SeminarAdrenal insufficiency
Introduction
Adrenal insufficiency is a common condition with multiple causes that can be divided into primary (adrenal), secondary (pituitary), and tertiary (hypothalamus) forms (figure 1). Each form of adrenal insufficiency has distinctive causes with implications for treatment and follow-up. Tertiary adrenal insufficiency caused by exogenous steroid treatment is a common form of adrenal insufficiency, and is easily missed due to its non-specific signs and symptoms that can be indistinguishable from manifestations of the underlying condition.2 Secondary adrenal insufficiency is rare, and occurs due to defects of pituitary gland function, which is often caused by pituitary adenomas or by their treatment.3, 4 Primary adrenal insufficiency occurs less frequently than secondary or tertiary adrenal insufficiency, and is caused by intrinsic adrenal gland pathology; commonly destructive autoimmunity or inborn error of steroidogenesis.
Adrenal insufficiency can manifest at any age, but often presents between the ages of 20 years and 50 years. Despite substantial advances in diagnostics and treatment over the past few decades, clinicians struggle to make a timely diagnosis before the occurrence of life-threatening complications or death.5, 6, 7 State-of-the-art diagnostic tests and treatment modalities are still unavailable in many parts of the world, and treatment and follow-up is not optimal. This observation is reflected in the associated increased mortality and reduced quality of life and working capacity.8, 9 This Seminar seeks to enable clinicians to make an early and correct diagnosis, and to treat and follow up patients in an optimal way so that complications and ill health is minimised.
Section snippets
Overview
Adrenal steroid secretion is tightly regulated at multiple levels (figure 1). The hypothalamic–pituitary–adrenal axis regulates cortisol production in response to light, stress, and numerous other inputs.7 The result of this regulation is a robust, but adaptable, circadian and ultradian (pulsation with a frequency shorter than 24 h) cortisol rhythm, characterised by secretory bursts every 60–90 min (figure 1).10 Aldosterone production is mainly regulated by the renin–angiotensin system (figure 1
Epidemiology
Primary adrenal insufficiency is rare; the highest prevalence has been reported in Nordic countries at 15–22 individuals per 100 000.44, 45, 46 Other European countries have numbers of around ten individuals per 100 000.47, 48 A survey from South Korea reported a prevalence of only 0·4 individuals per 100 000, with tumours and tuberculosis as the main causes.49 Data are insufficient from countries with high incidences of tuberculosis and HIV infections.
Secondary adrenal insufficiency is
Primary adrenal insufficiency
Genetic conditions are the most common cause of primary adrenal insufficiency in neonates (aged 0–4 weeks), infants (aged 0–2 years), and children (aged 2–12 years), including congenital adrenal hyperplasia, adrenoleukodystrophy, and congenital adrenal hypoplasia (figure 2). Adrenoleukodystrophy and congenital adrenal hypoplasia are linked to the X chromosome and only affect boys. An increasing number of other rare genetic syndromes with or without associated multisystem problems have been
Evaluation of adrenocortical function
The primary challenge in evaluating adrenocortical function is for clinicians to be constantly vigilant for adrenal insufficiency. Once suspected, it is usually easy to clinically confirm or refute the clinical suspicion. A survey indicated that hyponatraemia was present in 207 (84%) of 247 individuals with undiagnosed adrenal insufficiency,6 thyroid stimulating hormone was increased in 79 (52%) of 153 individuals, and hyperkalaemia was present in 82 (34%) of 242 individuals.6 Thus, unexplained
Treatment
Patients with primary adrenal insufficiency are deficient in glucocorticoids and mineralocorticoids and require replacement of both, together with salt intake as needed. By contrast, individuals with ACTH deficiency due to pituitary or hypothalamic dysfunction after exogenous steroid use usually require only glucocorticoid replacement. Patients with primary adrenal insufficiency and patients with ACTH deficiency also have androgen deficiency, but the benefits of androgen replacement are less
Future prospects
Patients still die of adrenal crisis, which should be entirely preventable, and many patients probably develop an adrenal crisis before the diagnosis of adrenal insufficiency is recognised. Therefore, physicians must be educated to recognise adrenal insufficiency earlier so that a diagnosis can be made before a crisis develops. Current treatment is not curative, but merely attempts to replace physiological cortisol concentrations, which is a challenge in itself given the fine-tuned
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