Lecture: NASH- How many hits does it take?

Today’s lecture delved into the pathophysiology of non-alcoholic steatohepatitis.  The first recognized hit that is most often associated with the condition is the increase in free fatty acids (FFA) that are taken into the hepatocyte.  TNF-alpha is among several cytokines that are up or downregulated within the intracellular cascade…and cause oxidative damage via free radicals. 

Not all patients with steatosis have steatohepatitis.  Furthermore, the presence of normal transaminases does not exclude the possibility of hepatitis.  Since it is difficult to know which patients have simple steatosis versus steatohepatitis, the decision to pursue liver biopsy is not always clear cut. 

What may be most important, and can help you determine who to biopsy, is the likelihood of advanced fibrosis.  Multivariate analysis tells us that age > 40 , BMI > 40 and diabetes mellitus are all risk factors for advanced fibrosis. An AST:ALT > 1 is also suggestive.  Without these RF, non-invasive measures may be more appropriate, particularly because treatment options aren’t that good anyway. 

Lastly, we spoke about the incidence of hepatocellular carcinoma in NASH.  There are many reports of HCC arising in a pre-cirrhotic liver with NASH, though overall it is still considered very rare and pre-cirrhotic screening cannot be recommended.  We spoke of the physiologic pathways of reactive oxygen species, CD 39 knockout models, apoptosis and cell proliferation to explain why it is possible to develop HCC in a pre-cirrhotic state.

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