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Circadian rhythms in acute intermittent porphyria – a pilot study
Author(s) -
Larion Sebastian,
Caballes Frederick R.,
Hwang SunIl,
Lee JinGyun,
Rossman Whitney E.,
Parsons Judy,
Steuerwald Nury,
Li Ting,
Maddukuri Vinaya,
Groseclose Gale,
Finkielstein Carla V.,
Bonkovsky Herbert L.
Publication year - 2013
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.12102
Subject(s) - porphobilinogen deaminase , endocrinology , medicine , circadian rhythm , acute intermittent porphyria , melatonin , biology , porphobilinogen synthase , porphyria , hormone , dehydratase , enzyme , biochemistry
Background Acute intermittent porphyria ( AIP ) is an inherited disorder of haem synthesis wherein a partial deficiency of porphobilinogen ( PBG ) deaminase ( PBGD ) with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic haem deficiency and uncontrolled up‐regulation of hepatic 5‐aminolevulinic acid ( ALA ) synthase‐1 ( ALAS 1) with over‐production of ALA and PBG . The treatment of choice is intravenous haem, which restores the deficient regulatory haem pool of the liver and represses ALAS 1. Recently, haem has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. Materials and methods Over a 21‐h period, we measured levels of serum cortisol, melatonin, ALA , PBG and m RNA levels (in peripheral blood mononuclear cells) of selected clock‐controlled genes and genes involved in haem synthesis in 10 C aucasian ( E uropean‐ A merican) women who were either postmenopausal or had been receiving female hormone therapy, six of whom have AIP and four do not and are considered controls. Results Four AIP subjects with biochemical activity exhibited higher levels of PBG and lower levels and dampened oscillation of serum cortisol, and a trend for lower levels of serum melatonin, than controls or AIP subjects without biochemical activity. Levels of clock‐controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS 1, ALAS 2 and PBGD were increased only at 11 p.m. in subjects with active AIP . Conclusions This pilot study provides evidence for disturbances of circadian markers in women with active AIP that may trigger or sustain some common clinical features of AIP .