If you haven't made changes inside the core files that your site depends on it should be fine.
But for sure you can make a back-up. If there is something wrong just put it back.
A rerun of the setup is the same as an update but this time for the same version.
I can't explain why but sometimes it fixxes problems.
You could also make a copy on dev.domain.com and than run the setup. If there are some problems you don't do it on the production domain.
You might give SiteCheck a try. It can sometimes find fairly mysterious problems:
http://bobsguides.com/sitecheck-tutorial.html. At the least, it will rule out some possibilities.
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