** SPOILER ALERT **
Previous guides help through the vast majority of the game, I'm only going to focus on the last 2 Chapters of Act 5. I will say that upgrading weapon damage and capacity are key, I didn't increase reload speed on any weapons, they all reload just fine by default. And once damage/capacity were fully upgraded I used all white crystals to purchase health bottles instead of red gems. There's also really no need to spend white crystals on ammo, there's plenty throughout the game. Trust me, this difficulty is not the one to use when going for the achievement where you acquire all red gems in the game.
The boss fight against Fleming is so BUNK, I tried every solution mentioned here and in the comments, and none worked. I was excited about other suggestions to allow the green dome shield to be destroyed by Fleming, but that didn't work for me because if I let Fleming destroy the green shield himself, he never reached the damaged state where he stands slumped and still. And no matter how many times I hit him with my hot boner, sticky payload, shotgun and/or macine gun (all upgraded, mind you), I couldn't get him to show the gold cracks in his armor. What eventually worked was the following.
I made sure my shotty (with max upgraded damage and capacity) was fully loaded. I launched a cannonball into the green dome and immediately charged forward to it without taking the time to reload. This is important because there's not much time between shield destruction and Fleming resuming his attacks. When the green dome exploded I was not harmed as it took all the damage, and I was positioned only a few feet from Fleming. While advancing I held LT/RT to load up 4 shells into the shotgun for max damage, and the 4th was in the chamber just as Fleming got into the stunned state. I hit him with all 4 shells, at which time the gold cracks appeared. DO NOT hold RT long enough to allow the cannonball to fire, make sure you release all 4 shells at him then immediately switch to the Hot Boner. He shoud show gold cracks at this time so stick him with a sticky payload and hope you have time to detonate it. I had to do this about 15 times before I could perform all the steps quickly enough, and after a long, hard fought battle, he finally went down. This was VERY frustrating to say the least, just an aweful way to (nearly) finish a game. Part of the problem was sometimes, even after hitting him with all 4 shotty shells, he wouldn't show gold cracks. The other problem was that the controls are also glitchy and many times, when the gold cracks did appear, I would hit left on the D-pad and it often WOULDN'T SWITCH to the Hot Boner at all. UGGGGGHHHHH!!!!!
The very last boss fight against Paula isn't all that tough IF it's managed correctly. The problem is that ammo for the Dentist (machine gun) becomes somewhat scarce and while they provide ammo crates every minute or so, she needs to be killed within a certain time frame and you need a lot of ammo to do it. The key, I believe, is finishing her off in her 1st form with as much ammo left in your Dentist as possible. In the enclosed room where you first face her, there is an infinitely respawning blue ammo crate. Make sure you fill up the Dentist with as many rounds as possible before taking her out so that when you hit the check point, your gun has a lot of ammo left, preferably more than 150 bullets. That way you'll be able to widdle down her 4 wings quickly and the 50 bullets at a time you get from subsequent crates will be enough to defeat her. The first time I got to that checkpoint I only had 11 rounds in my Dentist and I always ran out of time and died because I couldn't damage her quickly enough. I reloaded the whole chapter, went into the checkpoint with plenty of bullets as described above and down she went, first try, bleep-bloop, achievement unlocked.
Hope this helps any who are struggling to complete this game on Hard. Seems a shame to have to endure all those cutscenes, likely for the 2nd time, only to not finish a game due to glitches that really SHOULD be patched.