In American English, “What’s up?” is often used as a greeting. It means “What’s new?” or “What have you been doing recently?”
In British English, it means “What’s wrong?” or “What’s the matter?”
In Australia, we usually speak British English. I used to work with “Crazy” Steve, an American teacher. He would always greet me on Monday morning by saying, “What’s up?” Every time, I would pause before answering. I always had a moment when I thought maybe I looked sick or worried. We worked together for 3 years but I never got used to it.