A 4 weeks course of high-dose glucocorticoids (GCs) may cause prolonged adrenal suppression even after a 9 days tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment with high-dose prednisone. In 42 children with newly diagnosed ALL, a baseline serum cortisol level was assessed and after receiving a 28 days of high dose prednisone according to the Berlin-Frankfu¨rt-Mu¨nster 2009 protocol ad a 9 days tapering phase, serum cortisol level was assessed again and those whose serum cortisol level was normal underwent low-dose adrenocorticotropic hormone (LDACTH) stimulation 24 h after the last tapered steroid dose. Signs and symptoms of adrenal insufficiency were recorded during the observation period. All patients except one who was excluded had normal basal cortisol values at diagnosis. Twenty-four hours after last GC dose, morning cortisol was reduced in 15 (36.5%) patients. LDACTH testing showed adrenal suppression in 17 (41.4%) patients. High-dose GC therapy in ALL children may cause adrenal suppression even after a tapering phase. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated.

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT. We hypothesized that the accumulation of ZAAT is influenced by modulation of gp78 E3 ligase and SVIP (small VCP-interacting protein) interaction with p97/VCP in ZAAT-expressing hepatocytes. We showed that the SVIP inhibitory effect on ERAD due to overexpression causes the accumulation of ZAAT in a human Z hepatocyte-like cell line (AT01). Overexpression of gp78, as well as SVIP suppression, induces gp78-VCP/p97 interaction in AT01 cells. This interaction leads to retro-translocation of ZAAT and reduction of the SVIP inhibitory role in ERAD. In this context, overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD.