What's wrong with you?/What's the problem?/What's troubling you?
What's on your mind?
What are you concerned about?
Why the long face?
Is everything oK?
What's going on?/What's up with you?
A: What's wrong with you?
B: I just lost my job and now I don't know how I'm going to pay my bills.
A: You don't look too happy. What's up with you?
B: I just took my midterm exam and I think I bombed it.
A: Hello, Mrs Summers. This is Mrs Li. Mike hasn't come home yet, and I'm getting a little concerned. What time did he leave school?
B: About an hour ago. But I wouldn't worry too much, you know how boys are.
A: Yeah, I know. But it usually only takes him thirty minutes to walk home.
B: Maybe he stopped off at a friend's house.
A: Yeah. Maybe you're right. Oh, wait, I think I hear the door opening now.