Elsevier

The Lancet

Volume 361, Issue 9372, 31 May 2003, Pages 1881-1893
The Lancet

Seminar
Adrenal insufficiency

https://doi.org/10.1016/S0140-6736(03)13492-7Get rights and content

Summary

Adrenal insufficiency is caused by either primary adrenal failure (mostly due to autoimmune adrenalitis) or by hypothalamic-pituitary impairment of the corticotropic axis (predominantly due to pituitary disease). It is a rare disease, but is life threatening when overlooked. Main presenting symptoms such as fatigue, anorexia, and weight loss are nonspecific, thus diagnosis is often delayed. The diagnostic work-up is well established but some pitfalls remain, particularly in the identification of secondary adrenal insufficiency. Despite optimised life-saving glucocorticoid-replacement and mineralocorticoid-replacement therapy, health-related quality of life in adrenal insufficiency is more severely impaired than previously thought. Dehydroepiandrosterone-replacement therapy has been introduced that could help to restore quality of life. Monitoring of glucocorticoid-replacement quality is hampered by lack of objective methods of assessment, and is therefore largely based on clinical grounds. Thus, long-term management of patients with adrenal insufficiency remains a challenge, requiring an experienced specialist. However, all doctors should know how to diagnose and manage suspected acute adrenal failure.

Section snippets

Epidemiology

There are two types of adrenal insufficiency, primary and secondary (figure 1). Chronic primary adrenal insufficiency has a prevalence of 93–140 per million and an incidence of 4·7–6·2 per million in white populations.1, 2, 3, 4 These recent numbers are higher than those reported during the 1960s and 1970s,5, 6 despite a continuous decline in tuberculous adrenalitis in the developed world, suggesting an increasing incidence of autoimmune adrenalitis.3, 4 The age at diagnosis peaks in the fourth

Primary adrenal insufficiency (panel 1)12–38

During the times of Thomas Addison, tuberculous adrenalitis was by far the most prevalent cause of adrenal insufficiency and, in the developing world, it remains a major factor.39 In active tuberculosis, the incidence of adrenal involvement is 5%.40 In developed countries, 80–90% of patients with primary adrenal insufficiency have autoimmune adrenalitis, which can arise as isolated (40%; slight male preponderance) or as part of an autoimmune polyendocrine syndrome ([APS]; 60%; female

Secondary adrenal insufficiency (panel 2)48–55

The most frequent cause of secondary adrenal insufficiency is a tumour of the hypothalamic-pituitary region, usually associated with panhypopituitarism caused by tumour growth or treatment with surgery or irradiation. Autoimmune lymphocytic hypophysitis is less frequent, mostly affecting women during or shortly after pregnancy. Isolated adrenocorticotropic hormone (ACTH) deficiency could also be of autoimmune origin since some patients concurrently have other autoimmune disorders, most

Pathophysiology and clinical presentation (panel 3)

Glucocorticoids are secreted from the adrenal zona fasciculata under the control of hypothalamic corticotropin-releasing hormone and pituitary corticotropin. Cortisol secretion is diurnal with maximum concentrations measured early in the morning and trough concentrations noted around midnight.56 Mineralocorticoids are produced by the zona glomerulosa, mainly under the control of the renin-angiotensin system. Thus, mineralocorticoid secretion is preserved in secondary adrenal insufficiency.

Laboratory assessment of adrenal function (panel 4)

Concentrations of ACTH and cortisol vary throughout the day due to their closely related pulsatile release, which follows a diurnal rhythm. Therefore, the diagnostic usefulness of random samples is limited. Moreover, total cortisol, but not the biologically active free fraction, can increase as a result of hepatic cortisol-binding globulin production, which is increased, for example, by oestrogens.66 Finally, differences in cortisol assays can affect normative data and interpretation of dynamic

Secondary adrenal insufficiency

Baseline hormone measurements differ little between patients with secondary adrenal insufficiency and healthy individuals.16, 68 However, a morning cortisol value below 100 nmol/L indicates adrenal insufficiency whereas a serum cortisol greater than 500 mmol/L is consistent with an intact hypothalmic-pituitary-adrenal axis.72, 75, 76 Thus, in most instances, dynamic tests of the hypothalmic-pituitary-adrenal axis are required to establish a diagnosis of secondary adrenal insufficiency.

The

Adrenal insufficiency after pituitary surgery

Screening for adrenal insufficiency with the standard short corticotropin test or with the low-dose corticotropin test should be done 4–6 weeks or more after surgery for pituitary surgery,76, 101 since adrenal atrophy can develop only gradually after onset of ACTH deficiency. Until then, patients with a morning cortisol not excluding secondary adrenal insufficiency (<450 nmol/L at 3 days and <50 nmo/L at 7 days after surgery) should receive hydro-cortisone replacement, withheld for 24 h before

Chronic replacement therapy

Glucocorticoid replacement is usually given in two or three daily doses, with a half to two-thirds of the daily dose administered in the morning to mimic the physiological cortisol secretion pattern. Findings of studies indicate that daily cortisol production rates vary between 5 mg/m2 and 10 mg/m2,115, 116, 117, 118 equivalent to the oral administration of 15–25 mg hydrocortisone (cortisol) or 25·0–37·5 mg cortisone acetate.119, 120 Cortisone acetate requires conversion to cortisol by

Prevention and management of adrenal crisis

In a series of 53 patients with chronic adrenal insufficiency, representing 511 replacement-years, we noted an overall risk of adrenal crisis needing hospital admission of 3·3 per 100 years. Risk of crisis was much higher in primary adrenal insufficiency (3·8 per 100 vs2·5 per 100 years) and in women (4·4 per 100 vs1·6 per 100 years) with the highest overall risk in women with autoimmune adrenalitis (6·5 per 100 years). Most crises were due to glucocorticoid dose reduction or lack of

Thyroid dysfunction

Hyperthyroidism increases cortisol clearance.120 In patients with adrenal insufficiency and unresolved hyperthyroidism, glucocorticoid replacement should be doubled or tripled. To avoid adrenal crisis, thyroxine replacement for hypothyroidism should only be initiated after concomitant glucocorticoid deficiency has either been excluded or treated.

Pregnancy

Pregnancy is physiologically associated with a gradual increase in cortisol-binding globulin and, during the last term, also in free cortisol.139 Serum

Quality of life, disablility, and prognosis

Prospective data10 indicate excess mortality in hypopituitarism, including secondary adrenal insufficiency, mainly due to vascular and respiratory disease. However, deficiencies of other hormonal axes could also contribute. Mortality in patients with primary adrenal insufficiency has not been studied. Nevertheless, life expectancy may be reduced as a consequence of unrecognised adrenal crisis, underlying illness—eg, adrenomyeloneuropathy—and other as yet unidentified causes.4

Despite adequate

Search strategy

We searched Medline and PubMed for reviews and original articles related to adrenal insufficiency and published between 1966 and December, 2002. Keywords used included adrenal insufficiency and incidence, prevalence, cause, origin, diagnosis, function test, imaging, hydrocortisone, glucocorticoid, mineralocorticoid, dehydroepiandrosterone, management, treatment, therapy, replacement, surveillance, crisis, bone mineral density, quality of life, well-being, disablement, pregnancy,

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