Given the spectrum of clinical manifestations and disease progression seen within ALGS and PFIC patients that cannot be attributed solely to the underlying primary gene defects, our data is consistent with additional defects of IRE1α/XBP1 signaling which may impair ER stress resolution and increase these patients’ susceptibility to develop more rapid progression or more severe liver disease. The gene discussed is XBP1; the disease is progressive familial intrahepatic cholestasis.