Investigating the mechanism of adrenal insufficiency in individuals with porphyria

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.