IRL : Cheating, shuffling estates stuck together from reshuffle to reshuffle until you split the up in your discard, having your cards deteriorate with use, shuffling for hours, counting cards for hours with philosophers stone, taking 20 minutes to take cards out and back in the box to set up a single game.
Therefore, not buying philosopher's stone, nor any card that involve too much reshuffling just because they're annoying, and considering other games if you don't have time for the longer setup (especially with friends who are clueless on how to do this/which cards belong in which box).
Most importantly I have a harder time keeping track of my purchases as well as my opponent's IRL because I don't see the numbers next to the piles, and while I do not pay attention on ISO, when I come back to the game what happened is written on the screen. If I stop paying attention for a minute IRL (like I always do at some point sooner or later), well I missed what my opponent just bought.
ISO : Not getting the same feel than when you manipulate the cards and the same atmosphere in general, if you want to play one evening and feel all social and have a drink, well you'll end up drinking alone and having a casual "hi hf/gg" as a discussion.