Cirrhosis pathophysiology: Difference between revisions

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** '''[[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]].
** '''[[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]]''':  This disease is caused by the immunologic damage to the liver causing [[inflammation]] and eventually scarring and cirrhosis.
** '''[[Autoimmune hepatitis]]''':  This disease is caused by the immunologic damage to the liver causing [[inflammation]] and eventually scarring and cirrhosis.
==Pathophysiology of Alcoholic liver disease==
*[[Ethanol]] [[metabolism]] in the [[liver]] is carried out mainly by two [[enzymes]]:<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref>
**[[Alcohol dehydrogenase]]
**[[Aldehyde dehydrogenase]]
*Both of these [[enzymes]] use [[Nicotinamide adenine dinucleotide|NAD]]+ as a cofactor. [[Alcohol]] is converted to [[acetaldehyde]] and [[acetaldehyde]] is then further [[oxidized]] to [[acetate]]. [[Acetaldehyde]] is the [[toxic]] [[metabolite]] in this process.
*The [[metabolism]] of [[alcohol]] in the [[liver]] ends up producing an excess of reduced [[nicotinamide adenine dinucleotide]] (NADH). This changes the reduction-oxidation potential in the [[liver]] and inhibits key [[metabolic]] processes in the [[liver]] such as, the [[tricarboxylic acid cycle]] and the [[oxidation]] of [[Fatty acid|fatty acids]] and thereby ends up promoting lipogenesis.<ref name="pmid15194557">{{cite journal |vauthors=You M, Crabb DW |title=Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=287 |issue=1 |pages=G1–6 |year=2004 |pmid=15194557 |doi=10.1152/ajpgi.00056.2004 |url=}}</ref>
*Since [[acetaldehyde]] has an [[electrophilic]] nature it can form [[covalent]] chemical bonds with [[Protein|proteins]], [[Lipid|lipids]] and [[DNA]]. These [[Covalent bond|covalent]] bonds that are formed are extremely [[pathogenic]], as they have the ability to alter [[cell]] environments, [[protein]] structures and they can enable [[DNA]] damage and [[mutation]].<ref name="pmid16088993">{{cite journal |vauthors=Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR |title=Recent advances in alcohol-induced adduct formation |journal=Alcohol. Clin. Exp. Res. |volume=29 |issue=7 |pages=1310–6 |year=2005 |pmid=16088993 |doi= |url=}}</ref><ref name="pmid17590995">{{cite journal |vauthors=Niemelä O |title=Acetaldehyde adducts in circulation |journal=Novartis Found. Symp. |volume=285 |issue= |pages=183–92; discussion 193–7 |year=2007 |pmid=17590995 |doi= |url=}}</ref><ref name="pmid11841919">{{cite journal |vauthors=Tuma DJ |title=Role of malondialdehyde-acetaldehyde adducts in liver injury |journal=Free Radic. Biol. Med. |volume=32 |issue=4 |pages=303–8 |year=2002 |pmid=11841919 |doi= |url=}}</ref><ref name="pmid15540799">{{cite journal |vauthors=Tuma DJ, Casey CA |title=Dangerous byproducts of alcohol breakdown--focus on adducts |journal=Alcohol Res Health |volume=27 |issue=4 |pages=285–90 |year=2003 |pmid=15540799 |doi= |url=}}</ref><ref name="pmid16054980">{{cite journal |vauthors=Brooks PJ, Theruvathu JA |title=DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis |journal=Alcohol |volume=35 |issue=3 |pages=187–93 |year=2005 |pmid=16054980 |doi=10.1016/j.alcohol.2005.03.009 |url=}}</ref><ref name="pmid17718399">{{cite journal |vauthors=Seitz HK, Becker P |title=Alcohol metabolism and cancer risk |journal=Alcohol Res Health |volume=30 |issue=1 |pages=38–41, 44–7 |year=2007 |pmid=17718399 |pmc=3860434 |doi= |url=}}</ref><ref name="pmid9857222">{{cite journal |vauthors=Biewald J, Nilius R, Langner J |title=Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study |journal=Int. J. Mol. Med. |volume=2 |issue=4 |pages=389–96 |year=1998 |pmid=9857222 |doi= |url=}}</ref><ref name="pmid17543846">{{cite journal |vauthors=Seitz HK, Meier P |title=The role of acetaldehyde in upper digestive tract cancer in alcoholics |journal=Transl Res |volume=149 |issue=6 |pages=293–7 |year=2007 |pmid=17543846 |doi=10.1016/j.trsl.2006.12.002 |url=}}</ref>
*The [[cytochrome]] [[Cytochrome P450|P450]] enzymes (CYP) are a part of the [[Microsomal Ethanol Oxidizing System|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.<ref name="pmid3678578">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref>
*There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme [[CYP2E1]] is converting [[ethanol]] to [[acetaldehyde]] and then to [[acetate]]. When there is chronic [[alcohol]] abuse, there is induction of the microsomal system and there is an increase in the expression of [[CYP2E1]]. This increase in [[CYP2E1]] expression under chronic [[ethanol]] consumption can be hazardous, as this [[oxidation]] reaction can produces many different ROS; O<sub>2</sub><sup>-</sup>, H<sub>2</sub>O<sub>2</sub>, OH<sup>-</sup> and hydroxyethyl radical (HER).<ref name="pmid36785782">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref><ref name="pmid5009602">{{cite journal |vauthors=Lieber CS |title=Metabolism of ethanol and alcoholism: racial and acquired factors |journal=Ann. Intern. Med. |volume=76 |issue=2 |pages=326–7 |year=1972 |pmid=5009602 |doi= |url=}}</ref><ref name="pmid4402282">{{cite journal |vauthors=Lieber CS, DeCarli LM |title=The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo |journal=J. Pharmacol. Exp. Ther. |volume=181 |issue=2 |pages=279–87 |year=1972 |pmid=4402282 |doi= |url=}}</ref><ref name="pmid9114822">{{cite journal |vauthors=Lieber CS |title=Cytochrome P-4502E1: its physiological and pathological role |journal=Physiol. Rev. |volume=77 |issue=2 |pages=517–44 |year=1997 |pmid=9114822 |doi= |url=}}</ref><ref name="pmid2333153">{{cite journal |vauthors=Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C |title=Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system |journal=Neuroscience |volume=34 |issue=2 |pages=451–63 |year=1990 |pmid=2333153 |doi= |url=}}</ref><ref name="pmid17760783">{{cite journal |vauthors=Donohue TM, Cederbaum AI, French SW, Barve S, Gao B, Osna NA |title=Role of the proteasome in ethanol-induced liver pathology |journal=Alcohol. Clin. Exp. Res. |volume=31 |issue=9 |pages=1446–59 |year=2007 |pmid=17760783 |doi=10.1111/j.1530-0277.2007.00454.x |url=}}</ref><ref name="pmid17854134">{{cite journal |vauthors=Osna NA, Donohue TM |title=Implication of altered proteasome function in alcoholic liver injury |journal=World J. Gastroenterol. |volume=13 |issue=37 |pages=4931–7 |year=2007 |pmid=17854134 |pmc=4434615 |doi= |url=}}</ref><ref name="pmid18078827">{{cite journal |vauthors=Lu Y, Cederbaum AI |title=CYP2E1 and oxidative liver injury by alcohol |journal=Free Radic. Biol. Med. |volume=44 |issue=5 |pages=723–38 |year=2008 |pmid=18078827 |pmc=2268632 |doi=10.1016/j.freeradbiomed.2007.11.004 |url=}}</ref><ref name="pmid1545775">{{cite journal |vauthors=Yun YP, Casazza JP, Sohn DH, Veech RL, Song BJ |title=Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet |journal=Mol. Pharmacol. |volume=41 |issue=3 |pages=474–9 |year=1992 |pmid=1545775 |doi= |url=}}</ref><ref name="pmid2005876">{{cite journal |vauthors=Raucy JL, Lasker JM, Kraner JC, Salazar DE, Lieber CS, Corcoran GB |title=Induction of cytochrome P450IIE1 in the obese overfed rat |journal=Mol. Pharmacol. |volume=39 |issue=3 |pages=275–80 |year=1991 |pmid=2005876 |doi= |url=}}</ref><ref name="pmid11826398">{{cite journal |vauthors=Woodcroft KJ, Hafner MS, Novak RF |title=Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression |journal=Hepatology |volume=35 |issue=2 |pages=263–73 |year=2002 |pmid=11826398 |doi=10.1053/jhep.2002.30691 |url=}}</ref><ref name="pmid7700245">{{cite journal |vauthors=De Waziers I, Garlatti M, Bouguet J, Beaune PH, Barouki R |title=Insulin down-regulates cytochrome P450 2B and 2E expression at the post-transcriptional level in the rat hepatoma cell line |journal=Mol. Pharmacol. |volume=47 |issue=3 |pages=474–9 |year=1995 |pmid=7700245 |doi= |url=}}</ref><ref name="pmid9765518">{{cite journal |vauthors=Peng HM, Coon MJ |title=Regulation of rabbit cytochrome P450 2E1 expression in HepG2 cells by insulin and thyroid hormone |journal=Mol. Pharmacol. |volume=54 |issue=4 |pages=740–7 |year=1998 |pmid=9765518 |doi= |url=}}</ref><ref name="pmid1822117">{{cite journal |vauthors=Terelius Y, Norsten-Höög C, Cronholm T, Ingelman-Sundberg M |title=Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1) |journal=Biochem. Biophys. Res. Commun. |volume=179 |issue=1 |pages=689–94 |year=1991 |pmid=1822117 |doi= |url=}}</ref><ref name="pmid9726291">{{cite journal |vauthors=Wu YS, Salmela KS, Lieber CS |title=Microsomal acetaldehyde oxidation is negligible in the presence of ethanol |journal=Alcohol. Clin. Exp. Res. |volume=22 |issue=5 |pages=1165–9 |year=1998 |pmid=9726291 |doi= |url=}}</ref><ref name="pmid9309320">{{cite journal |vauthors=Brooks PJ |title=DNA damage, DNA repair, and alcohol toxicity--a review |journal=Alcohol. Clin. Exp. Res. |volume=21 |issue=6 |pages=1073–82 |year=1997 |pmid=9309320 |doi= |url=}}</ref>
*[[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 (genetics)|transcription]] factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
*Two key factors that play an important role in the [[inflammatory]] process that leads to the alcohol mediated liver injury are:<ref name="pmid6433728">{{cite journal |vauthors=Tsukamoto H, Reidelberger RD, French SW, Largman C |title=Long-term cannulation model for blood sampling and intragastric infusion in the rat |journal=Am. J. Physiol. |volume=247 |issue=3 Pt 2 |pages=R595–9 |year=1984 |pmid=6433728 |doi= |url=}}</ref><ref name="pmid11431739">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG |title=Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice |journal=Hepatology |volume=34 |issue=1 |pages=101–8 |year=2001 |pmid=11431739 |doi=10.1053/jhep.2001.25350 |url=}}</ref>
**[[Endotoxin]]
**Gut permeability
*[[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 [[Inflammation|inflammatory]] process.<ref name="pmid15723320">{{cite journal |vauthors=Wiest R, Garcia-Tsao G |title=Bacterial translocation (BT) in cirrhosis |journal=Hepatology |volume=41 |issue=3 |pages=422–33 |year=2005 |pmid=15723320 |doi=10.1002/hep.20632 |url=}}</ref><ref name="pmid8171045">{{cite journal |vauthors=Nanji AA, Khettry U, Sadrzadeh SM |title=Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease) |journal=Proc. Soc. Exp. Biol. Med. |volume=205 |issue=3 |pages=243–7 |year=1994 |pmid=8171045 |doi= |url=}}</ref>
*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.<ref name="pmid7806045">{{cite journal |vauthors=Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG |title=Antibiotics prevent liver injury in rats following long-term exposure to ethanol |journal=Gastroenterology |volume=108 |issue=1 |pages=218–24 |year=1995 |pmid=7806045 |doi= |url=}}</ref><ref name="pmid6141332">{{cite journal |vauthors=Bjarnason I, Peters TJ, Wise RJ |title=The leaky gut of alcoholism: possible route of entry for toxic compounds |journal=Lancet |volume=1 |issue=8370 |pages=179–82 |year=1984 |pmid=6141332 |doi= |url=}}</ref>
*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.<ref name="pmid11236841">{{cite journal |vauthors=Urbaschek R, McCuskey RS, Rudi V, Becker KP, Stickel F, Urbaschek B, Seitz HK |title=Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease |journal=Alcohol. Clin. Exp. Res. |volume=25 |issue=2 |pages=261–8 |year=2001 |pmid=11236841 |doi= |url=}}</ref>
*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.<ref name="pmid11884468">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gäbele E, Isayama F, Thurman RG |title=Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice |journal=J. Immunol. |volume=168 |issue=6 |pages=2963–9 |year=2002 |pmid=11884468 |doi= |url=}}</ref>
*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 cell|Kupffer cells]] requires 3 main cellular proteins:<ref name="pmid8045507">{{cite journal |vauthors=Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG |title=Inactivation of Kupffer cells prevents early alcohol-induced liver injury |journal=Hepatology |volume=20 |issue=2 |pages=453–60 |year=1994 |pmid=8045507 |doi= |url=}}</ref>
**[[CD14]] (monocyte differentiation antigen)<ref name="pmid11254735">{{cite journal |vauthors=Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG |title=Reduced early alcohol-induced liver injury in CD14-deficient mice |journal=J. Immunol. |volume=166 |issue=7 |pages=4737–42 |year=2001 |pmid=11254735 |doi= |url=}}</ref>
**Toll-like receptor 4 (TLR4)<ref name="pmid18792393">{{cite journal |vauthors=Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G |title=The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88 |journal=Hepatology |volume=48 |issue=4 |pages=1224–31 |year=2008 |pmid=18792393 |doi=10.1002/hep.22470 |url=}}</ref>
**MD2, a protein, binds [[TLR 4|TLR4]] with LPS-LPS binding protein
*The [[TLR 4|TLR4]] then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.<ref name="pmid11477402">{{cite journal |vauthors=Akira S, Takeda K, Kaisho T |title=Toll-like receptors: critical proteins linking innate and acquired immunity |journal=Nat. Immunol. |volume=2 |issue=8 |pages=675–80 |year=2001 |pmid=11477402 |doi=10.1038/90609 |url=}}</ref> 
*The nuclear factor-kB ([[NF-kB]]) and the [[TLR 4|TLR4]] adapter also play an important role in the activation of the [[Kupffer cell|kupffer cells]].<ref name="pmid18713975">{{cite journal |vauthors=Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK |title=TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol |journal=J. Immunol. |volume=181 |issue=5 |pages=3049–56 |year=2008 |pmid=18713975 |pmc=3690475 |doi= |url=}}</ref> 
*EGR1 plays the pivotal role in [[lipopolysaccharide]]-stimulated [[Tumor necrosis factor-alpha|TNF-α]] production. 
*In mice the absence of EGR1 prevents [[alcohol]] induced [[liver]] injury.<ref name="pmid15940638">{{cite journal |vauthors=McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE |title=Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice |journal=Gastroenterology |volume=128 |issue=7 |pages=2066–76 |year=2005 |pmid=15940638 |pmc=1959407 |doi= |url=}}</ref>
*[[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.<ref name="pmid11438480">{{cite journal |vauthors=Zhou Z, Sun X, Kang YJ |title=Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway |journal=Am. J. Pathol. |volume=159 |issue=1 |pages=329–38 |year=2001 |pmid=11438480 |pmc=1850406 |doi=10.1016/S0002-9440(10)61699-9 |url=}}</ref> 
*The cumulative effect of [[Tumor necrosis factor-alpha|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]].<ref name="pmid15131799">{{cite journal |vauthors=Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G |title=Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption |journal=Gastroenterology |volume=126 |issue=5 |pages=1387–99 |year=2004 |pmid=15131799 |doi= |url=}}</ref>
==Pathophysiology of Portal Hypertension==
==Pathophysiology of Portal Hypertension==
==== Increased resistance ====
==== Increased resistance ====

Revision as of 20:59, 19 December 2017

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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.

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.[16]
  • 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.[33][34][35]
  • Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:[36][37]
  • 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.[38][39]
  • 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.[40][41]
  • 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.[42]
  • 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.[43]
  • 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:[44]
    • CD14 (monocyte differentiation antigen)[45]
    • Toll-like receptor 4 (TLR4)[46]
    • 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.[47]
  • The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.[48]
  • EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
  • In mice the absence of EGR1 prevents alcohol induced liver injury.[49]
  • 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.[50]
  • 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.[51]

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[66]
  • An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis[67]
  • Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis[68]
  • 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:[69]

Homozygous missense mutation leads to:[70]

Adenosine deaminase (ADA) 608958 20q13.12 Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway Reduced[71] Some roles in modulating tissue response to IL-13

The main effects of IL-13 are:[72]

Phospholipase A2 (PL2G10) 603603 16p13.12 Catalyzing the release of fatty acids from phospholipids Reduced[71] 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[71] -
Glutathione peroxidase 3 (GPX3) 138321 5q33.1 Reduction of glutathione which reduce:[73] Increased[71] Protects various organs against oxidative stress:[74]
Leukotriene B4 (LTB4) 601531 14q12 Include:[75] Mutated Increase blood flow to target tissue (esp. heart) about 4 times more.[76]
Prostaglandin E receptor 2 (PTGER2) 176804 14q22.1 Various biological activities in diverse tissues Reduced[71] -
Endothelin (EDN1) 131240 6p24.1 Vasoconstriction[77] Increased The most powerful vasoconstrictor known[78]
Endothelin receptor type A (EDNRA) 131243 4q31.22-q31.23 Vasoconstriction through binding to endothelin Reduced[71] Directly related to hypertension in patients[77]
Natriuretic peptide receptor 3 (NPR3) 108962 5p13.3 Maintenance of: Increased[71] Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3[79]
Cluster of differentiation 44 (CD44) 107269 11p13 Reduced[71]
Transforming growth factor (TGF)-β 190180 19q13.2 Reduced[71] Hyper-expressed in African-American hypertensive patients[84]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) 607577 8p21.3 Increasing phosphatase activity in intracellular membrane-bound nucleosides Reduced[71] -
ATP-binding cassette, subfamily C, member 1 (ABCC1) 158343 16p13.11 Multi-drug resistance in small cell lung cancer[85] Reduced -

Associated Conditions

 
 
 
 
 
 
 
 
 
 
Portal Hypertension
associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological disorders
 
Infections
 
Medication and toxins
 
Genetic disorders
 
Prothrombotic conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Common variable immunodeficiency syndrome[86]
• Connective tissue diseases[87]
• Crohn’s disease[88]
• Solid organ transplant
•• Renal transplantation[89]
•• Liver transplantation[90]
• Hashimoto's thyroiditis[91]
• Autoimmune disease[92]
 
• Bacterial intestinal infections
• Recurrent E.coli infection[93]
• Human immunodeficiency virus (HIV) infection[94]
• Antiretroviral therapy[95]
 
• Thiopurine derivatives
•• Didanosine
•• Azathioprine[96]
•• Cis-thioguanine[97]
• Arsenicals[98]
• Vitamin A[99]
 
• Adams-Olivier syndrome[100]
• Turner syndrome[101]
• Phosphomannose isomerase deficiency[102]
• Familial cases[103]
 
• Inherited thrombophilias [104]
• Myeloproliferative neoplasm[104]
• Antiphospholipid syndrome[104]
• Sickle cell disease[105]
 
 

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[106]
Macronodular cirrhosis[107]

Splenomegaly

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

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[108]

Esophageal Varices

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

Esophageal varices[109]

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".[110]

Microscopic Pathology

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[111]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[112]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[113]

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[114]

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[115]

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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  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)
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  63. ↑ 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.
  64. ↑ 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.
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  66. ↑ 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)
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  109. ↑ <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">
  110. ↑ Pathology atlas, "cirrhosis".
  111. ↑ Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.
  112. ↑ "File:Cirrhosis high mag.jpg - Libre Pathology".
  113. ↑ "Esophageal varices - Libre Pathology".
  114. ↑ "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  115. ↑ "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".

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