In my head canon Dean'd gone too far long before he was taken over by the mark or became a demon. I think when he allowed Gadreel riding Sam's body, and still thought he'd do it over again, he hurt Sam bad, and that's very personal. That horror is no less than watching MoC!Dean slaughtering Abaddon or demon!Dean killing innocent people. And that horror doesn't leave as well. I kinda wonder if Sam, quite aware of the darkness in Dean, can be around Dean like before. So, yeah. Lots of things are killing Sam now.
Happy thanksgiving!