Reaching Out

We all have one of those friends who, when you're with them, is peppy and laughs a lot and seems happy enough. Then you get a glimpse of them when they think you're not looking and they seem very much not okay at all. So then you wonder: What's wrong? Of course, you ask, and the predictable "Oh, nothing!" and a smile is all you get. "Okay", you think to yourself, "Maybe i just interpreted it wrong". But you keep seeing signs that something just isn't right, and your friend is hurting beneath the surface. You want to ask what's wrong, but don't want to pry or be nosy. After all, you've already asked (a couple of times, in fact), and they opted not to share the problem(s) with you, thus making it none of your business. You want to keep trying, but you don't want to alienate them, so you let it be and look on and feel helpless struggling with the desire to be helpful. So there's my problem. How do i reach out when "What's wrong?" isn't enough?