Alcoholic hepatitis pathophysiology: Difference between revisions

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{{Alcoholic hepatitis}}
{{Alcoholic hepatitis}}
{{CMG}}; '''Assosciate Editor(s)-In-Chief:''' [[User: Prashanthsaddala|Prashanth Saddala M.B.B.S]]
{{CMG}}; {{AE}}{{S.M}}[[User: Prashanthsaddala|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==
== Pathophysiology==
* The pathogenesis is multifactorial:**Alcoholic Hepatitis is caused by interplay between ethanol metabolism, inflammation and innate immunity.<ref>{{cite journal|doi=10.1053/j.gastro.2011.09.002. Epub 2011 Sep 12.}}</ref>
===Pathogenesis===
*The Alcohol metabolism leads to a reduced ratio of the nicotinamide adenine dinucleotide (NAD) to NADH.<ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK470217/ |title=Alcoholic Hepatitis - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}<ref>
* The [[pathogenesis]] of [[Alcoholic Hepatitis]] is [[multifactorial]].
* The NAD depletion inhibit fatty acid oxidation; therefore, it cause fat accumulation in hepatocytes and lipogenesis.<ref>{{cite journal|doi=10.1053/j.gastro.2011.09.002. Epub 2011 Sep 12.}}</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>
*Due to increased intestinal permeability in patients with Alcoholic Hepatitis, high levels of Endotoxemia is recognized.<ref>{{cite journal|doi=10.1053/j.gastro.2011.09.002. Epub 2011 Sep 12.}}</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>
*Endotoxin binds to lipopolysacchride and translocate from intestine to hepatocytes.<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>
**[[Alcohol dehydrogenase]]
* In hepotocytes, lipopolysacchride bindes to CD14 molecule on surface of Kupffer cells which activates Kupffer cells.<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>
**[[Aldehyde dehydrogenase]]
* 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>
*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>  
*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>
**[[Endotoxin]] binds to [[lipopolysaccharide]] and translocate from [[intestine]] to [[hepatocytes]].<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>
** In [[hepatocytes]], [[lipopolysaccharide]] bindes to [[CD14]] molecule and [[toll-like receptor]] 4 on surface of [[Kupffer cells]].<ref name="pmid26600966">{{cite journal| author=Suraweera DB, Weeratunga AN, Hu RW, Pandol SJ, Hu R| title=Alcoholic hepatitis: The pivotal role of Kupffer cells. | journal=World J Gastrointest Pathophysiol | year= 2015 | volume= 6 | issue= 4 | pages= 90-8 | pmid=26600966 | doi=10.4291/wjgp.v6.i4.90 | pmc=4644891 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26600966  }} </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>


==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>


* The amount and duration of [[alcohol]] (EtOH) necessary to damage the [[liver]] is variable and relates to host factors.
*[[Obesity]]
* Most patients with established [[liver disease]] continuously consume 60-80 g/day of ETOH (about 8 beers, one liter of wine, or half a pint of liquor) for 10 to 20 years.  After 20 years of such behavior, most will have fatty changes, but only half will have [[Cirrhosis|cirrhosis]].
*Chronic viral [[hepatitis]]
*:* [[Cirrhosis]] occurs in women at ~40gm EtOH/day for >10 years
*[[Iron overload disorder|Iron overload]]
*:* [[Cirrhosis]] occurs in men at ~80gm EtOH/day for >10 years
*[[Cirrhosis]]
* Diffuse focal liver cell necrosis with polymorphonuclear, mononuclear, fatty infiltration.  Neutrophilic infiltration in particular is unusual for other forms of [[hepatitis]].
*[[Hepatocellular carcinoma]]
* [[Mallory bodies]]
*:* Perinuclear eosinophilic inclusions from intermediate filaments found in alcohol liver disease that can also be seen in [[Ddx:Fatty Liver|fatty liver]], [[Primary Biliary Cirrhosis|primary biliary cirrhosis]], [[Hepatitis C|hepatitis C]], [[Obesity|obesity]].
* Perivenular inflammation
* “Ballooning” of [[hepatocytes]] results from the accumulation of fat and water.
* Swollen hepatocytes and [[collagen]] deposition leads to increased sinusoidal pressures, and perhaps [[portal hypertension]].
* Perisinusoidal fat cells transform into [[fibroblasts]].
* Other non-essential changes that might be present include bridging necrosis, [[bile duct]] proliferation, and [[cholestasis]].
=== Molecular Biology ===
Potential mechanisms of alcohol associated liver disease include:
* ETOH generates excess [[NADH]], which slows [[gluconeogenesis]], increasing [[lactate]] production, and leading to [[fatty acid]] accumulation.
* [[Acetaldehyde]] is a toxic metabolite that can impair [[hepatocyte]] function
* Alcohol metabolism consumes oxygen and contributes to centrilobular hypoxia
* [[Neutrophil]] infiltration – perhaps in association with reactive oxygen species
* Other minor pathways of alcohol metabolism are upregulated in alcoholics, which may produce more dangerous oxygen intermediates.  A microsomal pathway has been called the microsomal enzyme oxidation system (MEOS).  Polymorphisms of enzymes in this system (P4502E1 in particular) may contribute to the predisposition of some individuals to alcohol associated liver damage.  P4502E1 also appears to increase [[acetominophen]] metabolism to toxic metabolites, and may play a role in acetominophen associated liver disease in patients who drink alcohol.
* Inflammation and collagen deposition in the perivenular (zone 3) region of the hepatic sinusoids and the space of Disse, impede flow, increasing pressure.  Perivenular cell necrosis may be found.


Some signs and pathological changes in liver histology include:
==Microscopic Pathology==
* [[Mallory body|Mallory's Hyaline]] - a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.<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>
On microscopic histopathological analysis characteristic findings of [[Alcoholic Hepatitis]] include:
* Ballooning degeneration - hepatocytes in the setting of alcoholic change often swell up with excess fat, water and [[proteins|protein]]; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby [[biliary duct]]s, leading to diffuse [[cholestasis]].<ref name="robspath"> </ref>
*[[Steatosis]]
* [[Inflammation]] - [[Neutrophil]]ic invasion is triggered by the necrotic changes and presence of cellular debris within the [[lobules]]. Ordinarily the amount of debris is removed by [[Kupffer cells]], although in the setting of inflammation they become overloaded, allowing other white cells to spill into the [[parenchyma]]. These cells are particularly attracted to hepatocytes with Mallory bodies.<ref name="robspath"> </ref>
** Macrovesicular [[steatosis]] - the [[cytoplasm]] of [[Hepatocyte|hepatocytes]] is occupied by large [[lipid]] droplets that end up displacing the [[nucleus]] and other organelles peripherally
If chronic liver disease is also present:
* [[Mallory body]]  
* [[Fibrosis]]
** 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>
* [[Cirrhosis]] - a progressive and permanent type of fibrotic degeneration of liver tissue.
* [[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:
** [[Fibrosis]]
** [[Cirrhosis]]


==References==
==References==

Latest revision as of 15:10, 31 July 2021

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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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