Editing Hepatitis (section)

== Mechanism ==

The specific mechanism varies and depends on the underlying cause of the hepatitis. Generally, there is an initial insult that causes liver injury and activation of an inflammatory response, which can become chronic, leading to progressive [[fibrosis]] and [[cirrhosis]].<ref name="Harrison's Principles, chapter 360 (Acute Viral)" />

=== Viral hepatitis ===

[[File:Stages of Liver disease NIDDK NIH.gif|thumb|upright=1.3|Stages of liver disease]]
The pathway by which hepatic viruses cause [[viral hepatitis]] is best understood in the case of hepatitis B and C.<ref name="Harrison's Principles, chapter 360 (Acute Viral)" /> The viruses do not directly activate [[apoptosis]] (cell death).<ref name="Harrison's Principles, chapter 360 (Acute Viral)" /><ref name="Nakamoto & Kaneko">{{Cite journal|last1=Nakamoto|first1=Yasunari|last2=Kaneko|first2=Shuichi|date=2003-09-01|title=Mechanisms of viral hepatitis induced liver injury|journal=Current Molecular Medicine|volume=3|issue=6|pages=537–544|issn=1566-5240|pmid=14527085|doi=10.2174/1566524033479591}}</ref> Rather, infection of liver cells activates the [[Innate immune system|innate]] and [[Adaptive immune system|adaptive]] arms of the [[immune system]] leading to an inflammatory response which causes cellular damage and death, including viral-induced apoptosis via the induction of the death receptor-mediated signaling pathway.<ref name="Harrison's Principles, chapter 360 (Acute Viral)" /><ref name="Nakamoto & Kaneko" /><ref>{{Cite journal|last1=Lin|first1=Shaoli|last2=Zhang|first2=Yan-Jin|date=August 2017|title=Interference of Apoptosis by Hepatitis B Virus|journal=Viruses|language=en|volume=9|issue=8|page=230|doi=10.3390/v9080230|pmid=28820498|pmc=5580487|doi-access=free}}</ref><ref>{{Cite journal|last1=Cao|first1=Lei|last2=Quan|first2=Xi-Bing|last3=Zeng|first3=Wen-Jiao|last4=Yang|first4=Xiao-Ou|last5=Wang|first5=Ming-Jie|date=2016|title=Mechanism of Hepatocyte Apoptosis|journal=Journal of Cell Death|language=en|volume=9|pages=19–29|doi=10.4137/JCD.S39824|pmid=28058033|pmc=5201115}}</ref>  Depending on the strength of the immune response, the types of immune cells involved and the ability of the virus to evade the body's defense, infection can either lead to clearance (acute disease) or persistence (chronic disease) of the virus.<ref name="Harrison's Principles, chapter 360 (Acute Viral)" />  The chronic presence of the virus within liver cells results in multiple waves of [[inflammation]], injury and [[wound healing]] that over time lead to scarring or [[fibrosis]] and culminate in [[hepatocellular carcinoma]].<ref name="Nakamoto & Kaneko" /><ref>{{Cite journal|last=Wong|first=Grace Lai-Hung|date=2014-09-01|title=Prediction of fibrosis progression in chronic viral hepatitis|journal=Clinical and Molecular Hepatology|volume=20|issue=3|pages=228–236|doi=10.3350/cmh.2014.20.3.228|issn=2287-285X|pmc=4197170|pmid=25320725}}</ref> People with impaired immune response are at greater risk of developing chronic infection.<ref name="Harrison's Principles, chapter 360 (Acute Viral)" /> [[Natural killer cell]]s are the primary drivers of the initial innate response and create a [[cytokine]] environment that results in the recruitment of [[T helper cell|CD4 T-helper]] and [[Cytotoxic T cell|CD8 cytotoxic T-cells]].<ref name="Rehermann Killer Cells">{{Cite journal|last=Rehermann|first=Barbara|date=2015-11-01|title=Natural Killer Cells in Viral Hepatitis|journal=Cellular and Molecular Gastroenterology and Hepatology|volume=1|issue=6|pages=578–588|doi=10.1016/j.jcmgh.2015.09.004|issn=2352-345X|pmc=4678927|pmid=26682281}}</ref><ref name="Heim & Thimme">{{Cite journal|last1=Heim|first1=Markus H.|last2=Thimme|first2=Robert|date=2014-11-01|title=Innate and adaptive immune responses in HCV infections|journal=Journal of Hepatology|volume=61|issue=1 Suppl|pages=S14–25|doi=10.1016/j.jhep.2014.06.035|issn=1600-0641|pmid=25443342|doi-access=free}}</ref>  [[Interferon type I|Type I interferons]] are the cytokines that drive the antiviral response.<ref name="Heim & Thimme" /> In chronic Hepatitis B and C, natural killer cell function is impaired.<ref name="Rehermann Killer Cells" />

=== Steatohepatitis ===

[[Steatohepatitis]] is seen in both alcoholic and non-alcoholic liver disease and is the culmination of a cascade of events that began with injury.  In the case of [[Non-alcoholic fatty liver disease|non-alcoholic steatohepatitis]], this cascade is initiated by changes in metabolism associated with obesity, insulin resistance, and lipid dysregulation.<ref name="Hardy Oakley Anstee Day">{{Cite journal|last1=Hardy|first1=Timothy|last2=Oakley|first2=Fiona|last3=Anstee|first3=Quentin M.|last4=Day|first4=Christopher P.|date=2016-03-03|title=Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum|journal=Annual Review of Pathology|doi=10.1146/annurev-pathol-012615-044224|issn=1553-4014|pmid=26980160|volume=11|pages=451–96|url=https://zenodo.org/record/3452754}}{{Dead link|date=February 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="Yoon & Cha Pathogenesis">{{Cite journal|last1=Yoon|first1=Hye-Jin|last2=Cha|first2=Bong Soo|date=2014-11-27|title=Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease|journal=World Journal of Hepatology|volume=6|issue=11|pages=800–811|doi=10.4254/wjh.v6.i11.800|issn=1948-5182|pmc=4243154|pmid=25429318 |doi-access=free }}</ref> In [[alcoholic hepatitis]], chronic excess alcohol use is the culprit.<ref name="Chayanupatkul & Liangpunsakul" />  Though the inciting event may differ, the progression of events is similar and begins with accumulation of free [[fatty acid]]s (FFA) and their breakdown products  in the liver cells in a process called [[steatosis]].<ref name="Hardy Oakley Anstee Day" /><ref name="Yoon & Cha Pathogenesis" /><ref name="Chayanupatkul & Liangpunsakul" /> This initially reversible process overwhelms the [[hepatocyte]]'s ability to maintain lipid homeostasis leading to a toxic effect  as fat molecules accumulate and are broken down in the setting of an [[Cellular stress response|oxidative stress response]].<ref name="Hardy Oakley Anstee Day" /><ref name="Yoon & Cha Pathogenesis" /><ref name="Chayanupatkul & Liangpunsakul" />  Over time, this abnormal lipid deposition triggers the [[immune system]] via [[Toll-like receptor|toll-like receptor 4]] (TLR4) resulting in the production of inflammatory [[cytokine]]s such as TNF that cause liver cell injury and death.<ref name="Hardy Oakley Anstee Day" /><ref name="Yoon & Cha Pathogenesis" /><ref name="Chayanupatkul & Liangpunsakul" />  These events mark the transition to [[steatohepatitis]] and in the setting of chronic injury, [[fibrosis]] eventually develops setting up events that lead to cirrhosis and hepatocellular carcinoma.<ref name="Hardy Oakley Anstee Day" /> Microscopically, changes that can be seen include steatosis with large and swollen hepatocytes ([[Ballooning degeneration|ballooning]]), evidence of cellular injury and cell death (apoptosis, necrosis), evidence of inflammation in particular in [[Liver|zone 3 of the liver]], variable degrees of fibrosis and [[Mallory body|Mallory bodies]].<ref name="Hardy Oakley Anstee Day" /><ref name="Definition, epidemiology, and magnitude">{{Cite journal|last1=Basra|first1=Sarpreet|last2=Anand|first2=Bhupinderjit S.|date=2011-05-27|title=Definition, epidemiology and magnitude of alcoholic hepatitis|journal=World Journal of Hepatology|volume=3|issue=5|pages=108–113|doi=10.4254/wjh.v3.i5.108|issn=1948-5182|pmc=3124876|pmid=21731902 |doi-access=free }}</ref><ref>{{Cite journal|last1=Haga|first1=Yuki|last2=Kanda|first2=Tatsuo|last3=Sasaki|first3=Reina|last4=Nakamura|first4=Masato|last5=Nakamoto|first5=Shingo|last6=Yokosuka|first6=Osamu|date=2015-12-14|title=Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis|journal=World Journal of Gastroenterology|volume=21|issue=46|pages=12989–12995|doi=10.3748/wjg.v21.i46.12989|issn=2219-2840|pmc=4674717|pmid=26675364 |doi-access=free }}</ref>