title: Circadian rhythms in acute intermittent porphyria--a pilot study.
abstract: 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 (ALAS1) 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 ALAS1. 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.
  
  
  METHODS
  Over a 21-h period, we measured levels of serum cortisol, melatonin, ALA, PBG and mRNA levels (in peripheral blood mononuclear cells) of selected clock-controlled genes and genes involved in haem synthesis in 10 Caucasian (European-American) 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 ALAS1, ALAS2 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.
authors: The Liver-Biliary-Pancreatic Center, Carolinas HealthCare System, Charlotte, NC 28236, USA.
authors: Sebastian
authors: S
authors: Larion
authors: Frederick R
authors: FR
authors: Caballes
authors: Sun-Il
authors: SI
authors: Hwang
authors: Jin-Gyun
authors: JG
authors: Lee
authors: Whitney E
authors: WE
authors: Rossman
authors: Judy
authors: J
authors: Parsons
authors: Nury
authors: N
authors: Steuerwald
authors: Ting
authors: T
authors: Li
authors: Vinaya
authors: V
authors: Maddukuri
authors: Gale
authors: G
authors: Groseclose
authors: Carla V
authors: CV
authors: Finkielstein
authors: Herbert L
authors: HL
authors: Bonkovsky
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000097:blood; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D006418:Heme / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008550:Melatonin / Q000097:blood; D008875:Middle Aged; D010865:Pilot Projects; D011162:Porphobilinogen / Q000097:blood; D017118:Porphyria, Acute Intermittent / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000097:blood
chemical_list: D012333:RNA, Messenger; D006418:Heme; D011162:Porphobilinogen; D000624:5-Aminolevulinate Synthetase; D008550:Melatonin; D006854:Hydrocortisone
references: Life Sci. 2003 Nov 14;73(26):3339-49
references: 14572876
references: Eur J Biochem. 1996 Aug 15;240(1):112-7
references: 8797843
references: Int J Biomed Comput. 1992 Jan;30(1):49-56
references: 1551736
references: Am J Med Sci. 1999 Oct;318(4):241-56
references: 10522552
references: Life Sci. 1993;53(8):621-7
references: 8350677
references: Philos Trans A Math Phys Eng Sci. 2009 Jan 28;367(1887):431-45
references: 18940774
references: Biochemistry. 2008 Jun 10;47(23):6157-68
references: 18479150
references: Neuro Endocrinol Lett. 2002 Jul;23 Suppl 2:82-3
references: 12163854
references: Chronobiologia. 1979 Oct-Dec;6(4):305-23
references: 548245
references: Arch Intern Med. 1990 Jul;150(7):1469-74
references: 2196028
references: Int J Endocrinol. 2010;2010:259345
references: 20145718
references: Lancet. 2004 Feb 28;363(9410):705-6
references: 15001330
references: Cancer Lett. 2000 Mar 31;150(2):205-13
references: 10704744
references: Biomed Chromatogr. 2006 Jun-Jul;20(6-7):612-21
references: 16779779
references: Trends Biochem Sci. 1989 Dec;14(12):492-6
references: 2696180
references: J Circadian Rhythms. 2011 May 10;9:3
references: 21569251
references: J Biol Chem. 1966 Oct 10;241(19):4323-9
references: 5922957
references: Toxicol Lett. 1991 Dec;59(1-3):169-73
references: 1755023
references: Science. 2002 Dec 20;298(5602):2385-7
references: 12446832
references: Am J Gastroenterol. 1991 Aug;86(8):1050-6
references: 1713408
references: Am J Med. 1966 Jul;41(1):149-62
references: 5939541
references: Science. 2001 Feb 9;291(5506):1040-3
references: 11232563
references: Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1824-8
references: 8127888
references: Int J Cancer. 1997 Jan 17;70(2):241-7
references: 9009166
references: Lancet. 2001 Sep 22;358(9286):999-1005
references: 11583769
references: Br J Cancer. 2004 Apr 19;90(8):1660-5
references: 15083200
references: Ann Intern Med. 2005 Mar 15;142(6):439-50
references: 15767622
references: Neuroscience. 2009 Dec 1;164(2):832-41
references: 19698763
references: J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):319-28
references: 9120442
references: Nature. 2004 Jul 22;430(6998):467-71
references: 15269772
references: Arch Environ Health. 1968 Aug;17(2):164-71
references: 5672531
references: Biochem Biophys Res Commun. 2008 Apr 18;368(4):955-8
references: 18280802
references: Epilepsy Behav. 2008 Oct;13(3):438-44
references: 18588999
references: Liver Transpl. 2012 Feb;18(2):195-200
references: 21618697
references: J Neurosci. 2001 Aug 15;21(16):6405-12
references: 11487664
references: Mol Cell Biol. 2008 Aug;28(15):4697-711
references: 18505821
references: Arch Biochem Biophys. 1991 Sep;289(2):387-92
references: 1898078
references: Proc Natl Acad Sci U S A. 1967 Nov;58(5):1944-8
references: 5237490
references: Proc Natl Acad Sci U S A. 1971 Nov;68(11):2725-9
references: 5288250
references: Neurosci Lett. 2003 Dec 15;353(1):9-12
references: 14642425
references: Cell. 2001 Jun 1;105(5):683-94
references: 11389837
references: Biochem Biophys Res Commun. 1989 Jul 14;162(1):102-7
references: 2751643
references: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jan 30;31(1):1-11
references: 16884842
references: J Clin Sleep Med. 2008 Feb 15;4(1):66-9
references: 18350967
references: J Biol Chem. 2011 Jul 29;286(30):26424-30
references: 21659532
references: Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3306-13
references: 19064543
references: Compr Physiol. 2013 Jan;3(1):365-401
references: 23720291
references: Biochem Biophys Res Commun. 1966 Sep 8;24(5):675-83
references: 5970500
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Aug 15;879(24):2389-96
references: 21783436
references: Transpl Int. 2010 Jun;23(6):e18-21
references: 20028496