Seminar

Adrenal insuciency
Eystein S Husebye, Simon H Pearce, Nils P Krone, Olle Kämpe

Adrenal insuciency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deciency, Lancet 2021; 397: 613–29
or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark Published Online
clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and January 20, 2021
https://doi.org/10.1016/
abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insuciency usually develop skin
S0140-6736(21)00136-7
hyperpigmentation and crave salt. Diagnosis of adrenal insuciency is usually delayed because the initial presentation
Department of Clinical Science
is often non-specic; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid and KG Jebsen Center for
replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with Autoimmune Disorders,
primary or secondary adrenal insuciency. Active and repeated patient education on managing adrenal insuciency, University of Bergen, Bergen,
Norway (Prof E S Husebye MD,
including advice on how to increase medication during intercurrent illness, medical or dental procedures, and
Prof O Kämpe MD); Department
profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insuciency of Medicine, Haukeland
after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, University Hospital, Bergen,
and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of Norway (Prof E S Husebye);
Department of Medicine,
glucocorticoid delivery could improve the quality of life in some patients with adrenal insuciency, and further
Karolinska Institutet,
advances in oral and parenteral therapy will probably emerge in the next few years. Stockholm, Sweden
(Prof E S Husebye,
Introduction and numerous other inputs.7 The result of this regulation Prof O Kämpe); Department of
Endocrinology, Translational
Adrenal insuciency is a common condition with multiple is a robust, but adaptable, circadian and ultradian
and Clinical Research Institute,
causes that can be divided into primary (adrenal), secondary (pulsation with a frequency shorter than 24 h) cortisol Newcastle University,
(pituitary), and tertiary (hypothalamus) forms (gure 1). rhythm, characterised by secretory bursts every 60–90 min Newcastle upon Tyne, UK
Each form of adrenal insuciency has distinctive causes (gure 1).10 Aldosterone production is mainly regulated by (Prof S H Pearce MD); Academic
Unit of Child Health,
with implications for treatment and follow-up. Tertiary the renin–angiotensin system (gure 1), but the hypo-
Department of Oncology and
adrenal insuciency caused by exogenous steroid treat- thalamic–pituitary–adrenal axis also causes circadian Metabolism, University of
ment is a common form of adrenal insuciency, and is variation of aldosterone. Sheffield, Sheffield, UK
easily missed due to its non-specic signs and symptoms Primary adrenal insuciency has numerous causes (N P Krone MD); Department of
Medicine III, University
that can be indistinguishable from manifestations of the (table 1). Notably, the most common inherited form of Hospital Carl Gustav Carus,
underlying condition.2 Secondary adrenal insuciency is primary adrenal insuciency is congenital adrenal Technische Universität
rare, and occurs due to defects of pituitary gland function, hyperplasia, which refers to a group of genetic Dresden, Dresden, Germany
which is often caused by pituitary adenomas or by their conditions characterised by decient steroidogenesis. (N P Krone); Center of Molecular
Medicine, and Department of
treatment.3,4 Primary adrenal insuciency occurs less More than 95% of congenital adrenal hyperplasia cases Endocrinology, Metabolism
frequently than secondary or tertiary adrenal insuciency, are caused by recessive mutations in the CYP21A2 gene, and Diabetes, Karolinska
and is caused by intrinsic adrenal gland pathology; which codes for steroid 21-hydroxylase, a key enzyme University Hospital,
commonly destructive autoimmunity or inborn error of in cortisol and aldosterone biosynthesis (appendix p 1). Stockholm, Sweden
(Prof O Kämpe)
steroidogenesis. A comprehensive review of congenital adrenal hyper-
Correspondence to:
Adrenal insuciency can manifest at any age, but plasia has already been published as a Seminar in Prof Eystein S Husebye,
often presents between the ages of 20 years and The Lancet;11 therefore, this condition will not be Department of Clinical
50 years. Despite substantial advances in diagnostics and discussed further in the current Seminar. Acquired Science, University of Bergen,
treatment over the past few decades, clinicians struggle primary adrenal insuciency is typically caused by N-5021 Bergen, Norway
eyhu@helse-bergen.no
to make a timely diagnosis before the occurrence of autoimmunity, infections, haemorrhage, metastases,
See Online for appendix
life-threatening complications or death.5–7 State-of-the- or bilateral adrenalectomy (table 1). Secondary adrenal
art diagnostic tests and treatment modalities are still insuciency (table 2) presents in two major forms;
unavailable in many parts of the world, and treatment either as one component of pituitary insuciency as
and follow-up is not optimal. This observation is reected an isolated defect in adrenocorticotropic hormone
in the associated increased mortality and reduced quality (ACTH) secretion or as deciency of ACTH and other
of life and working capacity.8,9 This Seminar seeks to pituitary hormones in combination.12 Finally, tertiary
enable clinicians to make an early and correct diagnosis, adrenal insuciency (table 3) is most commonly a
and to treat and follow up patients in an optimal way so consequence of pharmacological treatment with gluco-
that complications and ill health is minimised. corticoids or illicit use of opiates.

Pathophysiology and genetics Autoimmune primary adrenal insuciency

Overview Autoimmune primary adrenal insuciency is char-
Adrenal steroid secretion is tightly regulated at multiple acterised by autoimmune destruction of the adrenal
levels (gure 1). The hypothalamic–pituitary–adrenal axis cortex, with the immune system targeting 21-hydroxy-
regulates cortisol production in response to light, stress, lase.13 The condition can present at any age, but most

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 Seminar

A Regulation of cortisol secretion B Regulation of aldosterone secretion

Diurnal rhythm Renal arterial pressure
β-adrenergic action
Prostaglandins ANP
Dopamine
Stressors
Hypothalamus
(hypoglycaemia,
hypotension, fever,
trauma, or surgery) Extracellular volume
CRH ADH Renin Renal aterial pressure
Cytokines Na+ (and water) retention
Liver K+ excretion
Kidneys
Pituitary

Aldosterone ECF [K+]

ACTH Angiotensinogen

Adrenals
Adrenals
Angiotensin I
Cortisol
Lungs

Metabolism Cardiovascular system

Gluconeogenesis Myocardial contractility
Glycogenolysis Cardiac output ACE
Proteolysis Catecholamine pressor effect
Lipolysis Angiotensin II

C Cortisol D Aldosterone
15
15

10
10
nmol/L

pmol/L

5
5

0 0
2 5 8 11 14 17 20 23 2 5 8 11 14 17 20 23
Time of day (hours) Time of day (hours)

Figure 1: Regulation of cortisol and aldosterone secretion

Main hormones of the pathways are shown in red. (A) Regulation of cortisol secretion. Hypothalamic CRH stimulates pituitary ACTH secretion, which stimulates
cortisol production in the adrenal cortex. Cortisol shows negative feedback regulation of ACTH and CRH secretion (adapted from Melmed S et al,1 by permission of
Saunders). (B) Circadian regulation of aldosterone secretion by the renin and angiotensin system. ACTH has a minor stimulatory role (adapted from Melmed S et al,1
by permission of Saunders). (C) Circadian and pulsatile variation in free cortisol concentration in microdialysate obtained from subcutaneous tissue in a healthy
individual (Methlie P, unpublished). (D) Circadian and pulsatile variation in free aldosterone concentration in microdialysate obtained from subcutaneous tissue in a
healthy individual (Methlie P, unpublished). ACE=angiotensin-converting enzyme. ACTH=adrenocorticotropic hormone. ADH=antidiuretic hormone.
CRH=corticotropin-releasing hormone. ECF=extracellular uid.

individuals are diagnosed between the ages of 20 years
and 50 years, with a slight preponderance in women.5,14,15
Autoimmune primary adrenal insuciency can be
isolated in up to 40% of patients with autoimmune
primary adrenal insuciency or can appear in combi-
nation with one or more organ-specic autoimmune
endocrinopathies, such as autoimmune thyroid disease,
type 1 diabetes, and premature ovarian insuciency
(appendix p 2). Other organ-specic autoimmune dis-
eases frequently occur in combination with primary
adrenal insuciency, including autoimmune gastritis
with pernicious anaemia, coeliac disease, vitiligo, or
alopecia. All of these combinations can be classied as
autoimmune polyendocrine syndrome type 2.16
Heritability of autoimmune primary adrenal insuf-
ciency is high, and similar to that of coeliac disease.17
Numerous genetic variants contribute to the susceptibility
of autoimmune primary adrenal insuciency, mostly
in genes expressed in immune cells and inammatory
cells, many of which are shared by other autoimmune

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 Seminar

Gene (OMIM*) Associated clinical signs and symptoms

Adrenal destruction
Autoimmunity
Autoimmune primary
adrenal insuciency and
autoimmune polyendocrine
syndrome type 2
Autoimmune polyendocrine
syndrome type 1
Immunodeciency 31C
Peroxisomal defects
X-linked
adrenoleukodystrophy
Refsum disease
Neonatal
adrenoleukodystrophy
(autosomal recessive)
Zellweger syndrome
Mitochondrial defects
Kearns-Sayre syndrome
Haemorrhage
Trauma or surgery
Infection
Inltration
Drugs
Impaired steroidogenesis
Impaired cholesterol transport
Steroidogenic acute
regulatory protein
(congenital lipoid adrenal
hyperplasia)
Steroidogenic enzyme or cofactor deciency causing congenital adrenal hyperplasia
3β-hydroxysteroid
dehydrogenase type 2
21-hydroxylase
11β-hydroxylase
CYP17A1 deciency
P450 oxidoreductase
HLA-DR3, DR4, CTLA4, BACH2, Hypothyroidism, hyperthyroidism, premature ovarian insuciency, vitiligo, type 1
PTPN22, GATA3, CLEC16, MIC-A, diabetes, pernicious anaemia, and other organ-specic autoimmune features
MIC-B, NALP1, and AIRE
AIRE (240300) Hypoparathyroidism, chronic mucocutaneous candidiasis, other autoimmune
disorders, and rarely lymphomas
STAT1 (614162) Chronic mucocutaneous candidiasis, susceptibility to Staphylococcus aureus and other
bacterial, viral and fungal infections, and polyendocrinopathy (including
hypothyroidism and type 1 diabetes), and cerebral aneurysms
ABCD1 (300100) Progressive neurodegeneration, behavioural changes, cognitive decline, loss of
speech, hearing and vision, dementia, spasticity, and seizures
PEX7 (266500) Least severe form of peroxisome biosynthesis defects
PEX1 (601539) Craniofacial abnormalities and liver dysfunction; the absence of peroxisomes
PEX1 (214100) Craniofacial abnormalities, hepatomegaly, severe intellectual disability and growth
failure, hypotonia, deafness, blindness, genitourinary abnormalities, and stippled
epiphyses
Mitochondrial DNA deletions External ophthalmoplegia, retinal degeneration, and cardiac conduction defects;
(530000) other endocrinopathies
·· Bilateral adrenal haemorrhage of the newborn baby, primary antiphospholipid
syndrome, and anticoagulation
·· Bilateral adrenalectomy
·· Septic shock, meningococcal sepsis (Waterhouse-Friderichsen syndrome),
tuberculosis, fungal infections (eg, histoplasmosis, cryptococcosis,
coccidioidomycosis, and blastomycosis), cytomegalovirus, HIV-1, and syphilis
·· Metastatic cancers, primary adrenal lymphoma, amyloidosis, sarcoidosis, and
haemochromatosis
·· Ketoconazole, rifampicin, phenytoin, phenobarbital, aminoglutethimide, mitotane,
abiraterone acetate, etomidate, suramine, mifepristone, nivolumab, and
pembrolizumab
StAR (201710) 46,XY DSD and gonadal insuciency
HSD3B2 (201810) 46,XX and 46,XY DSD and gonadal insuciency
CYP21A2 (201 910) 46,XX DSD and hyperandrogenism
CYP11B1 (202 010) 46,XX DSD and arterial hypertension
CYP17A1 (202 110) 46,XY DSD, arterial hypertension, and gonadal insuciency
POR (201 750) 46,XX and 46,XY DSD, gonadal insuciency, bone malformation, and causes
dysfunction of all endoplasmic CYP450 enzymes
(Table 1 continues on next page)

diseases (appendix p 3).18 The strongest association for
autoimmune primary adrenal insuciency involves
MHC, particularly MHC class II genotypes. The
combination of DR3–DQ2 and DR4–DQ8 gives an
increased (30 times over) risk of developing auto-
immune primary adrenal insuciency.19 A number of
other genetic associations with autoimmune primary
adrenal insuciency have been reported, including
alleles of CTLA4, PTPN22, BACH2, GATA3, CLEC16,
MIC-A, MIC-B, and NALP1, none of which are specic
for autoimmune primary adrenal insuciency. A
possible exception is the autoimmune regulator (AIRE).20
A recent genome-wide association study showed a
strong association to a coding variant (Arg471Cys) located
in the PHD2 domain.20 Notably, mutations in AIRE
cause autoimmune polyendocrine syndrome type 1, a

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Gene (OMIM*) Associated clinical signs and symptoms

(Continued from previous page)
Steroidogenic enzyme deciency (non-congenital adrenal hyperplasia)
P450 side-chain cleavage
enzyme
Aldosterone synthase
Defects of cholesterol synthesis or metabolism
Wolman disease (lysosomal
acid lipase deciency, and
cholesterol ester storage
disease)
Smith-Lemli-Opitz disease
Abetalipoproteinaemia
Adrenal dysgenesis
X-linked adrenal hypoplasia
congenital
Adrenal hypoplasia
steroidogenic factor-1
deciency
IMAGe syndrome
MIRAGE syndrome
Pallister-Hall syndrome
Meckel syndrome
Pseudotrisomy 13
Hydrolethalus syndrome
Galloway-Mowat syndrome
ACTH resistance
Familial glucocorticoid
deciency type 1
Familial glucocorticoid
deciency type 2
Impaired redox homoeostasis
Triple A syndrome (Allgrove
syndrome)
Mitochondrial deciency of free NNT (614736) and TRXR2 (606448) NNT: hypoglycaemia, hyperpigmentation, a low cortisol concentration, increased
radical detoxication
Miscellaneous
Defects in DNA repair
Bioinactive ACTH
Sphingosine-1-phosphate
lyase 1
ACTH=adrenocorticotropic hormone. DSD=disorder of sex development. OMIM=Online Mendelian Inheritance in Man. *www.omim.org.
CYP11A1 (118 485) 46,XY DSD and gonadal insuciency
CYP11B2 (124 080) Isolated mineralocorticoid deciency
LIPA (278 000) Diuse punctate adrenal calcication, xanthomatous changes in multiple organs,
hypercholesterolaemia, steatorrhea, and poor prognosis
DHCR7 (270 400) Intellectual disability, craniofacial malformations, limb abnormalities, and growth
failure
MTP (200 100) Ataxia, retinopathy, acanthocytosis, and fat malabsorption
NROB1 (300 200) Combined primary and secondary hypogonadism, and Duchenne muscular
dystrophy in contiguous gene syndrome
NR5A1 (184757) 46,XY DSD and gonadal insuciency
CDKN1C (300 290) Intrauterine growth restriction, metaphyseal dysplasia, adrenal insuciency, and
genital anomalies (IMAGe)
SMAD9 (617 053) Myelodysplasia, infection, adrenal hypoplasia, growth restriction, genital anomalies,
and enteropathy (MIRAGE)
GLI3 (165 240) Hypothalamic hemartoblastoma, hypopituitarism, imperforate anus, and postaxial
polydactyly
MKS1 (249 000) CNS malformation, polycystic kidneys with brotic liver changes, and polydactyly
(264 480) Holoprosencephaly, severe facial anomalies, postaxial polydactyly, various other
congenital defects, and normal chromosomes
HYLS1 (236 680) Severe prenatal onset hydrocephalus and polydactyly
WDR73 (251 300) Early-onset severe encephalopathy, intractable epilepsy, nephrotic syndrome,
microcephaly, and hiatal hernia
MC2R (202 200) Tall stature, isolated deciency of glucocorticoids, and generally normal aldosterone
production
MRAP (607398) Isolated deciency of glucocorticoids and generally normal aldosterone production
AAAS (231550) Alacrimia and achalasia; neurological impairment, deafness, intellectual disability,
and hyperkeratosis
ACTH concentration, and isolated deciency of glucocorticoids; TRXR2: isolated
deciency of glucocorticoids
MCM4 (609981) Natural killer cell deciency, growth failure, and increased chromosomal breakage
POMC (201400) ··
SGPL1 (617575) Steroid-resistant nephrotic syndrome, ichthyosis, primary hypothyroidism,
cryptorchidism, and immunodeciency and neurological defects

Table 1: Causes of primary adrenal insuciency

monogenic disease that is characterised by primary
adrenal insuciency with onset during childhood or
adolescence (2–20 years of age) in combination with
hypoparathyroidism and chronic mucocutaneous can-
didiasis.16 Patients with autoimmune polyendocrine
syndrome type 1 present with a number of other
autoimmune organ-specic manifestations, including
premature ovarian insuciency (before puberty, but
typically before the age of 30 years), severe alopecia and
vitiligo, autoimmune gastritis, hepatitis and pneumonitis,
fever with rash, keratitis, and pitted nail dystrophy.21
Enamel hypoplasia of the permanent teeth is among the
most common manifestation of autoimmune polyen-
docrine syndrome type 1, and is a clinical indication to

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Gene Associated clinical signs and Gene Associated clinical signs and
(OMIM*) symptoms (OMIM*) symptoms

Acquired causes Acquired causes

Steroid withdrawal PDGFD Endogenous glucocorticoid
syndrome hypersecretion due to Cushing’s
syndrome, and exogenous
glucocorticoid administration
for more than 2 weeks
Steroid withdrawal PDGFD Endogenous glucocorticoid
syndrome hypersecretion due to Cushing’s
syndrome, and exogenous
glucocorticoid administration
for more than 2 weeks

Opioids ·· Hyopgonadotropic Opioids ·· Hyopgonadotropic

hypogonadism hypogonadism

Tumour ·· Craniopharyngioma, glioma, Inammatory ·· Abscess, meningitis, and

meningioma, ependymoma, disorders encephalitis
germinoma, and intrasellar or Trauma ·· ··
suprasellar metastases, Radiation therapy ·· Craniospinal irradiation in
adenoma, and carcinoma leukaemia and irradiation for
Trauma ·· Pituitary stalk lesions, battered tumours outside the
child syndrome, and vehicular hypothalamic-pituitary area
trauma Surgery ·· ··
Pituitary apoplexy ·· High blood loss or hypotension Tumour ·· Craniopharyngioma, glioma,
(Sheehan’s syndrome) meningioma, ependymoma,
Congenital causes germinoma, and intrasellar or
Aplasia or hypoplasia suprasellar metastases

PROP1 deciency PROP1 Additional deciency of growth Inltrative diseases ·· Sarcoidosis, histiocytosis X,
(262600) hormone, prolactin, thyroid- and haemochromatosis
stimulating hormone, and Congenital causes
luteinising hormone or follicle Septo-optic dysplasia HESX1 Combined pituitary hormone
stimulating hormone, or both (de Morsier Syndrome) (182230) deciency, optic-nerve
LHX4 deciency LHX4 Additional deciency of growth hypoplasia, and midline brain
(262700) hormone, and thyroid- defects
stimulating hormone Corticotropin- ·· ··
SOX3 deciency SOX3 Additional deciencies of releasing hormone
(312000) pituitary hormones deciency
Isolated ACTH deciency
OMIM=Online Mendelian Inheritance in Man. *www.omim.org.
TBX19 deciency TBX19 Severe neonatal-onset adrenal
(201400) insuciency Table 3: Causes of tertiary adrenal insuciency
Proopiomelanocortin POMC Adrenal insuciency, early-
(609734) onset obesity, and red hair
pigmentation therapeutic agents (eg, interferon alfa,30 pembrolizumab,31
Proprotein PCSK1 Hypoglycaemia, malabsorption, and nivolumab32) have been implicated. The rst sign of
convertase 1 (600955) and hypogonadotropic
an ongoing adrenalitis is the presence of autoantibodies
hypogonadism
against 21-hydroxylase.13,33 Prospective follow-up indicated
ACTH=adrenocorticotropic hormone. OMIM=Online Mendelian Inheritance in Man.
that 28 (25%) of 114 individuals developed overt adrenal
*www.omim.org.
insuciency during a follow-up of 10 years.34 However,
Table 2: Causes of secondary adrenal insuciency in the form of the main eectors are cytotoxic CD8 T cells and helper
pituitary disorders CD4 T cells with reactivities against 21-hydroxylase35,36
that are thought to inltrate and adversely aect the
the diagnosis.22 Although most frequently indicated as adrenal cortex. Adrenocortical cells might be involved in
an autosomal recessive disease, several reports show their own demise by secreting CXCL10, a chemokine that
that dominant inheritance occurs when mutations are attracts T cells.37 Secretion of CXCL10 can be induced
located in certain domains (PHD1 and SAND).23–25 This by a viral infection by way of activating TLR3,38 which
non-classic (and often milder) form of autoimmune provides a tentative mechanism for how viruses can
polyendocrine syndrome type 1 can have autoimmune trigger severe autoimmune reactions.
adrenal insuciency as one of its components and might
show familial aggregation. Other rare causes of mono- Secondary adrenal insuciency
genic autoimmune disease involve mutations in STAT126 The most common cause of secondary adrenal insuf-
and mitochondrial DNA (Kearns-Sayre syndrome).27 ciency is a tumour in the pituitary gland or its
It is assumed that one or more environmental triggers immediate surroundings, with the associated ACTH
start an autoimmune cascade, which can lead to adrenal deciency caused by the tumour itself or its treatment
insuciency in a genetically susceptible individual. The (eg, surgery or radiation therapy). Craniopharyngiomas,
nature of these triggers is largely unknown, but stress- meningiomas, and other intrasellar tumours can also
related mental health disorders,28 viral infections,29 and present with secondary adrenal insuciency. Adrenal

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 Seminar
CAH
ACH
Genetic
X-ALD
APS-1
Autoimmune
Acquired
Haemorrhage
Tumour
0 20 40 60 80
Age (years)
Figure 2: Spectrum of adrenal disorders at dierent ages
Prevalence at dierent ages of the main causes of adrenal insuciency. Genetic
diseases usually appear in childhood but can have delayed onset. CAH and AHC
are usually diagnosed in the neonatal period, but milder cases appear later.
Primary adrenal insuciency in childhood could be a manifestation of APS-1.
Autoimmune primary adrenal insuciency and autoimmune polyendocrine
syndrome type 2 typically occur after puberty, specically between the ages of
20 years and 50 years. Milder forms of X-ALD develop into adrenal insuciency
in adolescence and adulthood. Haemorrhage and tumours appear most
commonly in older aged individuals. Pituitary tumours can appear at all ages.
AHC=adrenal hypoplasia congenital. APS-1=autoimmune polyendocrine
syndrome type 1. CAH=congenital adrenal hyperplasia.
X-ALD=adrenoleukodystrophy.
insuciency presents with variable combinations of
other pituitary hormone deciencies, including thyroid
stimulating hormone, growth hormone, luteinising
hormone or follicle stimulating hormone. Diabetes
insipidus does not occur spontaneously in pituitary
adenoma and its presence suggests craniopharyngioma,
meningioma, lymphoma, or metastases.
Trauma, pituitary apoplexy in an adenoma, or infarction
caused by post-partum blood loss and hypotension (post-
partum pituitary gland necrosis) are less common causes
of secondary adrenal insuciency than pituitary tumours
and their treatments. Hypophysitis is a rare condition
that occurs in various forms, and is often related to
pregnancy. Functionally, isolated ACTH deciency or
deciencies of multiple pituitary hormones will occur.39
Hypophysitis has become a more frequently observed
adverse event of immune checkpoint inhibitors.40
Around 3% of individuals treated with ipilimumab
develop hypophysitis, which often presents with
headache and hyponatraemia.40
Numerous rare mutations in transcription factors,
hormone-coding genes, and their receptors result in
secondary adrenal insuciency alone or in combination
with other hormonal defects (table 2).41 Transient or
permanent secondary adrenal insuciency is also
regularly noted after treatment of ACTH-dependent
and ACTH-independent forms of Cushing’s syndrome.42
However, it is less known that a third of patients treated
with unilateral adrenalectomy for an aldosterone-
producing adenoma develop secondary adrenal insuf-
ciency postoperatively, probably due to concomitant
autonomous cortisol secretion.43
618
Epidemiology
Primary adrenal insuciency is rare; the highest
prevalence has been reported in Nordic countries at
15–22 individuals per 100 000.44–46 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
insucient from countries with high incidences of
tuberculosis and HIV infections.
Secondary adrenal insuciency is reported in about
14–28 individuals per 100 000 according to the numbers
from Spain4 and the UK,50 representing a mixture of
isolated ACTH insuciency and ACTH insuciency in
combination with other pituitary hormone deciencies.
Around 1% of the population from the UK and the USA
are treated with glucocorticoids for inammatory or
immune-mediated conditions.51,52 Daily use of 5 mg or
more of prednisolone for longer than 3 weeks might lead
to tertiary adrenal insuciency in relation to dose and
duration, on account of the resultant ACTH deciency.
Opiates can also suppress ACTH release and lead to
functional adrenal failure, which is noted in 10–20% of
individuals using daily morphine-equivalent doses of
100 mg or more.53,54
Clinical presentation
Primary adrenal insuciency
Genetic conditions are the most common cause of primary
adrenal insuciency 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 (gure 2). Adrenoleuko-
dystrophy and congenital adrenal hypoplasia are linked to
the X chromosome and only aect boys. An increasing
number of other rare genetic syndromes with or without
associated multisystem problems have been dened over
the past decade (table 1). Most genetic defects can also
present later in life with mild or atypical disease. In
autoimmune polyendocrine syndrome type 1, autoimmune
primary adrenal insuciency presents from about the age
of 3 years or older.55 Most of these patients will exhibit
autoantibodies against 21-hydroxylase, and interferon alfa
or interferon omega.16 After puberty, autoimmunity is the
main cause of primary adrenal insuciency in Europe
and North America. In other parts of the world, infections
have a larger role, especially tuberculosis, but few surveys
have been reported.49,56 In individuals aged 20 years or
older, haemorrhage due to anticoagulant therapy, trauma
or antiphospholipid syndrome, primary tumours (eg,
lymphoma) or metastases, or inltrative diseases (eg,
haemochromatosis, Erdheim-Chester disease, and amy-
loidosis) causes primary adrenal insuciency57 (gure 2,
table 1). Other causative infectious agents include HIV,58,59
Treponema pallidum,60 Cryptococcus spp, and histoplas-
mosis.61 Despite treatment, adrenal insuciency after
infections is often irreversible.61
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Autoimmune primary adrenal insuciency typically
has an insidious start, with symptoms such as decreased
appetite and unintentional weight loss, nausea, and
pain in the abdomen, joints, and muscles. Fatigue and
lethargy are prominent. Due to salt loss through the
urine and the ensuing reduction in blood volume, blood
pressure decreases and orthostatic hypotension develops
together with salt craving. Glucocorticoid deciency can
sometimes lead to severe hypoglycaemia, especially in
children.6 The most distinctive feature of autoimmune
primary adrenal insuciency is increased pigmentation
of the skin and mucous membranes, especially on areas
subject to sun exposure and friction, such as the
knuckles, creases in the hand, and elbows (gure 3). The
increased pigmentation is caused by high concentra-
tions of circulating ACTH, which stimulate dermal
melanocortin receptors.
Symptoms progress over the course of months,
sometimes even years. Unfortunately, many patients
with adrenal insuciency are not diagnosed before a
life-threatening adrenal crisis develops.6 It is particularly
hazardous for a young woman with unexplained weight
loss to be presumed to have a primary eating disorder,
without due consideration of a physical cause for weight
loss. The number of deaths due to undiagnosed adrenal
insuciency is unknown.
Many patients with primary adrenal insuciency
have associated conditions suggestive of the diagnosis
and cause (table 1, appendix p 2).5,15 Autoimmune thyroid
disease, both Hashimoto thyroiditis and Graves’ disease,
occurs in 50% of patients with primary adrenal insuf-
ciency; type 1 diabetes is present in 10–15% of such
patients in Scandinavian countries but is less frequent
elsewhere. Coeliac disease is present in about 5% of
patients with primary adrenal insuciency, and auto-
immune gastritis with vitamin B12 deciency occurs in
around 10% of those patients. Women with primary
adrenal insuciency are at risk of primary ovarian
insuciency that can appear as early as the teenage years
(but usually in their twenties or thirties); overall, this
disorder is present in about 10% of patients with primary
adrenal insuciency.5,15 In contrast to other forms,
individuals with primary ovarian insuciency caused by
autoimmunity initially seem to retain some follicular
reserve, which is reected in a normal concentration
of anti-müllerian hormone.62 Numerous pregnancies have
been reported, even after several years of amenorrhoea.63
By contrast, hypogonadism in male individuals is rare.
If present, a mild variant of adrenoleukodystrophy
should be considered in male individuals who test
negative for 21-hydroxylase autoantibodies. Alternatively,
hypogonadism might be owing to late-onset congenital
adrenal hypoplasia or other non-classic steroidogenic
enzyme deciencies (table 1). The presence of hypo-
parathyroidism or candida infections should prompt
investigation for autoimmune polyendocrine syndrome
type 1 (gure 4).64,65
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Seminar
A B
Figure 3: Black and white autoimmunity of the skin
A patient with autoimmune primary adrenal insuciency showing the typical hyperpigmentation of the skin and
vitiligo with patchy hypopigmentation on the back and arms (A) and hands (B).
Data from national registries indicate an approximate
doubling of mortality rate in patients with primary
adrenocortical insuciency.9,66 Some of the excess
mortality is related to acute adrenal crises, especially
among male individuals younger than 30 years,67 and is
associated with concomitant diseases (eg, diabetes). In a
2017 study,68 patients with primary adrenal insuciency
and diabetes had an almost four times increased
mortality rate compared with patients with diabetes
alone. Another major cause of death in individuals
with primary adrenal insuciency is cardiovascular dis-
ease,9,66,69 especially in women, and this nding is linked
to high doses of corticosteroid replacement therapy.69
Scrutiny of prescription databases indicates an overuse
of lipid-lowering and antimicrobial drugs before and
after diagnosis of primary adrenal insuciency, and
antihypertensives after diagnosis of primary adrenal
insuciency.70,71 This nding supports those of increased
frequencies of hypertension, diabetes, and hospital
admission for infectious diseases based on data from a
health insurance database.72
Other possible complications associated with primary
adrenal insuciency are osteoporosis and fractures.
Several studies have shown low bone mineral density in
individuals with primary adrenal insuciency, especially
in those treated with synthetic steroids.73 Low bone
mineral density might manifest as established spinal
osteoporosis with vertebral body deformity and fracture,
despite relatively preserved hip bone mineral density.74
Likewise, the risk of hip fracture is increased in indivi-
duals with primary adrenal insuciency. Curiously, the
highest risk of hip fracture was within the time period of
619
 Seminar

Adrenal insufficiency?

Confirm abnormally low cortisol

concentration (basal or stimulated,
or both)

Tertiary adrenal
Yes Concurrent or recent steroid use?
insufficiency

No

Primary adrenal Secondary adrenal

Yes High ACTH? No
insufficiency insufficiency

21-hydroxylase CT adrenal glands MRI pituitary Measure anterior

No
autoantibodies? pituitary hormones

Yes Normal Enlarged Abnormal Normal Abnormal

Serum VLCFA Steroid profile

Genetic test

Autoimmune Adrenoleuko- CAH, tumour Infiltrative tumour Isolated Combined pituitary

primary adrenal dystrophy, metastasis, or apoplexy ACTH-deficiency hormone deficiency
insufficiency genetic disorder or tuberculosis

Unusual phenotype,
young age, positive
for IFN autoantibody

Yes APS-1

Figure 4: Algorithm for the diagnosis of suspected adrenal insuciency in adults

Unusual phenotype could include hypocalcaemia, chronic mucocutaneous candidiasis, keratitis, abnormal ngernails or teeth, alopecia, failure to thrive, fever with
rash, or malabsorption. ACTH=adrenocorticotropic hormone. APS-1=autoimmune polyendocrine syndrome type 1. CAH=congenital adrenal hyperplasia.
IFN=interferon. VLCFA=very long-chain fatty acids.

primary adrenal insuciency diagnosis, which indicates
that factors other than replacement therapy have an
important role in hip fractures.75 If over-replacement with
glucocorticoids is avoided, bone mineral density is often
minimally aected, but periodic bone mineral density
measurement is recommended in all patients with
primary adrenal insuciency.76,77
Health-related quality of life was rst systematically
examined in patients with primary adrenal insuciency
by Løvås and colleagues in 2002;8 the study showed that
general health and vitality in these patients was reduced.
These results have been replicated in a number of
cohorts in dierent European countries,78,79 which also
used the adrenal insuciency-specic questionnaire,
AddiQoL.80,81 Reduced health-related quality of life results
in reduced employability, indicated by a high proportion
of patients with primary adrenal insuciency on sick-
ness pensions.5 Health-related quality of life is also
reduced in patients with secondary adrenal insuciency,
but the eect of adrenal insuciency is dicult to
discern from the eect of other hormone deciencies
that are often present in these patients. Reduced
health-related quality of life is commonly assumed, but
not proven, to be caused by the inability of standard
replacement therapy to mimic the circadian and ultradian
rhythmicity of cortisol.82
Acute adrenal crisis is a life-threatening emergency
that requires immediate diagnosis and treatment. The
frequencies among patients with primary or secondary
adrenal insuciency are in the range of three to 11
per 100 person-years,83–85 even in those patients who
have received patient education from clinicians about
managing adrenal insuciency.86 Gastroenteritis or food
poisoning are the most frequent causes of adrenal crisis,
followed by infections, surgical and dental procedures,
injuries, myocardial infarction, allergic reactions, severe
hypoglycaemia in patients with diabetes, severe psycho-
logical stress, and treatment abstention in patients who

620 www.thelancet.com Vol 397 February 13, 2021


are poorly educated in managing adrenal insuciency
or not compliant.
Symptoms of acute adrenal crisis are profound malaise,
fatigue, nausea, vomiting, abdominal pain (sometimes
with peritoneal irritation), headache, muscle pain or
cramps, and dehydration, which lead to hypotension and
shock. Impaired cognitive function, including confusion,
loss of consciousness, and coma, is common during
adrenal crisis. Hyponatraemia, hyperkalaemia, and
increased concentrations of creatinine caused by prerenal
failure, hypoglycaemia (especially in children), and some-
times mild hypercalcaemia is typical during adrenal
crisis. Severely ill patients might present with normal
serum potassium and sodium, due to intense vomiting
with loss of potassium and dehydration.
Secondary and tertiary adrenal insuciency
Secondary adrenal insuciency is usually milder than
primary adrenal insuciency in the sense that
mineralocorticoid production is intact and adrenal
insuciency is partial. However, hormone deciencies
other than ACTH can inuence and even dominate
the clinical picture. A study from the UK reported a
standardised mortality ratio of 1·87 related to cardio-
vascular, cerebrovascular, and respiratory diseases,
whereas data from the KIMS registry (Pzer International
Metabolic Database) showed a lower, but still signicantly
increased, standardised mortality ratio of 1·13 in
individuals with growth hormone deciency.50,87 The
standardised mortality ratio was higher in patients with
non-functioning pituitary adenoma requiring more
than 20 mg hydrocortisone per day than in those patients
that required 20 mg daily or no hydrocortisone,88 sug-
gesting a possible role of glucocorticoid over-replacement
in mortality.
Adrenal insuciency secondary to steroid treatment
is a heterogeneous group of conditions, because many
individuals with this type of secondary adrenal insuf-
ciency paradoxically have Cushingoid features as a
consequence of pharmacological steroid treatment.2
Concomitant administration of drugs that inhibit
glucocorticoid metabolism (eg, ritonavir and itraconazole)
can lead to profound adrenal suppression, even with use
of local and topical steroids. Gradual steroid withdrawal
over several months allows many individuals to regain
adrenal function. The standard cosyntropin (ACTH1–24)
stimulation test can be used to assess the chance of
hypothalamic–pituitary–adrenal axis recovery.89
Diagnosis
Evaluation of adrenocortical function
The primary challenge in evaluating adrenocortical
function is for clinicians to be constantly vigilant for
adrenal insuciency. Once suspected, it is usually easy
to clinically conrm or refute the clinical suspicion.
A survey indicated that hyponatraemia was present
in 207 (84%) of 247 individuals with undiagnosed
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Seminar
adrenal insuciency,6 thyroid stimulating hormone was
increased in 79 (52%) of 153 individuals, and hyper-
kalaemia was present in 82 (34%) of 242 individuals.6
Thus, unexplained hyponatraemia should always trigger
the consideration of adrenal insuciency.
Once adrenal insuciency is suspected, adrenocortical
function should be assessed (gure 4). In many cases, a
paired assay of serum cortisol and ACTH indicating low
cortisol concentration (often less than 100 nmol/L) and
an ACTH concentration double the upper reference
limit is sucient to diagnose adrenal insuciency.
Furthermore, low aldosterone and high renin concentra-
tions or high plasma renin activity and low dehydroepi-
androsterone sulphate concentrations are also helpful
indications of adrenal insuciency.77 In secondary
and tertiary adrenal insuciency, a morning cortisol
concentration of less than 83 nmol/L is considered
diagnostic; however, concentrations between 83 nmol/L
and 400 nmol/L should prompt cosyntropin stimulation
testing.90 We recommend the standard 250 µg test,
measuring cortisol samples at 30 min and 60 min. Serum
cortisol concentrations of 412 nmol/L at 30 min and
485 nmol/L at 60 min are dened as the lower limits of
a normal response with liquid chromatography tandem
mass spectrometry.91 Many individuals who did not
reach the threshold at 30 min will do so at 60 min.91
Thus, we recommend testing at 30 min and 60 min after
cosyntropin administration to avoid overdiagnosis of
adrenal insuciency. When relying on immunoassays,
500 nmol/L of cortisol is often used as the threshold.
A potential pitfall is pregnancy and oral oestrogen
treatment, which can lead to increased corticosteroid-
binding globulin concentrations and subsequently
mask adrenal insuciency. Conversely, a number of
conditions, including inammation, sepsis, cirrhosis,
and polymorphisms in the SERPINA6 gene encoding
corticosteroid-binding globulin, reduce the concentration
of corticosteroid-binding globulin.92
Causative diagnosis
Once adrenal insuciency is diagnosed, it is mandatory
to determine the cause (gure 4). In cases of acquired
primary adrenal insuciency, clinicians recommend
to test for 21-hydroxylase autoantibodies,13,77 which are
commercially available.93 If positive, the diagnosis of
autoimmune primary adrenal insuciency is estab-
lished. Autoantibody assay by immunouorescence is
less sensitive and less specic than the 21-hydroxylase
autoantibody assay, and not standardised. Patients
should be screened for related conditions, such as
autoimmune thyroid disease, type 1 diabetes, coeliac
disease, and autoimmune gastritis, at diagnosis and
annual follow-ups (appendix p 3).77 In patients younger
than 20 years, autoimmune polyendocrine syndrome
type 1 should always be considered.65 Steroid side-chain
cleavage enzyme autoantibodies are associated with
autoimmune premature ovarian insuciency, and the
621
 Seminar
presence of these autoantibodies might indicate a risk
of developing ovarian insuciency.94
If autoantibodies against 21-hydroxylase are absent,
a broader diagnostic approach can be used, guided by
the clinical presentation (gure 4). CT imaging is useful
to diagnose infections, tumours, and bleeding, each
of which have specic imaging features. All male
individuals should have their serum tested for very
long-chain fatty acids to diagnose adrenoleukodys-
trophy or adrenomyeloneuropathy, which are caused by
defects in the ABCD1 gene. Conditions with clear
clinical phenotypes, such as X-linked congenital adrenal
hypoplasia due to NR0B1 mutations, triple A syndrome
(with achalasia and alacrimia),95 and Kearns-Sayre
syndrome (with ophthalmoplegia and myopathy),27 can
be diagnosed by sequencing the relevant genes.
However, because genetic changes can present with
overlapping phenotypes,96 next-generation sequencing
panels, or even whole-genome sequencing, are
increasingly used.
If secondary adrenal insuciency is diagnosed, the
status of other pituitary hormones must be assessed
together with MRI of the pituitary region, to detect the
presence of a tumour or other inltrative processes
(eg, lymphocytic hypophysitis or granulomatous inl-
tration). Isolated ACTH deciency is a diagnosis of
exclusion, and all patients will require an MRI. In
children, it is important to consider the many genetic
causes (eg, PROP1 deciency) and other conditions often
associated with multiple pituitary hormone deciency
(table 2).
For drug-induced adrenal insuciency, not all cases
will be immediately apparent, and a detailed history
must be taken, including use of dermal, inhaled, and
injected steroids. Additionally, opiates are the second
most common drugs to cause adrenal insuciency, and
clinicians need to be alert that recreational opioid users
are unlikely to be accessing these drugs on prescription.
Treatment
Patients with primary adrenal insuciency are decient
in glucocorticoids and mineralocorticoids and require
replacement of both, together with salt intake as needed.
By contrast, individuals with ACTH deciency due to
pituitary or hypothalamic dysfunction after exogenous
steroid use usually require only glucocorticoid replace-
ment. Patients with primary adrenal insuciency and
patients with ACTH deciency also have androgen
deciency, but the benets of androgen replacement are
less clearly dened.97–99
Glucocorticoid replacement
Glucocorticoids are secreted into the systemic
circulation in an ultradian and circadian manner,
reaching a peak in the morning and a nadir at midnight
(gure 1). The standard choice of glucocorticoid
treatment is oral hydrocortisone or cortisone acetate.
622
Cortisone acetate has a slightly delayed onset of action
because it needs to be activated to hydrocortisone by
hepatic 11β-hydroxysteroid dehydrogenase (11βHSD)
type 1. Hydrocortisone is the preferred medication to
treat adrenal insuciency in most countries, and data
from the European Adrenal Insuciency Registry
(EU-AIR) study showed that 1029 (87%) of 1166 European
patients with primary adrenal insuciency or secondary
adrenal insuciency were using this treatment.100
Normal functioning adrenal glands produce between
5 mg and 10 mg of cortisol per m2 body surface area in
a day,101 which (allowing for incomplete intestinal
absorption) is equivalent to an oral replacement dose of
15–25 mg hydrocortisone per day for an adult. In
children, an optimal dose based on body surface area is
8–10 mg/m² per day. Small and frequent dosing gives a
more physiological plasma cortisol prole. Most adults
take two or three doses of hydrocortisone daily, but
some prefer four or even more. The rst and largest
dose should be taken as soon as the patient is awake,
and the last dose should be taken 4–6 h before bedtime
to avoid sleep disturbances. Evening hydrocortisone
dosing has been associated with insulin resistance and
should be avoided (panel).102 The increase in area under
the curve and maximum serum concentrations of
cortisol with increasing doses is linear but not
proportional.103 Thus, there is little advantage in taking
a morning hydrocortisone dose greater than 10 mg
because blood cortisol concentrations are not sub-
stantially increased by taking single doses higher than
this.104
Treatment with modied-release hydrocortisone once
daily (15–25 mg) might be considered for patients who do
not feel well despite attempts to optimise conventional
therapy.105 Benecial metabolic eects on weight, blood
pressure, and glucose concentrations have been reported
in patients with adrenal insuciency taking modied-
release hydrocortisone.105–108 Conversely, treatment of
adrenal insuciency with prednisolone might result in
more dyslipidaemia and reduced bone mineral content
compared with standard replacement with hydro-
cortisone.109,110 Smith and colleagues111 claim that prednis-
olone is not associated with a worse metabolic prole
than hydrocortisone, if given in doses of 3–5 mg daily.
Notably, in many parts of the world, prednisolone
is currently the only treatment option for adrenal
insuciency. Evidence was presented that, compared
with immediate-release hydrocortisone, modied-release
hydrocortisone confers an improvement of a putative
proinammatory state108 and promotes normalisation of
the expression of clock genes.112 Given that the morning
peak of cortisol has the same timing whether immediate-
release or modied-release hydrocortisone is given,
further investigation is required. A paediatric granular
formulation of hydrocortisone has been developed to
tailor hydrocortisone doses in infants, children,
and adolescents up to the age of 18 years (panel).113
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Panel: Treatment of adrenal insuciency and adrenal crisis
Treatment of adrenal insuciency
• Hydrocortisone (hydrocortisone is available in regular tablets,
modied-release formulation to be given once daily [5 mg
and 20 mg], and as capsules for children [as 0·5 mg, 1·0 mg,
2·0 mg, and 5·0 mg capsules])
• Tablets
• Adults (18 years or older): 10–25 mg daily (eg,
10·0 mg + 5·0 mg; 7·5 mg + 5·0 mg + 2·5 mg,
10·0 mg + 5·0 mg + 2·5 mg, 10·0 mg + 10·0 mg,
10·0 mg + 5·0 mg + 5·0 mg, or
10·0 mg + 5·0 mg + 5·0 mg + 5·0 mg)
• Children and adolescents (up to 18 years of age):
8–10 mg/m² (in three to four doses, 50–66% as
morning dose)
• Modied-release
• Adults (18 years or older): 15–25 mg once daily
• Capsules
• Children and adolescents (up to 18 years of age):
8–10 mg/m² (in three to four doses, 50–66% as
morning dose)
• Cortisone acetate tablets
• Adults (18 years or older): 12·5–37·5 mg daily
• Fludrocortisone tablets (only in primary adrenal insuciency)
• Adults (18 years or older): 0·05–0·20 mg once daily
(most commonly 0·1 mg)
• Older children and adolescents (aged 6–17 years):
0·075–0·100 mg/m² once daily
• Children (aged 1–12 years): 0·100–0·150 mg/m² once daily
• Infants (up to the age of 2 years): 0·150 mg/m² once daily
Treatment of adrenal crisis
• Hydrocortisone
• Adults (18 years or older): 100 mg bolus intravenously
given immediately, followed by 200 mg/day continuous
Dexamethasone is not indicated for replacement therapy
due to its long half-life and associated high risk of
Cushingoid side-eects.
Concentrations of plasma ACTH and serum cortisol
are not useful parameters to assess the adequacy of
glucocorticoid replacement. Generally, nausea, poor
appetite, weight loss, and increased skin pigmentation
suggest under-replacement with glucocorticoid. By
contrast, weight gain, insomnia, cutaneous infections,
and glucose intolerance indicate over-replacement.
Some people report poor stamina, fatigue, headache, or
somnolence only at certain times of the day. Changing
the timing of doses (ideally to as early as possible in
the morning, even 2–3 h before getting out of bed)
and dividing into more frequent smaller doses can
be eective. Given that even subtle overdosing with
glucocorticoids predisposes to complications, such as
obesity, type 2 diabetes, and osteoporosis in the long
term, it is worth exploring whether doses could be safely
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Seminar
infusion, or frequent intravenous or intramuscular
boluses of 50 mg every 6 h
• ≤1 years: 25 mg bolus, 25–30 mg/day, procedure as
above
• 1–6 years: 50 mg bolus, 50–60 mg/day, procedure as
above
• >6 years: 100 mg bolus, 100 mg/day, procedure as
above
• Intravenous substitution of uids
• Adults (18 years or older): 3–4 L of 0·9% saline or
5% dextrose in isotonic saline, with an initial infusion
rate of approximately 1 L per h; frequent haemodynamic
monitoring and measurement of serum electrolytes is
required to avoid uid overload
• Children and adolescents (up to 18 years of age):
0·9% sodium chloride, 20 mL/kg bolus intravenously
given over 30–60 min (which is repeated until
circulation is restored); remaining decit is replaced with
maintenance uid over 24–48 h (with 0·9% sodium
chloride and 5% glucose)
• Hypoglycaemia can be treated with an intravenous
bolus of 10% dextrose 2–5 mL/kg under blood glucose
monitoring
• Treatment of intercurrent illness
• The cause of adrenal crisis should be diagnosed and
treated if relevant; admission to the intensive care or
high-dependency unit should be considered
• Prevention
• Teach self-administration of parenteral steroids
(eg, intramuscular injection of hydrocortisone)
• Vaccination against inuenza; pneumococcus (>60 years
of age)
• Provide steroid card to each patient (eg, appendix p 5)
reduced. In cases when malabsorption is suspected,
serum cortisol114,115 or salivary cortisone116 day concentra-
tion curves might be useful to guide dosing. Finally,
subcutaneous pump treatment is an option, and the only
eective way of reconstituting the circadian variation in
cortisol.117–120
Mineralocorticoid replacement
Most patients with primary adrenal insuciency will
require mineralocorticoid and salt replacement to
ameliorate sodium depletion, which manifests as light-
headedness and salt craving, postural hypotension,
hyponatraemia, and hyperkalaemia. Emerging evidence
indicates that mineralocorticoid deciency is associated
with low mood and reduced cognition.121 Aldosterone
deciency is treated with udrocortisone replacement, in
a once daily morning dose typically 0·05–0·20 mg,
although young children require higher relative doses per
body surface area due to relative aldosterone resistance.
623
 Seminar
People who are physically active frequently need higher
doses than sedentary older people, and patients should
be advised to take salt as needed and to ignore health
recommendations to avoid salt intake. Individuals with
ACTH deciency due to pituitary or hypothalamic
disease, or suppression after taking exogenous steroids,
do not need mineralocorticoid replacement.
Fludrocortisone under-replacement is common,5 and
is sometimes compensated by over-replacement of
glucocorticoids,122 which could predispose patients to
comorbidities of hypercortisolaemia.69 Mineralocorti-
coid replacement is evaluated clinically by asking
the patient about persistent salt cravings or light-
headedness, measuring blood pressure in the supine
and standing positions, and identifying the presence of
peripheral oedema. It is common to measure con-
centrations of renin or plasma renin activity to evaluate
mineralocorticoid dose and aim for a value between the
upper reference range and double the upper reference
range. However, the association between mineralo-
corticoid dose and renin activity is complex and
dependent on the time of day, body position, and
medication intake. Therefore, renin values are often not
helpful to evaluate an individual patient.123
Diuretics and drugs that aect blood pressure
and electrolytes might interact with udrocortisone.
Liquorice and grapefruit juice potentiate the mineralo-
corticoid eect of hydrocortisone and should be
avoided. Essential hypertension in a patient with
primary adrenal insuciency should be treated with an
angiotensin-converting enzyme inhibitor or a calcium
channel blocker, not by stopping the mineralocorticoid
replacement, although a dose reduction should be
considered.124
Adrenal androgen replacement
Adrenal androgen deciency occurs in primary adrenal
insuciency and secondary adrenal insuciency,
which leads to loss of secondary sexual hair in women.
Several randomised studies have examined the eects
of dehydroepiandrosterone replacement in adrenal
insuciency. Overall, benecial subjective eects of
dehydroepiandrosterone are minor,99 but doses between
10 mg and 25 mg daily could improve libido and
emotional and mental wellbeing.97,125,126 Dehydro-
epiandrosterone is also converted to oestrogen, giving a
currently unquantied risk of oestrogen-sensitive
cancers, cardiovascular disease, and venous embolism.
Long-term safety data are insucient, and a recent
Endocrine Society guideline recommends against
routine use.127
Treatment of adrenal crisis
Treatment of patients who present with a possible
adrenal crisis should not be delayed by diagnostic
procedures. Blood testing for serum sodium, potas-
sium, creatinine, urea, glucose, cortisol, ACTH, and
624
other biochemistry for precipitating causes (such as
bacterial or viral infections) should be done if possible,
but therapy must be initiated immediately, even if
tests cannot be carried out (panel). Fast intravenous
administration of 100 mg hydrocortisone is important
to saturate 11βHSD type 2, thereby obtaining a desired
mineralocorticoid eect. The administration of 0·9%
saline (initially 1 L over 1 h) and treatment of any
precipitating conditions is equally important. Saline
infusion at a slower rate with parenteral hydrocortisone
administered as a continuous intravenous infusion
of 200 mg per day (or as 50 mg four times a day)
should be continued for 24–48 h until the patient can
take oral medication. Continuous infusion seems to
best mimic the cortisol response to major stress128
(panel).
To prevent future adrenal crises, it is important to
determine the medical and behavioural causes precipi-
tating each crisis, including treatment compliance and
salt consumption. Additionally, patients should be
advised to have an annual inuenza immunisation,
vaccination for pneumococci when older than 60 years,
and to take particular care to inform health-care prac-
titioners of their steroid dependency during any
medical or dental procedures. The introduction of
education courses for patients with adrenal insuf-
ciency, provision of parenteral hydrocortisone directly
to patients, and the creation of a European emergency
card for cortisol deciency for children and adults (now
translated into numerous languages; appendix p 5)129
are important measures to reduce the risks of adrenal
crisis (panel).
Dose adjustments and sick day rules
Patients with adrenal insuciency who are steroid
dependent for any reason need to adjust their daily dose
of glucocorticoid during intercurrent illness or severe
psychological stress. In the case of an infection causing
a temperature greater than 38·5°C, u-like illness,
diarrhoea, or an upper respiratory tract infection, the
daily dose of glucocorticoid should be doubled over 24 h
in adults and increased to 30 mg/m² per day (divided in
four doses) in children. Vomiting or severe diarrhoea
also represent important hazards to patients with
adrenal insuciency who might not be able to keep
down their necessary daily medication long enough to
absorb it.
Steroid replacement during surgery and medical
procedures
Patients with adrenal insuciency need to increase
their steroid doses during surgery and medical
procedures according to the degree of stress induced.
We advise the patients to use the recommendations
developed by the UK’s Addison’s disease Self-Help
Group and Addison’s disease Clinical Advisory Panel
(appendix p 6).
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Steroid replacement in pregnancy
Pregnancy is associated with a gradual, but pronounced,
physiological increase in corticosteroid-binding globulin
and total serum cortisol concentrations. Free cortisol
concentrations rise during the third trimester, resulting
in an increased requirement for hydrocortisone (by
2·5 mg to 10·0 mg daily).130 Serum progesterone has
anti-mineralocorticoid eects, and hence the udro-
cortisone dose often needs to be increased in the third
trimester.131 Plasma renin activity is not a good parameter
for udrocortisone dose adjustment in this scenario
because the plasma renin activity physiologically
increases during pregnancy, leaving evaluation of salt
cravings, blood pressure, and serum electrolytes as the
best means for dosage monitoring. A 2020 survey of
pregnancies in adrenal insuciency showed that,
although the glucocorticoid dose was increased in
78 (66%) of 128 pregnant women during the second and
third trimester, for many this was not the case. Most
women did not need to increase mineralocorticoid
replacement.132 During delivery, a bolus dose of 100 mg
parenteral hydrocortisone should be given and continued
with 50 mg boluses or continuous infusion every 6 h
(appendix p 6).
Dosing in various situations
No evidence exists to show that extra dosing improves
physical activity,133 but many patients report a need for
extra dosing during stressful situations and extended
physical activity, including unaccustomed exercise,
a race, or a sporting competition. In such cases,
2·5–5·0 mg hydrocortisone before the start of exercise
and repeated doses every 2–4 h during the exertion can
be useful. Endurance athletes might also need to
increase udrocortisone doses or take additional salt
during prolonged exertion, particularly in hot climates.
Similarly, patients travelling to hot environments
might require increased doses of udrocortisone or
increased salt intake, or both. Furthermore, patients
who work night shifts need to adjust their dose
schedule according to the work pattern (eg, take 10 mg
on waking before work, and not at the usual morning
time).
Drug and xenobiotic interactions
Azoles, such as ketoconazole, and the anaesthetic drug
etomidate inhibit steroidogenesis. Several tyrosine
kinase inhibitors are also reported to lower cortisol
concentration, which should prompt monitoring of
patients on these drugs.134 Hepatic steroid metabolism
might be inuenced by carbamazepine, phenytoin,
topiramate, and rifampicin or rifabutin, which all induce
the CYP3A4 enzyme, accelerating cortisol metabolism.
Conversely, individuals taking the antiretroviral drug
ritonavir commonly develop Cushingoid features and
adrenal suppression by very modest doses of steroid
(eg, when using a steroid inhaler).135 Abiraterone acetate
www.thelancet.com Vol 397 February 13, 2021
Seminar
used in prostate cancer can cause glucocorticoid
deciency and mineralocorticoid excess.136 Liquorice
inhibits 11βHSD type 2, which protects the renal
mineralocorticoid receptor from cortisol, and concurrent
use with glucocorticoids can lead to oedema, hyper-
tension, and hypokalaemia. Grapefruit juice inhibits
cytochrome P450 3A4 and induces intestinal drug
transporters, increasing the availability of hydrocortisone
and enhancing its eects.137
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
insuciency is recognised. Therefore, physicians must
be educated to recognise adrenal insuciency 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 ne-tuned physiological
circadian and ultradian variation in cortisol concentra-
tions. Well-designed double-blind randomised studies
that compare current medication regimens are overdue.
In the long term, treatment aimed at stopping and
possibly reversing autoimmune destruction is desired.
There are reports that around 15–30% of patients retain
some corticosteroid production, even years after diag-
nosis.138,139 However, the clinical signicance of this is
currently unclear. Studies using rituximab to inhibit
B cells140 or chronic stimulation by cosyntropin141 have
been able to revamp adrenocortical function in isolated
cases. Production of autologous stem cells is another
promising approach. Transplantation of adrenocortical
tissue is feasible and has been done with kidney
transplantation in a patient with adrenal insuciency
secondary to meningococcal septicaemia.142 Future tissue
engineering strategies and insight into the pathophysio-
logy of adrenal insuciency, especially autoimmune
primary adrenal insuciency, should enable the delivery
of immunomodulatory and regenerative therapies in
the future.
Contributors
ESH, SHP, NPK, and OK planned, wrote, and revised the text. ESH edited
the nal paper and led the work.
Declaration of interests
ESH reports grants from the Novo Nordisk Foundation, personal fees
from Shire, personal fees from Thermo Fisher Scientic, and
non-nancial support from GlaxoSmithKline, outside of the submitted
work. SHP reports grants from the Medical Research Council, UK,
personal fees from Shire, and grants from EU-FP7, during the study.
SHP also reports personal fees from Merck Serono, Quidel, and Apitope,
outside of the submitted work. NPK reports grants from the Medical
Research Council, UK, the International Fund Congenital Adrenal
Hyperplasia, the German Research Foundation (DFG), and the National
Institute for Health Research Rare Disease Translational Research
Collaboration, outside of the submitted work. NPK also reports
consultancy fees from Diurnal, Neurocrine Biosciences, outside of the
submitted work. NPK also reports fees from Sandoz, Merck, and Novo
Nordisk Foundation, during the study. OK reports grants from the
Swedish Research Council, The Knut and Alice Wallenberg Foundation,
625
 Seminar
Torsten and Ragnar Söderberg Foundations, the Novo Nordisk
Foundation as well as grants from EU-funding, and grants from Shire,
outside of the submitted work. OK is also a board member and
shareholder of Olink Biosciences AB, and Navinci Diagnostics, Uppsala,
Sweden.
Acknowledgments
This Seminar was supported by the KG Jebsen Center for Autoimmune
Disorders, the Novo Nordisk Foundation, the Knut and Alice Wallenberg
Foundation, Swedish and Norwegian Research Councils, Regional
Health Authorities of Western Norway, Stockholm County Council,
the Torsten and Ragnar Söderberg Foundations, the German Research
Foundation (DFG; KR3363/3–1), the Medical Research Council,
UK (MR/J002526/1), and the Robotham family.
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