regenerative hepatocyte nodule formation, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
  • The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
  • Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
  • The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
  • Due to portal hypertension, the spleen becomes congested, which leads to hypersplenism and increased platelet sequestration.
  • Pathogenesis of cirrhosis based upon its individual cause is as follows:
  • The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
  • The development of fibrosis requires several months, or even years, of ongoing injury.
  • Stellate cell activation leads to disturbance of the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by matrix breakdown and replacement by connective tissue-secreted matrix.[22]
  • Matrix metalloproteinase (MMP) are calcium dependent enzymes that specifically degrade collagen and non collagenous substrate.
  • MMP-2 and stromyelysin-1 are produced by stellate cells.
  • MMP-2 degrades collagen and stromelysin-1 degrades proteoglycan and glycoprotein.
  • These mechanisms simultaneously occurring in the liver lead to fibrous tissue band (septa) and regenerative hepatocyte nodule formation, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
  • Portal hypertension may develop as a consequence of cirrhosis.
  • Due to portal hypertension, the spleen becomes congested, which leads to hypersplenism and increased platelet sequestration.
  • Portal hypertension is responsible for the most severe complications of cirrhosis.

Cirrhosis

Pathophysiology [1][2][3][4][5][6]

  • When an injured issue is replaced by a collagenous scar, it is termed as fibrosis.
  • 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 cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
  • Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
  • If the damage progresses, panlobular cirrhosis may result.
  • Cirrhosis involves the following steps: [7]
    • Inflammation
    • Hepatic stellate cell activation
    • Angiogenesis
    • Fibrogenesis
  • Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
  • The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
  • 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.
  • Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
  • Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
  • Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
  • The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
  • Cirrhosis leads to hepatic microvascular changes characterised by [9]
    •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
    • hepatic endothelial dysfunction
  • The endothelial dysfunction is characterised by [12]
    • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
    • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
  • Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.[15][16][17]
  • The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
  • Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
  • Portal HTN results from the combination of the following:
    • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
    •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

  • More than 66 percent of all American adults consume alcohol.
  • Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
  • Mechanisms of alcohol-induced damage include:
    • Impaired protein synthesis, secretion, glycosylation
  • Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
    • Lipoprotein secretion
    • Decreased fatty acid oxidation
    • Increased fatty acid uptake
  • Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
  • Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
    • Trafficking of hepatic proteins
    • Interrupting microtubule formation
    • Interfering with enzyme activities
  • Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.[6]
  • Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
  • Stellate cell activation leads to the production of extracellular matrix and collagen.
  • Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
  • Shrinkage of the liver occurs over years due to repeated insults that lead to:
    • Loss of hepatocytes
    • Increased production and deposition of collagen


Pathology

  • There are four stages of Cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading 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 leading to regenerative nodule formation.

Pathophysiology of Alcoholic liver disease

  • The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.[33]
  • Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.[50][51][52]
  • Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:[53][54]
  • Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.[55][56]
  • Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.[57][58]
  • The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.[59]
  • After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.[60]
  • The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
  • Activation of these Kupffer cells requires 3 main cellular proteins:[61]
    • CD14 (monocyte differentiation antigen)[62]
    • Toll-like receptor 4 (TLR4)[63]
    • MD2, a protein, binds TLR4 with LPS-LPS binding protein
  • The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.[64]
  • The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.[65]
  • EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
  • In mice the absence of EGR1 prevents alcohol induced liver injury.[66]
  • Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.[67]
  • The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.[68]

Pathophysiology of Portal Hypertension

Increased resistance

Hyperdynamic circulation in portal hypertension

Genetics

  • Certain TERT (Telomerase reverese transcriptase)gene variants resulting in reduced telomerase activity has been found to be a risk factor for sporadic cirrhosis[83]
  • An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis[84]
  • Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis[85]
  • 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:[86]

Homozygous missense mutation leads to:[87]

Adenosine deaminase (ADA) 608958 20q13.12 Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway Reduced[88] Some roles in modulating tissue response to IL-13

The main effects of IL-13 are:[89]

Phospholipase A2 (PL2G10) 603603 16p13.12 Catalyzing the release of fatty acids from phospholipids Reduced[88] 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[88] -
Glutathione peroxidase 3 (GPX3) 138321 5q33.1 Reduction of glutathione which reduce:[90] Increased[88] Protects various organs against oxidative stress:[91]
Leukotriene B4 (LTB4) 601531 14q12 Include:[92] Mutated Increase blood flow to target tissue (esp. heart) about 4 times more.[93]
Prostaglandin E receptor 2 (PTGER2) 176804 14q22.1 Various biological activities in diverse tissues Reduced[88] -
Endothelin (EDN1) 131240 6p24.1 Vasoconstriction[94] Increased The most powerful vasoconstrictor known[95]
Endothelin receptor type A (EDNRA) 131243 4q31.22-q31.23 Vasoconstriction through binding to endothelin Reduced[88] Directly related to hypertension in patients[94]
Natriuretic peptide receptor 3 (NPR3) 108962 5p13.3 Maintenance of: Increased[88] Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3[96]
Cluster of differentiation 44 (CD44) 107269 11p13 Reduced[88]
Transforming growth factor (TGF)-β 190180 19q13.2 Reduced[88] Hyper-expressed in African-American hypertensive patients[101]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) 607577 8p21.3 Increasing phosphatase activity in intracellular membrane-bound nucleosides Reduced[88] -
ATP-binding cassette, subfamily C, member 1 (ABCC1) 158343 16p13.11 Multi-drug resistance in small cell lung cancer[102] Reduced -

Associated Conditions

 
 
 
 
 
 
 
 
 
 
Portal Hypertension
associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological disorders
 
Infections
 
Medication and toxins
 
Genetic disorders
 
Prothrombotic conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Common variable immunodeficiency syndrome[103]
• Connective tissue diseases[104]
• Crohn’s disease[105]
• Solid organ transplant
•• Renal transplantation[106]
•• Liver transplantation[107]
• Hashimoto's thyroiditis[108]
• Autoimmune disease[109]
 
• Bacterial intestinal infections
• Recurrent E.coli infection[110]
• Human immunodeficiency virus (HIV) infection[111]
• Antiretroviral therapy[112]
 
• Thiopurine derivatives
•• Didanosine
•• Azathioprine[113]
•• Cis-thioguanine[114]
• Arsenicals[115]
• Vitamin A[116]
 
• Adams-Olivier syndrome[117]
• Turner syndrome[118]
• Phosphomannose isomerase deficiency[119]
• Familial cases[120]
 
• Inherited thrombophilias [121]
• Myeloproliferative neoplasm[121]
• Antiphospholipid syndrome[121]
• Sickle cell disease[122]
 
 

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[123]
Macronodular cirrhosis[124]

Splenomegaly

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

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[125]

Esophageal Varices

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

Esophageal varices[126]

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".[127]

Microscopic Pathology

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[128]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[129]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[130]

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[131]

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[132]

Chronic active hepatitis - Cirrhosis

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Micronodular cirrhosis

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Primary biliary cirrhosis

{{#ev:youtube|Jj8ozr_IttM}}

References

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  123. ↑ <CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)>
  124. ↑ "www.meddean.luc.edu".
  125. ↑ 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
  126. ↑ <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">
  127. ↑ Pathology atlas, "cirrhosis".
  128. ↑ Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.
  129. ↑ "File:Cirrhosis high mag.jpg - Libre Pathology".
  130. ↑ "Esophageal varices - Libre Pathology".
  131. ↑ "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  132. ↑ "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".

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