Pozo Oscar J, Marcos Josep, Fabregat Andreu, Ventura Rosa, Casals Gregori, Aguilera Paula, Segura Jordi, To-Figueras Jordi
Bioanalysis Research Group, IMIM, Hospital del Mar Medical Research Institute, Doctor Aiguader 88, Barcelona 08003, Spain.
Orphanet J Rare Dis. 2014 Apr 16;9:54. doi: 10.1186/1750-1172-9-54.
Acute Intermittent Porphyria (AIP) is a rare disease that results from a deficiency of hydroxymethylbilane synthase, the third enzyme of the heme biosynthetic pathway. AIP carriers are at risk of presenting acute life-threatening neurovisceral attacks. The disease induces overproduction of heme precursors in the liver and long-lasting deregulation of metabolic networks. The clinical history of AIP suggests a strong endocrine influence, being neurovisceral attacks more common in women than in men and very rare before puberty. To asses the hypothesis that steroidogenesis may be modified in AIP patients with biochemically active disease, we undertook a comprehensive analysis of the urinary steroid metabolome.
A case-control study was performed by collecting spot morning urine from 24 AIP patients and 24 healthy controls. Steroids in urine were quantified by liquid chromatography-tandem mass spectrometry. Parent steroids (17-hydroxyprogesterone; deoxycorticosterone; corticoesterone; 11-dehydrocorticosterone; cortisol and cortisone) and a large number of metabolites (N = 55) were investigated. Correlations between the different steroids analyzed and biomarkers of porphyria biochemical status (urinary heme precursors) were also evaluated. The Mann-Whitney U test and Spearman's correlation with a two tailed test were used for statistical analyses.
Forty-one steroids were found to be decreased in the urine of AIP patients (P < 0.05), the decrease being more significant for steroids with a high degree of hydroxylation. Remarkably, 13 cortisol metabolites presented lower concentrations among AIP patients (P < 0.01) whereas no significant differences were found in the main metabolites of cortisol precursors. Nine cortisol metabolites showed a significant negative correlation with heme precursors (p < 0.05). Ratios between the main metabolites of 17-hydroxyprogesterone and cortisol showed positive correlations with heme-precursors (correlation coefficient > 0.51, P < 0.01).
Comprehensive study of the urinary steroid metabolome showed that AIP patients present an imbalance in adrenal steroidogenesis, affecting the biosynthesis of cortisol and resulting in decreased out-put of cortisol and metabolites. This may result from alterations of central origin and/or may originate in specific decreased enzymatic activity in the adrenal gland. An imbalance in steroidogenesis may be related to the maintenance of an active disease state among AIP patients.
急性间歇性卟啉病（AIP）是一种罕见疾病，由血红素生物合成途径的第三种酶——羟甲基胆色素原合酶缺乏所致。AIP携带者有发生危及生命的急性神经内脏发作的风险。该疾病会导致肝脏中血红素前体的过度产生以及代谢网络的长期失调。AIP的临床病史表明内分泌有很大影响，神经内脏发作在女性中比在男性中更常见，且在青春期前非常罕见。为了评估在生化指标活跃的AIP患者中类固醇生成可能发生改变的假设，我们对尿类固醇代谢组进行了全面分析。
进行了一项病例对照研究，收集了24例AIP患者和24例健康对照者的晨尿样本。通过液相色谱 - 串联质谱法定量尿液中的类固醇。研究了母体类固醇（17 - 羟孕酮；脱氧皮质酮；皮质酮；11 - 脱氢皮质酮；皮质醇和可的松）以及大量代谢物（N = 55）。还评估了所分析的不同类固醇与卟啉病生化状态生物标志物（尿血红素前体）之间的相关性。采用曼 - 惠特尼U检验和双尾检验的斯皮尔曼相关性进行统计分析。
发现41种类固醇在AIP患者尿液中减少（P < 0.05），对于高度羟基化的类固醇，减少更为显著。值得注意的是，13种皮质醇代谢物在AIP患者中的浓度较低（P < 0.图 01），而皮质醇前体的主要代谢物未发现显著差异。9种皮质醇代谢物与血红素前体呈显著负相关（p < 0.05）。17 - 羟孕酮和皮质醇的主要代谢物之间的比率与血红素前体呈正相关（相关系数 > 0.51，P < 0.01）。
对尿类固醇代谢组的全面研究表明，AIP患者存在肾上腺类固醇生成失衡，影响皮质醇的生物合成，导致皮质醇及其代谢物的产出减少。这可能是中枢性改变的结果和/或可能源于肾上腺中特定酶活性的降低。类固醇生成失衡可能与AIP患者活跃疾病状态的维持有关。
