Adrenal insufficiency

doi:10.1016/S0140-6736(21)00136-7

The Lancet

Volume 397, Issue 10274, 13–19 February 2021, Pages 613-629

https://doi.org/10.1016/S0140-6736(21)00136-7 Get rights and content

Summary

Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insufficiency usually develop skin hyperpigmentation and crave salt. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often non-specific; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with primary or secondary adrenal insufficiency. Active and repeated patient education on managing adrenal insufficiency, including advice on how to increase medication during intercurrent illness, medical or dental procedures, and profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insufficiency after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of glucocorticoid delivery could improve the quality of life in some patients with adrenal insufficiency, and further advances in oral and parenteral therapy will probably emerge in the next few years.

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

References (142)

PM Stewart et al.
Chapter 15: The adrenal cortex
I Bancos et al.
Diagnosis and management of adrenal insufficiency
Lancet Diabetes Endocrinol
(2015)
D El-Maouche et al.
Congenital adrenal hyperplasia
Lancet
(2017)
O Winqvist et al.
21-Hydroxylase, a major autoantigen in idiopathic Addison's disease
Lancet
(1992)
BE Oftedal et al.
Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases
Immunity
(2015)
JK Abbott et al.
Dominant-negative loss of function arises from a second, more frequent variant within the SAND domain of autoimmune regulator (AIRE)
J Autoimmun
(2018)
J Toubiana et al.
Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
Blood
(2016)
WF Paolo et al.
Adrenal infections
Int J Infect Dis
(2006)
R Krysiak et al.
Autoimmune polyglandular syndrome type 2 induced by treatment with interferon alpha
Am J Med Sci
(2011)
J Bednarek et al.
Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease
FEBS Lett
(1992)

E Bratland et al.

Induction of CXCL10 chemokine in adrenocortical cells by stimulation through toll-like receptor 3

Mol Cell Endocrinol

(2013)

WW Eaton et al.

Epidemiology of autoimmune diseases in Denmark

J Autoimmun

(2007)

AS Olafsson et al.

Increasing prevalence of Addison disease: results from a nationwide study

Endocr Pract

(2016)

JW Tomlinson et al.

Association between premature mortality and hypopituitarism

Lancet

(2001)

B Bleicken et al.

Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients

Am J Med Sci

(2010)

CP Woods et al.

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol

Eur J Endocrinol

(2015)

M Regal et al.

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

Clin Endocrinol (Oxf)

(2001)

MM Erichsen et al.

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

J Clin Endocrinol Metab

(2009)

AB Saevik et al.

Clues for early detection of autoimmune Addison's disease—myths and realities

J Intern Med

(2018)

JK Gjerstad et al.

Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility

Stress

(2018)

K Løvås et al.

Subjective health status in Norwegian patients with Addison's disease

Clin Endocrinol (Oxf)

(2002)

R Bergthorsdottir et al.

Premature mortality in patients with Addison's disease: a population-based study

J Clin Endocrinol Metab

(2006)

SL Lightman et al.

The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration

Nat Rev Neurosci

(2010)

AM Hannon et al.

Clinical features and autoimmune associations in patients presenting with Idiopathic Isolated ACTH deficiency

Clin Endocrinol (Oxf)

(2018)

C Betterle et al.

Addison's disease: a survey on 633 patients in Padova

Eur J Endocrinol

(2013)

F Dalin et al.

Clinical and immunological characteristics of autoimmune Addison disease: a nationwide Swedish multicenter study

J Clin Endocrinol Metab

(2017)

ES Husebye et al.

Autoimmune polyendocrine syndromes

N Engl J Med

(2018)

J Skov et al.

Heritability of Addison's disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins

Endocrine

(2017)

AL Mitchell et al.

Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts

PLoS One

(2014)

AG Myhre et al.

Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features

J Clin Endocrinol Metab

(2002)

Eriksson D, Røyrvik EC, Aranda-Gullien M, et al. GWAS for autoimmune Addison's disease identifies multiple risk loci...

GM Constantine et al.

Lessons from primary immunodeficiencies: autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Immunol Rev

(2019)

Ø Bruserud et al.

A longitudinal follow-up of autoimmune polyendocrine syndrome type 1

J Clin Endocrinol Metab

(2016)

F Cetani et al.

A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis

J Clin Endocrinol Metab

(2001)

PS Sanaker et al.

Clinical evolution of Kearns-Sayre syndrome with polyendocrinopathy and respiratory failure

Acta Neurol Scand Suppl

(2007)

H Song et al.

Association of stress-related disorders with subsequent autoimmune disease

JAMA

(2018)

AC Paepegaey et al.

polyendocrinopathy resulting from pembrolizumab in a patient with a malignant melanoma

J Endocr Soc

(2017)

H Trainer et al.

Hyponatraemia secondary to nivolumab-induced primary adrenal failure

Endocrinol Diabetes Metab Case Rep

(2016)

L Naletto et al.

The natural history of autoimmune Addison's disease from the detection of autoantibodies to development of the disease: a long-term follow-up study on 143 patients

Eur J Endocrinol

(2019)

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)

A Dawoodji et al.

High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients

J Immunol

(2014)

M Rotondi et al.

Elevated serum interferon-gamma-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines

J Clin Endocrinol Metab

(2005)

S Gubbi et al.

Primary hypophysitis and other autoimmune disorders of the sellar and suprasellar regions

Rev Endocr Metab Disord

(2018)

R Barroso-Sousa et al.

Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis

JAMA Oncol

(2018)

RE Bancalari et al.

Pituitary gland development: an update

Endocr Dev

(2012)

LHA Broersen et al.

The incidence of adrenal crisis in the postoperative period of HPA axis insufficiency after surgical treatment for Cushing's syndrome

Eur J Endocrinol

(2019)

DA Heinrich et al.