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J Intern Med. 2018 Jul;284(1):78-91. doi: 10.1111/joim.12750. Epub 2018 Mar 26.

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

Author information

1
Centre Français des Porphyries, Hôpital Louis Mourier, Assistance publique-Hôpitaux de Paris (AP-HP), Colombes, France.
2
Centre de Recherche sur l'Inflammation (CRI), UMR1149 INSERM, Université Paris Diderot, site Bichat, Paris, France.
3
Laboratoire d'excellence, GR-Ex, Paris, France.
4
STIM CNRS ERL 7368, Physiologie des Cellules Cardiaques et Vasculaires, Tours, France.
5
Laboratory for Clinical Biochemistry and Proteomics, Institute for Regenerative Medicine and Biotherapy (IRMB), CHU de Montpellier and Université Montpellier, Montpellier, France.
6
Centre National de la Recherche Scientifique, Institut des Hautes Études Scientifiques, Bures-sur-Yvette, France.
7
Center for Innate Immunity and Immune Disease (CIIID), University of Washington School of Medicine, Seattle, WA, USA.
8
DHU Unity, Pathology Department, Hôpital Beaujon, AP-HP, Clichy, France.
9
Department of Gastroenterology and Hepatology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
10
Laboratory for Clinical Biochemistry, Norwegian Porphyria Centre (NAPOS), Haukeland University Hospital, Bergen, Norway.
11
Department of Global Health and Primary Health Care, University of Bergen, Bergen, Norway.
12
Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
13
Department of Gastroenterology and Hepatology, St. Olav's University Hospital, Trondheim, Norway.
14
Department of Transplantation Medicine, Norwegian PSC Research Center and Section of Gastroenterology, Oslo University Hospital and University of Oslo, Oslo, Norway.
15
Centre Hospitalier Universitaire Bordeaux, Chirurgie Hépatobiliaire et Pancréatique, Maison du Haut Lévèque, Bordeaux, France.
16
Service d'Anatomie Pathologique, Centre Hospitalo-Universitaire de Caen, Caen, France.
17
Service d'anatomopathologie, Institut Gustave Roussy, Villejuif, France.
18
Biochemistry and Molecular Genetics Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain.
19
CSIC/UAB Proteomics Laboratory, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
20
Laboratory for Clinical Biochemistry, Hôpital Beaujon, AP-HP, Clichy, France.

Abstract

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.

KEYWORDS:

acute intermittent porphyria; haem oxygenase 1; hemin; inflammation; iron overload

PMID:
29498764
DOI:
10.1111/joim.12750
[Indexed for MEDLINE]

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