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Q1: What is the differential diagnosis?
The extremely low serum cortisol concentration, which failed to rise in response to tetracosactrin confirms adrenal failure. A normal adrenal response to tetracosactrin is considered to be an increase in serum cortisol concentration to a peak exceeding 550 nmol/l. However, this failure may be primary (Addison's disease), secondary to a pituitary lesion or, very rarely, tertiary (hypothalamic). Failure of the adrenal gland to respond to tetracosactrin by increasing production of cortisol may be observed in all forms of adrenal failure: in primary adrenal failure due to destruction of the adrenal gland itself (for example, due to autoimmune adrenalitis, infarction, or tuberculosis) and in secondary and tertiary adrenal failure due to atrophy of the gland as a result of insufficient stimulation by adrenocorticotrophic hormone (ACTH, corticotrophin). Conversely, a normal cortisol response in the short tetracosactrin test cannot exclude secondary adrenal insufficiency.
Q2: What further investigations would you request?
Serum ACTH concentration measured at 9 am, 24 hours after his previous dose of hydrocortisone, was inappropriately low (12 ng/l, reference range 5–36) compared with paired serum cortisol concentration (56 nmol/l), suggesting secondary (or possibly tertiary) adrenal failure (fig 1). This was further investigated with a Depot Synacthen test (tetracosactrin with zinc phosphate complex; 1 mg Depot Synacthen given at 8 am each morning for four mornings). Serum cortisol concentrations increased from a baseline before the dose of 33 nmol/l on the first morning to concentrations after the dose of 174, 451, 521, and 520 nmol/l on the first to fourth mornings respectively, confirming that his adrenal would respond to sustained ACTH stimulation with stepwise increments in cortisol production. This test confirmed that his adrenal failure was secondary to either a pituitary or hypothalamic lesion. Magnetic resonance imaging (MRI) with contrast was entirely normal, showing no focal lesion in the pituitary or hypothalamus. Given the normal MRI, further testing to discriminate between secondary or tertiary adrenal failure was deemed clinically unnecessary.
Q3: How would you manage the patient?
Patients with acute adrenal insufficiency require immediate treatment with intravenous hydrocortisone and correction of any fluid or electrolyte deficit. In the long term, patients with primary adrenal failure will require replacement of both the glucocorticoid and mineralocorticoid components of adrenal steroid production. Consequently the patient received hydrocortisone (30 mg/day in a divided dose: 20 mg am, 10 mg pm) and fludrocortisone (50 μg/day). Fludrocortisone was discontinued when the diagnosis of secondary adrenal failure was confirmed, since the mineralocorticoid pathway is intact in secondary adrenal failure. After the institution of treatment, the patient felt much better (“10 years younger”); his dizziness (blood pressure 140/90 mm Hg lying and standing), diarrhoea, and anaemia completely resolved. His appetite improved and over several months his weight rose to 81 kg.
Clinical features which are due to cortisol deficiency are common to both primary and secondary causes of adrenal failure and, as in the present case, can include weight loss, anorexia, diarrhoea, decreased libido and potency, and a normocytic anaemia. Postural hypotension occurs in both primary and secondary adrenal failure, despite the fact that the mineralocorticoid axis is intact in the latter. This effect is explained by the requirement of adrenaline (epinephrine) synthesis for high local concentrations of cortisol in the adrenal medulla and the decreased expression of vascular catecholamine receptors in secondary adrenal failure.1
Primary hypothyroidism is commonly associated with primary adrenal failure as part of the type II autoimmune polyglandular syndrome (Schmidt's syndrome) and initially this was felt to be the most likely diagnosis in the present case. However, many of the common features of primary adrenal failure (for example, hyperpigmentation, hyponatraemia, hyperkalaemia, uraemia, and adrenal antibodies) were absent. This raised the possibility of secondary (or tertiary) adrenal failure, which was confirmed by the demonstration of an inappropriately low ACTH and an adequate adrenal response to sustained corticotrophin stimulation.
On the basis of normal pituitary and hypothalamic anatomy on imaging, normal serum prolactin, an intact pituitary-gonadal axis and intact thyrotroph response to primary thyroid failure, the diagnosis of isolated ACTH deficiency was established. This is a rare cause of adrenal failure with less than 200 cases having been reported in the literature by 1990.2 Although histological confirmation is lacking, it is possible that our patient had lymphocytic hypophysitis, a rare inflammatory lesion of the pituitary gland which can cause autoimmune destruction of one pituitary cell line with resultant failure of the target organ.3 This condition is commonly associated with autoimmune thyroid disease3 4 and is far commoner in women than men.
Secondary adrenal failure is easily missed since many of the classical symptoms of Addison's disease are absent.
The short tetracosactrin (Synacthen) test does not discriminate between primary, secondary, or tertiary adrenal failure.
Secondary, as well as primary, adrenal failure may have autoimmune associations.
In summary, our case demonstrates the difficulty of recognising the clinical features of secondary adrenal failure and of establishing the diagnosis biochemically. Finally, it is important to remember that other autoimmune disease may be associated with secondary, as well as primary, adrenal failure.
Isolated ACTH deficiency.