His parasite's removal — In Resident Evil 4, it's stated that the surgery required to get the parasite out can damage the conciousness of the host. Maybe it screwed up his emotional state.
The voice actor, Paul Mercier, was constipated at the time — Proposed by this troper's brother. That would explain why Leon isn't pissy in Darkside Chronicles.
Leon was infected with the Veronica Virus — Javier started releasing spores in Operation: Javier...
He has to face the T and G-viruses again — They caused a lot more trouble than the Las Plagas, and taking down the viruses is his goal.
They ran out of money — After animating Angela's polka-dot dress, they ran out of funds to give Leon different facial expressions so they had Paul Mercier redo all his lines to give the monotone voice to match the only face of Leon they had already created.