Circadian rhythms in acute intermittent porphyria – a pilot study

Abstract

Acute intermittent porphyria (AIP) is an inherited disorder of heme 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 heme deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1] with overproduction of ALA and PBG. The treatment of choice is intravenous heme, which restores the deficient regulatory heme pool of the liver and represses ALAS1. Recently, heme has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. 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 heme synthesis in 10 Caucasian [European-American] women who were either post-menopausal or had been receiving female hormone therapy, 6 of whom have AIP and 4 do not and are considered controls. 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 am and 11 pm, whereas mRNA levels of ALAS1, ALAS2, and PBGD were increased only at 11 pm in subjects with active AIP. 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.

Adrenal hormonal imbalance in acute intermittent porphyria patients: results of a case control study

“…The overall decrease of corticosteroid excretion reported here is in agreement with the observations of Larion et al [ 13 ] who found a decrease of cortisol in plasma in 3 AIP women with active disease. Moreover, we found a negative correlation between heme precursor concentrations in urine and most of the cortisol metabolites.…”

“…A pilot study by Larion et al [ 13 ] studied circadian rhythms in AIP and found a decrease of plasma cortisol in patients with biochemically active disease. These findings suggested that in addition to hepatic involvement, AIP may be associated with hormonal disturbances originating in the adrenal gland.…”

Evaluating the Patient-Reported Outcomes Measurement Information System scales in acute intermittent porphyria

“…In addition to anxiety, the sleep disturbance model also did not have many clinical features associated with the domain. Disturbances in circadian rhythms of AIP patients has been previously shown 34 and the recently completed EXPLORE study also showed that many patients with recurrent attacks experience tiredness. Further assessments are needed to determine whether sleep disturbance is a critical domain to be measured when assessing QoL in AIP.…”

Complicity of haem in some adverse drug-reactions

“…107 This may be of clinical relevance since AIP patients with biochemical activity apparently have abnormalities in circadian rhythms or levels of clock-controlled genes, including ALAS1. 108 In addition, dietary iron can control circadian gluconeogenesis in the liver via the regulation of haem synthesis. 109…”