Adrenal Insufficiency
Patients suffering from adrenal insufficiency (AI) are unable to produce their own cortisol. To survive, they need replacement therapy with glucocorticoids – usually hydrocortisone – and mineralocorticoids. Because it is a chronic condition, they require this life-saving therapy throughout their lives. Cortisol is replaced using hydrocortisone, the chemically identical synthetic form of cortisol.
The onset of AI may vary from insidious to an acute life-threatening situation with severe salt and water deficit, which leads to shock and death within hours if not treated adequately. Frequently reported symptoms associated with AI are: asthenia, weakness, lethargy, easy fatigability, nervousness, irritability, apathy, dizziness, headache, myalgia, anorexia, weight loss, nausea, abdominal pain, vomiting and diarrhoea.
Adrenal insufficiency may be:
- Primary, as a result of a disease in the adrenal cortex.
- Secondary (central) due to an underlying hypothalamic-pituitary disorder.
Primary AI is usually referred to as Addison’s Disease.
Adrenal insufficiency is a potentially lethal disorder with a 1-year mortality of more than 80% before the availability of glucocorticoids1. With the advent of glucocorticoid replacement therapy for the management of AI, patients’ lives were prolonged. However, patients suffer increased morbidity and premature mortality even with the currently available oral replacement therapy.
In recent population-based, retrospective observational studies, the relative risk of death was more than 2-fold higher in patients with primary AI (Addison's disease) on currently available oral replacement therapy compared to the background population.2 Very similar data have been reported in patients with hypopitutarism and secondary AI3. Moreover, young adults with hypopituitarism including AI have more than 7-fold the expected mortality rate4. Cardiovascular, malignant and infectious diseases were responsible for the higher mortality rate in these studies.
Patients with AI have also been found to have increased frequency of cardiovascular risk factors5 including
- abdominal obesity
- hypertension
- dyslipidaemia
- reduced health-related quality of life
- reduced bone mineral density
A possible explanation is an inadequate glucocorticoid replacement therapy with both an unphysiological glucocorticoid exposure and inadequate treatment in response to stress and intercurrent illnesses, such as infections. In addition, an attenuated diurnal variation (less in the morning and more in the evening and during the night) in the plasma cortisol profile has been associated with abdominal obesity and the metabolic syndrome6.
Based on the outcome data from patients with AI, it is likely that many patients are receiving overly high oral doses of glucocorticoids that do not mimic endogenous production in healthy subjects. Importantly, the treatment regimen results in an unphysiological and fluctuating plasma concentration-time profile. Multiple daily dosing can also result in patient failure to fully comply with treatment. Therefore, there is a clinical need to improve replacement therapy in AI.
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- Dunlop 1963
- Bergthorsdottir et al 2006; Bensing et al 2008
- Rosén et al 1990; Tomlinson et al 2001
- Mills et al 2004
- Hahner et al 2007; Filipsson et al 2006; Zelissen et al 1994
- Dallman et al 2000; Dallman et al 2004