Alcoholic hepatitis pathophysiology: Difference between revisions

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==Overview==
==Overview==
The [[pathophysiology]] of [[Alcoholic Hepatitis]] is caused by interplay between [[alcohol]] [[metabolism]], [[inflammation]] and [[innate]] [[immunity]].
The [[pathophysiology]] of [[Alcoholic Hepatitis]] is caused by interplay between [[alcohol]] [[metabolism]], [[inflammation]] and [[innate]] [[immunity]]. [[Alcohol]] metabolism leads to depletion of [[ NAD]] and subsequent [[lipogenesis]]. Additionally, increased endotoxemia causes translocation of [[lipopolysaccharide]] from [[intestine]] to [[hepatocytes]]. In [[hepatocytes]], [[lipopolysaccharide]] activates [[kupffer cells]]. Therefore, activated [[cells]] release [[inflammatory]] markers which lead to [[Alcoholic hepatitis]].
 
== Pathophysiology==
== Pathophysiology==
===Pathogenesis===
===Pathogenesis===
* The [[pathogenesis]] of [[Alcoholic Hepatitis]] is [[multifactorial]].
* The [[pathogenesis]] of [[Alcoholic Hepatitis]] is [[multifactorial]].
**[[Alcoholic Hepatitis]] is caused by interplay between [[alcohol]] [[metabolism]], [[inflammation]] and [[innate]] [[immunity]]. <ref name="GaoBataller2011">{{cite journal|last1=Gao|first1=Bin|last2=Bataller|first2=Ramon|title=Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets|journal=Gastroenterology|volume=141|issue=5|year=2011|pages=1572–1585|issn=00165085|doi=10.1053/j.gastro.2011.09.002}}</ref>
**[[Alcoholic Hepatitis]] is caused by interplay between [[alcohol]] [[metabolism]], [[inflammation]] and [[innate]] [[immunity]]. <ref name="GaoBataller2011">{{cite journal|last1=Gao|first1=Bin|last2=Bataller|first2=Ramon|title=Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets|journal=Gastroenterology|volume=141|issue=5|year=2011|pages=1572–1585|issn=00165085|doi=10.1053/j.gastro.2011.09.002}}</ref>
*[[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 [[Alcohol]] [[metabolism]] leads to a reduced ratio of the [[nicotinamide adenine dinucleotide]] ([[NAD]]) to [[NADH]]. The [[NAD]] depletion inhibit [[fatty acid ]][[oxidation]] and causes [[fat]] accumulation in [[hepatocytes]] associated with [[lipogenesis]]. <ref name="GaoBataller2011">{{cite journal|last1=Gao|first1=Bin|last2=Bataller|first2=Ramon|title=Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets|journal=Gastroenterology|volume=141|issue=5|year=2011|pages=1572–1585|issn=00165085|doi=10.1053/j.gastro.2011.09.002}}</ref>  
*The [[Alcohol]] [[metabolism]] leads to a reduced ratio of the [[nicotinamide adenine dinucleotide]] ([[NAD]]) to [[NADH]]. The [[NAD]] depletion inhibit [[fatty acid ]][[oxidation]] and causes [[fat]] accumulation in [[hepatocytes]] associated with [[lipogenesis]]. <ref name="GaoBataller2011">{{cite journal|last1=Gao|first1=Bin|last2=Bataller|first2=Ramon|title=Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets|journal=Gastroenterology|volume=141|issue=5|year=2011|pages=1572–1585|issn=00165085|doi=10.1053/j.gastro.2011.09.002}}</ref>  
*Due to increased [[intestinal]] permeability in patients with [[Alcoholic Hepatitis]], high levels of [[Endotoxemia]] is recognized.<ref name="GaoBataller2011">{{cite journal|last1=Gao|first1=Bin|last2=Bataller|first2=Ramon|title=Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets|journal=Gastroenterology|volume=141|issue=5|year=2011|pages=1572–1585|issn=00165085|doi=10.1053/j.gastro.2011.09.002}}</ref>
*Due to increased [[intestinal]] permeability in patients with [[Alcoholic Hepatitis]], high levels of [[Endotoxemia]] is recognized.<ref name="GaoBataller2011">{{cite journal|last1=Gao|first1=Bin|last2=Bataller|first2=Ramon|title=Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets|journal=Gastroenterology|volume=141|issue=5|year=2011|pages=1572–1585|issn=00165085|doi=10.1053/j.gastro.2011.09.002}}</ref>
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** These bindings activate [[Kupffer cells]] to release [[reactive oxygen species]].<ref name="Bautista2001">{{cite journal|last1=Bautista|first1=Abraham P|title=Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease|journal=Journal of Gastroenterology and Hepatology|volume=15|issue=4|year=2001|pages=349–356|issn=0815-9319|doi=10.1046/j.1440-1746.2000.02174.x}}</ref>
** These bindings activate [[Kupffer cells]] to release [[reactive oxygen species]].<ref name="Bautista2001">{{cite journal|last1=Bautista|first1=Abraham P|title=Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease|journal=Journal of Gastroenterology and Hepatology|volume=15|issue=4|year=2001|pages=349–356|issn=0815-9319|doi=10.1046/j.1440-1746.2000.02174.x}}</ref>
* This activation release [[tumor necrosis factor-alpha]] ([[TNF alpha]]), [[interleukin-8]], [[monocyte]] [[chemotactic protein]] 1 ([[MCP-1]]), and[[ platelet-derived growth factor]] ([[PDGF]]) which are responsible for characterized [[symptoms]] including  [[malaise]], [[fever]], and [[peripheral]] [[neutrophil]] [[leukocytosis]]. <ref name="pmid7810274">{{cite journal| author=Bird G| title=Interleukin-8 in alcoholic liver disease. | journal=Acta Gastroenterol Belg | year= 1994 | volume= 57 | issue= 3-4 | pages= 255-9 | pmid=7810274 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7810274  }} </ref> <ref name="pmid9347083">{{cite journal| author=Laso FJ, Lapeña P, Madruga JI, San Miguel JF, Orfao A, Iglesias MC | display-authors=etal| title=Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake. | journal=Alcohol Clin Exp Res | year= 1997 | volume= 21 | issue= 7 | pages= 1226-31 | pmid=9347083 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9347083  }} </ref>
* This activation release [[tumor necrosis factor-alpha]] ([[TNF alpha]]), [[interleukin-8]], [[monocyte]] [[chemotactic protein]] 1 ([[MCP-1]]), and[[ platelet-derived growth factor]] ([[PDGF]]) which are responsible for characterized [[symptoms]] including  [[malaise]], [[fever]], and [[peripheral]] [[neutrophil]] [[leukocytosis]]. <ref name="pmid7810274">{{cite journal| author=Bird G| title=Interleukin-8 in alcoholic liver disease. | journal=Acta Gastroenterol Belg | year= 1994 | volume= 57 | issue= 3-4 | pages= 255-9 | pmid=7810274 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7810274  }} </ref> <ref name="pmid9347083">{{cite journal| author=Laso FJ, Lapeña P, Madruga JI, San Miguel JF, Orfao A, Iglesias MC | display-authors=etal| title=Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake. | journal=Alcohol Clin Exp Res | year= 1997 | volume= 21 | issue= 7 | pages= 1226-31 | pmid=9347083 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9347083  }} </ref>
=== Histologic Findings===
 
==Genetics==
* [[Genetic predisposition]] in [[alcoholism]] and developing alcohol -related [[liver injury]]:<ref name="pmid16440362">{{cite journal| author=Zintzaras E, Stefanidis I, Santos M, Vidal F| title=Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? | journal=Hepatology | year= 2006 | volume= 43 | issue= 2 | pages= 352-61 | pmid=16440362 | doi=10.1002/hep.21023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16440362  }} </ref>
** There is a significant association between [[ADH2]], [[ADH3]], and [[ALDH2]] [[alleles]] and the risk of [[alcoholism]]
*** The [[ADH2]] and [[ADH3]] [[alleles]] are associated with [[alcoholism]] in [[East Asians]] population
*** The [[ADH2]] [[allele]] is associated with [[alcoholism]] in [[Caucasians]]
** The association between [[genetic predisposition]] and development of [[alcoholic]] [[liver injury]] is unknown
 
==Associated Conditions==
Conditions associated with alcoholic liver disease include:<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><ref name="LuceyMathurin2009">{{cite journal|last1=Lucey|first1=Michael R.|last2=Mathurin|first2=Philippe|last3=Morgan|first3=Timothy R.|title=Alcoholic Hepatitis|journal=New England Journal of Medicine|volume=360|issue=26|year=2009|pages=2758–2769|issn=0028-4793|doi=10.1056/NEJMra0805786}}</ref>
 
*[[Obesity]]
*Chronic viral [[hepatitis]]
*[[Iron overload disorder|Iron overload]]
*[[Cirrhosis]]
*[[Hepatocellular carcinoma]]
 
==Microscopic Pathology==
On microscopic histopathological analysis characteristic findings of [[Alcoholic Hepatitis]] include:
*[[Steatosis]]
*[[Steatosis]]
* [[Mallory body]] - a condition where [[pre-keratin]] [[filaments]] accumulate in [[hepatocytes]]. This [[sign]] is not limited to [[alcoholic]] [[liver disease]].<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| location=Philadelphia| id=0-7216-7335-X}}</ref>
** Macrovesicular [[steatosis]] - the [[cytoplasm]] of [[Hepatocyte|hepatocytes]] is occupied by large [[lipid]] droplets that end up displacing the [[nucleus]] and other organelles peripherally
* [[Ballooning]] [[degeneration]] - [[hepatocytes]] in the setting of [[alcoholic]] change often swell up with excess [[fat]], [[water]] and [[protein]]. Accompanied with ballooning, there is [[necrotic]] damage. The [[swelling]] blocks [[biliary duct]]s, leading to diffuse [[cholestasis]].<ref name="robspath"> </ref>
* [[Mallory body]]  
* [[Inflammation]] - [[Neutrophil]]ic invasion is triggered by the [[necrotic]] changes and [[cellular]] [[debris]] within the [[lobules]].<ref name="robspath"> </ref>
** A condition where [[pre-keratin]] [[filaments]] accumulate in [[hepatocytes]]. This [[sign]] is not limited to [[alcoholic]] [[liver disease]].<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| location=Philadelphia| id=0-7216-7335-X}}</ref>
* [[Ballooning]] [[degeneration]]  
**[[Hepatocytes]] in the setting of [[alcoholic]] change often swell up with excess [[fat]], [[water]] and [[protein]]. Accompanied with ballooning, there is [[necrotic]] damage. The [[swelling]] blocks [[biliary duct]]s, leading to diffuse [[cholestasis]].<ref name="robspath"> </ref>
* [[Inflammation]]  
** [[Neutrophil]]ic invasion is triggered by the [[necrotic]] changes and [[cellular]] [[debris]] within the [[lobules]].<ref name="robspath"> </ref>
*If [[chronic]] [[liver disease]] is also present:
*If [[chronic]] [[liver disease]] is also present:
** [[Fibrosis]]
** [[Fibrosis]]
** [[Cirrhosis]]
** [[Cirrhosis]]
==Genetics==
* The role of [[alcohol]] in developing [[alcohol]] [[liver]] injury is not clear. <ref name="pmid16440362">{{cite journal| author=Zintzaras E, Stefanidis I, Santos M, Vidal F| title=Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? | journal=Hepatology | year= 2006 | volume= 43 | issue= 2 | pages= 352-61 | pmid=16440362 | doi=10.1002/hep.21023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16440362  }} </ref>
*People who are not [[alcoholics]] do not develop [[alcohol]] [[liver]] injury.<ref name="pmid16440362">{{cite journal| author=Zintzaras E, Stefanidis I, Santos M, Vidal F| title=Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? | journal=Hepatology | year= 2006 | volume= 43 | issue= 2 | pages= 352-61 | pmid=16440362 | doi=10.1002/hep.21023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16440362  }} </ref>


==References==
==References==

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]Prashanth Saddala M.B.B.S

Overview

The pathophysiology of Alcoholic Hepatitis is caused by interplay between alcohol metabolism, inflammation and innate immunity. Alcohol metabolism leads to depletion of NAD and subsequent lipogenesis. Additionally, increased endotoxemia causes translocation of lipopolysaccharide from intestine to hepatocytes. In hepatocytes, lipopolysaccharide activates kupffer cells. Therefore, activated cells release inflammatory markers which lead to Alcoholic hepatitis.

Pathophysiology

Pathogenesis

Genetics

Associated Conditions

Conditions associated with alcoholic liver disease include:[2][8]

Microscopic Pathology

On microscopic histopathological analysis characteristic findings of Alcoholic Hepatitis include:

References

  1. ↑ 1.0 1.1 1.2 Gao, Bin; Bataller, Ramon (2011). "Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets". Gastroenterology. 141 (5): 1572–1585. doi:10.1053/j.gastro.2011.09.002. ISSN 0016-5085.
  2. ↑ 2.0 2.1 Ceni E, Mello T, Galli A (2014). "Pathogenesis of alcoholic liver disease: role of oxidative metabolism". World J. Gastroenterol. 20 (47): 17756–72. doi:10.3748/wjg.v20.i47.17756. PMC 4273126. PMID 25548474.
  3. ↑ 3.0 3.1 Bautista, Abraham P (2001). "Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease". Journal of Gastroenterology and Hepatology. 15 (4): 349–356. doi:10.1046/j.1440-1746.2000.02174.x. ISSN 0815-9319.
  4. ↑ Suraweera DB, Weeratunga AN, Hu RW, Pandol SJ, Hu R (2015). "Alcoholic hepatitis: The pivotal role of Kupffer cells". World J Gastrointest Pathophysiol. 6 (4): 90–8. doi:10.4291/wjgp.v6.i4.90. PMC 4644891. PMID 26600966.
  5. ↑ Bird G (1994). "Interleukin-8 in alcoholic liver disease". Acta Gastroenterol Belg. 57 (3–4): 255–9. PMID 7810274.
  6. ↑ Laso FJ, Lapeña P, Madruga JI, San Miguel JF, Orfao A, Iglesias MC; et al. (1997). "Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake". Alcohol Clin Exp Res. 21 (7): 1226–31. PMID 9347083.
  7. ↑ Zintzaras E, Stefanidis I, Santos M, Vidal F (2006). "Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?". Hepatology. 43 (2): 352–61. doi:10.1002/hep.21023. PMID 16440362.
  8. ↑ Lucey, Michael R.; Mathurin, Philippe; Morgan, Timothy R. (2009). "Alcoholic Hepatitis". New England Journal of Medicine. 360 (26): 2758–2769. doi:10.1056/NEJMra0805786. ISSN 0028-4793.
  9. ↑ 9.0 9.1 9.2 Cotran. Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. 0-7216-7335-X. Unknown parameter |coauthors= ignored (help)

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