Investigating the mechanism of adrenal insufficiency in individuals with porphyria

血红素是一种化学化合物，通常被认为是产生血红蛋白的关键成分，而血红蛋白是结合血液中氧气所必需的。血红素的产生涉及八种酶，其中任何一种酶的缺乏都会导致体内化学物质的积累，导致一组临床上重要的疾病，称为卟啉症。它们被分为两种类型：第一种类型被称为急性，主要影响神经系统，患者出现严重的腹痛、恶心、便秘、精神错乱和癫痫，这可能危及生命；第二种类型被称为皮肤卟啉症，会导致皮肤脆弱和起泡。急性发作可由许多情况引发，如手术和感染，症状类似于肾上腺功能衰竭，此时不会产生皮质醇等重要的类固醇激素。除了是血红蛋白的主要成分外，血红素也是产生参与类固醇激素产生的酶的关键。类固醇激素对人体的维持和正常功能至关重要，此外，它还是人体对外部和内部应激源做出斗争或逃跑反应的核心要素。这一过程发生在肾上腺(位于肾脏顶部的小腺)和性腺中。由于任何原因导致这些激素产生的途径失败，会导致一种称为肾上腺功能不全的情况，如果不进行治疗，这种情况可能是致命的，特别是在所谓的肾上腺危机期间，这基本上是一种肾上腺类固醇生产能力达不到要求的疾病状态。最近，我们发现血红素合成酶严重缺陷，即使在患者没有压力的情况下，也会导致肾上腺功能不全和门静脉阻塞。因此，我们认为在卟啉症中可能存在一系列疾病，许多患者可能患有未被识别的危及生命的肾上腺疾病，这些疾病可以通过简单的激素替代方案进行治疗。通过利用细胞和小鼠模型，我们将研究血红素酶在正常肾上腺类固醇产生和疾病状态下的作用。这将通过在细胞培养中培养的肾上腺细胞系中产生突变来产生缺乏酶的细胞来实现，然后我们将测量包括皮质醇和血红素在内的不同化学物质的水平。这将导致了解这些条件的确切机制，以及维持正常功能所需的残留酶活性水平。我们希望继续测量不同门静脉症患者的类固醇水平，看看这些变化在多大程度上适用于人类。这将使我们能够提出适当的干预措施，在他们的治疗中增加类固醇，这将有助于长期或对那些遭受严重危机的人。

Haem is a chemical compound most commonly recognised as a component critical to the production of haemoglobin, which is necessary to bind oxygen in the bloodstream. Haem production involves eight enzymes and a deficiency in any one of these enzymes leads to accumulation of chemicals in the body causing a clinically significant group of disorders known as porphyrias.They are classified into two types: the first type known as acute, mainly affects the nervous system, and patients present with severe abdominal pain, nausea, constipation, confusion and seizures, which may be life threatening; the second type known as cutaneous porphyria, causes skin fragility and blisters. Acute attacks can be triggered by many conditions, such as surgery and infections, with symptoms being similar to those seen with adrenal failure, where important steroid hormones such as cortisol are not produced.As well as being the main component of haemoglobin, haem is also essential for the production of enzymes that take part in the production of steroid hormones. Steroid hormones are crucial for the maintenance and normal functioning of the human body, in addition to representing the core element in its fight or flight response to both external and internal stressors. This process takes place in both the adrenal glands (small glands located on top of the kidneys), and the gonads.Failure of the pathway that leads to production of these hormones due to whatever cause result in a condition known as adrenal insufficiency, which if left untreated could be fatal, particularly, during what is known as adrenal crisis, which is basically a disease state in which the steroid producing capacity of the adrenals does not meet the demand.Recently, we have discovered severe defects in haem synthesis enzymes giving rise to adrenal insufficiency as well as porphyria even when the patients are not stressed. We therefore think there may be a spectrum of disease in porphyria and many patients may have unrecognised, life-threatening adrenal disease, which could be amenable to treatment with simple hormone replacement regimes.By utilising cell and mouse models, we will investigate the role of the haem enzymes in normal adrenal gland steroid production and in the diseased state. This will be achieved by creating mutations in adrenal cell lines grown in cell cultures to produce cells that lack the enzymes, we will then measure the levels of different chemicals including cortisol and haem. This will lead to understanding the exact mechanism of these conditions and the level of residual enzyme activity required to maintain normal function. We hope to go on and measure steroids in patients with different porphyrias to see to what degree these changes are translated in humans. This will allow us to suggest appropriate interventions in terms of adding steroids to their treatment which would be helpful long-term or, alternatively, for those suffering acute crises.