Why does Louisa always ask “What does it matter?” What is the significance of that question, rather than, for example, “Why me?” or “Why do you care?” or even “What do you think?”

Louisa has been brought up to only consider life in Utilitarian terms (check out Shmoop's "In a Nutshell" section for some background info on Utilitarianism). She tries to see everything numerically, either through the hard sciences or through statistical evaluation of human behavior. This is as unnatural as it sounds. She is so completely detached that most human emotions and experiences are beyond her grasp. In a novel full of some of the most tragic characters Dickens ever wrote, she is probably the saddest.