After playing for a little, some observations i've made:
The Tremendous Vestige Decay modifier (and trophy) is going to be the worst. This is worse than Ironman because at least with the permadeath modifier, you can save scum. The TVDm for short doesn't affect temporary seeds, but the FIXED Vestiges, and by the sounds of the descriptions, there will only be a few throughout the game ;(. Just hopefully this isn't random. Basically going through the game with almost no warp points ;(. They have at least shown some mercy with this by now allowing you to carry 99 Vestige Seeds instead of 5!
With the Pre-Upgraded loot, this seems like the only beneficial modifier. At level 68, equipment was being found at upgrade level +5 or +6. So perhaps at character level 100+, everything found be upgrade level 10...???
The Enemy Randomised modifier, although you can get endgame enemies at the start, they seem to have the same health as the enemy they replaced. Either that or the area impacts there level, so it's not as bad as it sounds, enemies are still mega weak to begin with. I also think umbral enemies may not be affected by this, but can't say for sure yet.
For the Randomised Loot, the description states boss drops, quest items, key items etc are NOT affected. From what i've noticed so far, world loot is shuffled amongst itself and enemy loot is shuffled amongst itself. Can't tell if drop rates are affected though.
EDIT:
So for the Tremendous Vestige Decay modifier, I ran through to Skyrest and the first FIXED vestige i found was, well Skyrest XD.
So even before the first tutorial boss (lightreaper) that you have to die to for various trophies later, vestige before him isnt there. So if you have no Seeds, then you will respawn back at the start!! Though where each FIXED vestige was, you can put down a seed.
For TVDm, you pretty much need a big supply of seeds, but luckily Molhu sells an infinite amount for 1200 a piece, just make sure you have 1 when starting otherwise means you will respawn at the start if you die to Lighty