Elsevier

The Lancet

Volume 383, Issue 9935, 21–27 June 2014, Pages 2152-2167
The Lancet

Seminar
Adrenal insufficiency

https://doi.org/10.1016/S0140-6736(13)61684-0Get rights and content

Summary

Adrenal insufficiency is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in mineralocorticoids and adrenal androgens. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic–pituitary axis. Prompt diagnosis and management are essential. The clinical manifestations of primary adrenal insufficiency result from deficiency of all adrenocortical hormones, but they can also include signs of other concurrent autoimmune conditions. In secondary or tertiary adrenal insufficiency, the clinical picture results from glucocorticoid deficiency only, but manifestations of the primary pathological disorder can also be present. The diagnostic investigation, although well established, can be challenging, especially in patients with secondary or tertiary adrenal insufficiency. We summarise knowledge at this time on the epidemiology, causal mechanisms, pathophysiology, clinical manifestations, diagnosis, and management of this disorder.

Introduction

Adrenal insufficiency is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic–pituitary axis.1, 2, 3 It is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in mineralocorticoids and adrenal androgens. The cardinal clinical symptoms of adrenocortical insufficiency, as first described by Thomas Addison in 1855, include weakness, fatigue, anorexia, abdominal pain, weight loss, orthostatic hypotension, and salt craving; characteristic hyperpigmentation of the skin occurs with primary adrenal failure.4, 5 Whatever the cause, adrenal insufficiency was invariably fatal until 1949, when cortisone was first synthesised,6, 7, 8, 9 and glucocorticoid-replacement treatment became available. However, despite this breakthrough, the diagnosis and treatment of patients with the disorder remain challenging.

Section snippets

Epidemiology

According to the underlying mechanism, adrenal insufficiency is classed as primary, secondary, or tertiary. Primary adrenal insufficiency results from disease intrinsic to the adrenal cortex. Central adrenal insufficiency, the collective name for the secondary and tertiary types, is caused by impaired production or action of corticotropin. Secondary adrenal insufficiency results from pituitary disease that hampers the release of corticotropin or from a lack of responsiveness of the adrenal

Primary adrenal insufficiency

The causes of primary adrenal insufficiency are listed in table 1. In developed countries, 80–90% of cases of primary adrenal insufficiency are caused by autoimmune adrenalitis, which can be isolated (40%) or part of an autoimmune polyendocrinopathy syndrome (60%).1, 2, 19, 32, 33, 34 Autoimmune Addison's disease is characterised by destruction of the adrenal cortex by cell-mediated immune mechanisms. Antibodies against steroid 21-hydroxylase are detected in about 85% of patients with

Pathophysiology and clinical presentation

The adrenal cortex has three distinct zones, which secrete the various hormones under the direct control of well understood feedback mechanisms. Aldosterone is synthesised in the outermost zone, the zona glomerulosa. Its secretion is predominantly regulated by the renin–angiotensin system and extracellular potassium concentrations; therefore, it is not impaired in secondary and tertiary adrenal insufficiency. Cortisol secretion from the zona fasciculata is primarily regulated by corticotropin,

Diagnosis of adrenal insufficiency

There are three main aims in the diagnosis of adrenal insufficiency (table 5): to confirm inappropriately low cortisol secretion; to find out whether the adrenal insufficiency is primary or central; and to delineate the underlying pathological process.1, 2, 3

Whatever the cause, the diagnosis of adrenal insufficiency depends entirely on the demonstration that cortisol secretion is inappropriately low. All current stimulation tests measure total cortisol concentration, which is related closely to

Treatment

Adrenal insufficiency is potentially life-threatening. Treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis (panel).1, 2, 3, 4, 5

A very important part of the management of chronic adrenal insufficiency is education of the patient and his or her family. They need to understand the importance of life-long replacement therapy, the need to increase the usual glucocorticoid dose during stress, and the need to notify medical staff if

Adrenal insufficiency in critically ill patients

Adrenal insufficiency is common in critically ill patients and is increasingly reported in sepsis, severe pneumonia, adult respiratory stress syndrome, trauma, HIV infection, or after treatment with etomidate.2, 123, 124, 125, 126, 127 It can also be associated with structural damage to the adrenal gland, pituitary gland, or hypothalamus; however, many critically ill patients develop reversible failure of the HPA axis.2, 123, 124, 125, 126

The underlying pathophysiological mechanisms leading to

Search strategy and selection criteria

We searched PubMed and the Cochrane Library for original articles and reviews related to adrenal insufficiency, which were published in English between 1966 and April, 2013. We used the search terms “adrenal insufficiency”, in combination with the terms “incidence”, “prevalence”, “cause”, “origin”, “diagnosis”, “function test”, “imaging”, “hydrocortisone”, “glucocorticoid”, “mineralocorticoid”, “dehydroepiandrosterone”, “management”, “treatment”, “therapy”, “replacement”, “surveillance”,

References (136)

  • N Nader et al.

    Interactions of the circadian CLOCK system and the HPA axis

    Trends Endocrinol Metab

    (2010)
  • T Tan et al.

    Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease

    J Hepatol

    (2010)
  • M Fleseriu et al.

    Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review

    Endocr Pract

    (2010)
  • GW Boland

    Adrenal imaging: from Addison to algorithms

    Radiol Clin North Am

    (2011)
  • T Ouyang et al.

    Imaging of the pituitary

    Radiol Clin North Am

    (2011)
  • S Hahner et al.

    Therapeutic management of adrenal insufficiency

    Best Pract Res Clin Endocrinol Metab

    (2009)
  • SR Bornstein

    Predisposing factors for adrenal insufficiency

    N Engl J Med

    (2009)
  • N Neary et al.

    Adrenal insufficiency: etiology, diagnosis and treatment

    Curr Opin Endocrinol Diabetes Obes

    (2010)
  • T Addison

    On the constitutional and local effects of disease of the supra-renal capsules

    (1855)
  • EC Kendall

    Hormones of the adrenal cortex in health and disease

    Proc Am Philos Soc

    (1953)
  • T Reichstein

    [The most important hormones of adrenal cortex]

    Acta Endocrinol (Copenh)

    (1954)
  • SG Hillier

    Diamonds are forever: the cortisone legacy

    J Endocrinol

    (2007)
  • AS Mason et al.

    Epidemiological and clinical picture of Addison's disease

    Lancet

    (1968)
  • J Nerup

    Addison's disease—clinical studies. A report of 108 cases

    Acta Endocrinol (Copenh)

    (1974)
  • MF Kong et al.

    Eighty-six cases of Addison's disease

    Clin Endocrinol (Oxf)

    (1994)
  • AC Willis et al.

    The prevalence of Addison's disease in Coventry, UK

    Postgrad Med J

    (1997)
  • S Laureti et al.

    Is the prevalence of Addison's disease underestimated?

    J Clin Endocrinol Metab

    (1999)
  • K Løvås et al.

    High prevalence and increasing incidence of Addison's disease in western Norway

    Clin Endocrinol (Oxf)

    (2002)
  • MM Erichsen et al.

    Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry

    J Clin Endocrinol Metab

    (2009)
  • D Dunlop

    Eighty-six cases of Addison's disease

    BMJ

    (1963)
  • C Betterle et al.

    Autoimmune Addison's disease

    Endocr Dev

    (2011)
  • R Perry et al.

    Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal

    J Clin Endocrinol Metab

    (2005)
  • AS Bates et al.

    The effect of hypopituitarism on life expectancy

    J Clin Endocrinol Metab

    (1996)
  • B Nilsson et al.

    Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and mortality

    J Clin Endocrinol Metab

    (2000)
  • M Regal et al.

    Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain

    Clin Endocrinol (Oxf)

    (2001)
  • NM Appelman-Dijkstra et al.

    Pituitary dysfunction in adult patients after cranial radiotherapy: systematic review and meta-analysis

    J Clin Endocrinol Metab

    (2011)
  • MT Gomez et al.

    The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome

    J Clin Endocrinol Metab

    (1993)
  • M Reincke et al.

    Impairment of adrenocortical function associated with increased plasma tumor necrosis factor-alpha and interleukin-6 concentrations in African trypanosomiasis

    Neuroimmunomodulation

    (1994)
  • E Charmandari et al.

    Chrousos syndrome: a seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signalling changes

    Eur J Clin Invest

    (2010)
  • E Charmandari

    Primary generalized glucocorticoid resistance and hypersensitivity

    Horm Res Paediatr

    (2011)
  • E Charmandari

    Primary generalized glucocorticoid resistance and hypersensitivity: the end-organ involvement in the stress response

    Sci Signal

    (2012)
  • E Charmandari et al.

    Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity

    Endocr Dev

    (2013)
  • AL Mitchell et al.

    Autoimmune Addison disease: pathophysiology and genetic complexity

    Nat Rev Endocrinol

    (2012)
  • G Reato et al.

    Premature ovarian failure in patients with autoimmune Addison's disease: clinical, genetic, and immunological evaluation

    J Clin Endocrinol Metab

    (2011)
  • E Bratland et al.

    T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency

    J Clin Endocrinol Metab

    (2009)
  • PR Baker et al.

    Haplotype analysis discriminates genetic risk for DR3-associated endocrine autoimmunity and helps define extreme risk for Addison's disease

    J Clin Endocrinol Metab

    (2010)
  • PR Baker et al.

    Dominant suppression of Addison's disease associated with HLA-B15

    J Clin Endocrinol Metab

    (2011)
  • B Skinningsrud et al.

    Multiple loci in the HLA complex are associated with Addison's disease

    J Clin Endocrinol Metab

    (2011)
  • EM Akirav et al.

    The role of AIRE in human autoimmune disease

    Nat Rev Endocrinol

    (2011)
  • AW Michels et al.

    Autoimmune polyglandular syndromes

    Nat Rev Endocrinol

    (2010)

    • Cited by (459)

    • The Physiological and Pharmacological Significance of the Circadian Timing of the HPA Axis: A Mathematical Modeling Approach

      2024, Journal of Pharmaceutical Sciences

    • Regulation of lipid droplets and cholesterol metabolism in adrenal cortical cells

      2024, Vitamins and Hormones

    • Adrenal Emergencies

      2023, Emergency Medicine Clinics of North America

    • Patient-reported impact of symptoms in adrenoleukodystrophy (PRISM-ALD)

      2024, Orphanet Journal of Rare Diseases

    • Prevalence of Adrenal Insufficiency in Korean Patients undergoing Total Knee Arthroplasty

      2024, Annals of Geriatric Medicine and Research

    • Use of overnight metyrapone test in suspected secondary adrenal insufficiency: A retrospective single centre-study

      2024, Clinical Endocrinology
    View all citing articles on Scopus
    View full text
    Copyright © 2014 Elsevier Ltd. All rights reserved.