Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

• Published in: Journal of internal medicine Vol. 284; no. 1; pp. 78 - 91
• Main Authors: Schmitt, C., Lenglet, H., Yu, A., Delaby, C., Benecke, A., Lefebvre, T., Letteron, P., Paradis, V., Wahlin, S., Sandberg, S., Harper, P., Sardh, E., Sandvik, A. K., Hov, J. R., Aarsand, A. K., Chiche, L., Bazille, C., Scoazec, J.‐Y., To-Figueras, J., Carrascal, M., Abian, J., Mirmiran, A., Karim, Z., Deybach, J.‐C., Puy, H., Peoc'h, K., Manceau, H., Gouya, L.
• Format: Journal Article
• Language: English; Norwegian
• Published: England Blackwell Publishing Ltd 01.07.2018; Blackwell Science Ltd; Wiley
• Subjects: acute intermittent porphyria; Aminolevulinic acid; Endocrinology and metabolism; Gene expression; Haem; haem oxygenase 1; Hemin; Human health and pathology; Hydroxymethylbilane synthase; inflammation; Inflammatory response; iron overload; Life Sciences; Liver; Liver diseases; Macrophages; Malalties del fetge; Medical treatment; Medicin och hälsovetenskap; Metabolism; Patients; Pharmacology; Porfíria; Porphyria; Proteomes; iron overload; hemin; acute intermittent porphyria; inflammation; haem oxygenase 1
• ISSN: 0954-6820; 1365-2796; 1365-2796
• DOI: 10.1111/joim.12750

Background Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life‐threatening acute neurovisceral attacks due to the induction of hepatic δ‐aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. Objective The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. Methods A follow‐up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs−/− mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. Results The introduction of hemin into the pharmacopeia has coincided with a 4.4‐fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. Conclusion Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti‐inflammatory therapies should be considered in patients with recurrent AIP.