Ran into my first issue.
My project was previously Unity 2017.4.32f1, and I updated it to Unity 2018.4.8f1 and 2D Toolkit v2.5.8.16.
If I edit a prefab that was originally created in Unity 2017, and I modify any tk2d component in the prefab, the changes are not saved in the prefab.
If I modify any non-tk2d component in the prefab after making some changes to tk2d components in the prefab, the tk2d components will be correctly saved/updated in the prefab. So the changes are being recognized, they just aren't triggering a save of the prefab.
If I remove a tk2d component, and add the same component back in (as a new component), it has the same behavior (so I don't think it's necessarily due to the update from Unity 2017 to 2018?).
So far this seems to only be an issue with the tk2d UI components, not the regular components (example: tk2dBaseSprite is fine, but tk2dUIUpDownButton has the bug). Possibly it's only components that have tk2dUIBaseItemControlEditor.cs as a base class?
Only test project I can provide would be a complete copy of my entire game, which I'm willing to do if that would help, just let me know!