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Review
. 2010 Feb;103(2):71-83.
doi: 10.1093/qjmed/hcp158. Epub 2009 Nov 13.

Pathogenesis of non-alcoholic fatty liver disease

J K Dowman  1 , J W Tomlinson, P N Newsome
Affiliations
Review

Pathogenesis of non-alcoholic fatty liver disease

J K Dowman et al. QJM. 2010 Feb.
No abstract available

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Figures

Figure 1.
Figure 1.
(a) The traditional 2-hit hypothesis: steatosis represents the ‘first hit’, which then sensitises the liver to injury mediated by ‘second hits’, such as inflammatory cytokines, adipokines, oxidative stress and mitochondrial dysfunction, leading to steatohepatitis and fibrosis. The presence of high levels of oxidative stress reduces the ability of mature hepatocytes to proliferate, resulting in reduced endogenous liver repair. (b) Modified 2-hit hypothesis: the accumulation of FFA alone has been suggested to be sufficient to induce liver damage, without recourse for a second hit. Indeed, rather than being harmful, triglyceride accumulation in the form of steatosis may actually be protective by preventing FFA-induced inflammation and oxidative stress. (c) The 3-hit hypothesis: oxidative stress reduces the ability of mature hepatocytes to proliferate, resulting in the recruitment of other pathways of liver regeneration, such as HPCs. These cells have the capability of differentiating into both cholangiocytes and hepatocytes and contributing to liver repair. It has been suggested that an inability to mount such a ductular response, as is seen in patients transplanted for NASH who have denervated livers, may be responsible for a more progressive pattern of liver damage. Thus, impaired proliferation of hepatocyte progenitors represents the proposed ‘third hit’ in NAFLD pathogenesis.
Figure 1.
Figure 1.
(a) The traditional 2-hit hypothesis: steatosis represents the ‘first hit’, which then sensitises the liver to injury mediated by ‘second hits’, such as inflammatory cytokines, adipokines, oxidative stress and mitochondrial dysfunction, leading to steatohepatitis and fibrosis. The presence of high levels of oxidative stress reduces the ability of mature hepatocytes to proliferate, resulting in reduced endogenous liver repair. (b) Modified 2-hit hypothesis: the accumulation of FFA alone has been suggested to be sufficient to induce liver damage, without recourse for a second hit. Indeed, rather than being harmful, triglyceride accumulation in the form of steatosis may actually be protective by preventing FFA-induced inflammation and oxidative stress. (c) The 3-hit hypothesis: oxidative stress reduces the ability of mature hepatocytes to proliferate, resulting in the recruitment of other pathways of liver regeneration, such as HPCs. These cells have the capability of differentiating into both cholangiocytes and hepatocytes and contributing to liver repair. It has been suggested that an inability to mount such a ductular response, as is seen in patients transplanted for NASH who have denervated livers, may be responsible for a more progressive pattern of liver damage. Thus, impaired proliferation of hepatocyte progenitors represents the proposed ‘third hit’ in NAFLD pathogenesis.
Figure 2.
Figure 2.
Mechanisms of hepatic fat accumulation.
Figure 3.
Figure 3.
Proposed pathogenesis of NASH. The likelihood of progression to advanced NASH/cirrhosis results from a complex interplay between genetic predisposition and the mechanisms described earlier.
See this image and copyright information in PMC

Comment in

  • QJM. 2010 Feb;103(2):69-70

References

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