Seminar
`
`Published Online
`February 4, 2014
`http://dx.doi.org/10.1016/
`S0140-6736(13)61684-0
`Division of Endocrinology,
`Metabolism, and Diabetes,
`First Department of Pediatrics,
`University of Athens Medical
`School, Aghia Sophia Children’s
`Hospital, Athens, Greece
`(E Charmandari MD,
`N C Nicolaides MD,
`Prof G P Chrousos MD); and
`Division of Endocrinology and
`Metabolism, Clinical Research
`Center, Biomedical Research
`Foundation of the Academy of
`Athens, Athens, Greece
`(E Charmandari, N C Nicolaides,
`Prof G P Chrousos)
`Correspondence to:
`Dr Evangelia Charmandari,
`Division of Endocrinology,
`Metabolism and Diabetes, First
`Department of Pediatrics,
`University of Athens Medical
`School, Aghia Sophia Children’s
`Hospital, Athens 11527, Greece
`evangelia.charmandari@
`googlemail.com
`
`Adrenal insuffi ciency
`
`Evangelia Charmandari, Nicolas C Nicolaides, George P Chrousos
`
`Adrenal insuffi ciency is the clinical manifestation of defi cient production or action of glucocorticoids, with or without
`defi ciency 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 insuffi ciency result from
`defi ciency of all adrenocortical hormones, but they can also include signs of other concurrent autoimmune conditions.
`In secondary or tertiary adrenal insuffi ciency, the clinical picture results from glucocorticoid defi ciency 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 insuffi ciency. We summarise
`knowledge at this time on the epidemiology, causal mechanisms, pathophysiology, clinical manifestations, diagnosis,
`and management of this disorder.
`
`Introduction
`Adrenal insuffi ciency is a life-threatening disorder that
`can result from primary adrenal failure or secondary
`adrenal disease due to impairment of the hypothalamic–
`pituitary axis.1–3 It is the clinical manifestation of defi cient
`production or action of glucocorticoids, with or without
`defi ciency also
`in mineralocorticoids and adrenal
`androgens. The
`cardinal
`clinical
`symptoms of
`adrenocortical
`insuffi ciency, as fi rst 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
`insuffi ciency was invariably fatal until 1949, when
`cortisone was fi rst synthesised,6–9 and glucocorticoid-
`replacement
`treatment became available. However,
`despite this breakthrough, the diagnosis and treatment
`of patients with the disorder remain challenging.
`
`Epidemiology
`the underlying mechanism, adrenal
`According
`to
`insuffi ciency is classed as primary, secondary, or tertiary.
`Primary adrenal insuffi ciency results from disease
`intrinsic
`to
`the adrenal cortex. Central adrenal
`insuffi ciency, the collective name for the secondary and
`tertiary types, is caused by impaired production or action
`of corticotropin. Secondary adrenal insuffi ciency results
`from pituitary disease that hampers the release of
`corticotropin or from a lack of responsiveness of the
`adrenal glands to this hormone. Tertiary adrenal
`insuffi ciency results from the impaired synthesis or
`action of corticotropin-releasing hormone, arginine
`vasopressin, or both, from the hypothalamus, which in
`turn inhibits secretion of corticotropin.
`In Europe, the prevalence of chronic primary adrenal
`insuffi ciency has increased from 40–70 cases per million
`people in the 1960s10,11 to 93–144 cases per million by the
`end of the 20th century,12–16 with an estimated incidence
`now of 4·4–6·0 new cases per million population per
`year.15 Tuberculosis was the most common cause of
`primary adrenal insuffi ciency during the fi rst half of the
`
`lately autoimmune adrenal
`century,17 but
`20th
`insuffi ciency has become the most common form.16 The
`increase
`in
`the
`frequency of primary adrenal
`insuffi ciency over the past few decades, associated with a
`decline in the prevalence of tuberculosis, is indicative of
`the rising proportion of cases of autoimmune adrenal
`insuffi ciency.18 In a series of 615 patients with Addison’s
`disease, studied between 1969 and 2009, the autoimmune
`form was diagnosed in 82% of cases, the tuberculosis-
`related form in 9%, and other causes in about 8% of
`cases.19 Primary adrenal insuffi ciency occurs more
`frequently in women than in men, and can present at
`any age, although most often appears between the ages
`of 30 and 50 years.12
`The frequency of the various forms of primary adrenal
`insuffi ciency in children diff ers substantially from that
`in the adult population; the genetic forms are more
`common. In a series of 103 children with Addison’s
`
`Search strategy and selection criteria
`
`We searched PubMed and the Cochrane Library for original
`articles and reviews related to adrenal insuffi ciency, which
`were published in English between 1966 and April, 2013. We
`used the search terms “adrenal insuffi ciency”, in combination
`with the terms “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”, “pregnancy”,
`“prognosis”, “morbidity”, and “mortality”. We largely chose
`publications from the past 5 years, but we did not exclude
`commonly referenced and highly regarded older publications.
`We also searched the reference lists of articles identifi ed by
`this search strategy and selected those we judged relevant.
`Several review articles or book chapters were included
`because they provide comprehensive overviews that are
`beyond the scope of this Seminar. The reference list was
`modifi ed during the peer-review process on the basis of
`comments from reviewers.
`
`www.thelancet.com Published online February 4, 2014 http://dx.doi.org/10.1016/S0140-6736(13)61684-0
`
`1
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`

`

`Seminar
`
`disease seen over 20 years (1981–2001), the most frequent
`cause was congenital adrenal hyperplasia (72%), and
`other genetic causes accounted
`for another 6%;
`autoimmune disease was diagnosed in only 13%.20
`Secondary adrenal insuffi ciency is more common
`than primary adrenal insuffi ciency.1 It has an estimated
`prevalence of 150–280 per million and aff ects women
`more frequently than men.14,21–24 The age at diagnosis
`peaks in the sixth decade of life.22,23 A systematic review
`and meta-analysis of
`reported prevalences of
`hypopituitarism in adult patients who had received
`cranial irradiation for non-pituitary tumours showed
`that
`the point prevalence of any degree of
`hypopituitarism was 0·66 (95% CI 0·55–0·76) and the
`prevalence of corticotropin defi ciency was 0·22
`(0·15–0·30).25 The most common cause of tertiary
`adrenal insuffi ciency is long-term administration of
`exogenous glucocorticoids, which leads to prolonged
`suppression of hypothalamic secretion of corticotropin-
`releasing hormone.26
`
`Causal mechanisms
`Primary adrenal insuffi ciency
`The causes of primary adrenal insuffi ciency are listed in
`table 1. In developed countries, 80–90% of cases of
`primary adrenal insuffi ciency are caused by autoimmune
`adrenalitis, which can be isolated (40%) or part of an
`autoimmune polyendocrinopathy syndrome (60%).1,2,19,32–34
`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
`idiopathic primary adrenal insuffi ciency,16 but only rarely
`in patients with other causes of adrenal insuffi ciency.35 In
`addition,
`other
`autoantigens,
`including
`steroid
`17α-hydroxylase and the cholesterol side-chain cleavage
`enzyme, have been
`identifi ed
`in patients with
`autoimmune Addison’s disease, as well as patients with
`primary ovarian failure.32,36 T cells and cellular immunity
`also have important roles in the pathogenesis of
`autoimmune Addison’s disease, and the generation of
`
`Autoimmune adrenalitis
`Isolated
`
`APS type 1 (APECED)
`
`APS type 2
`
`APS type 4
`
`Infectious adrenalitis
`Tuberculous adrenalitis
`AIDS
`Fungal adrenalitis
`Syphilis
`African trypanosomiasis27
`Bilateral adrenal haemorrhage
`
`Bilateral adrenal metastases
`Bilateral adrenal infi ltration
`
`Bilateral adrenalectomy
`
`Pathogenetic mechanisms
`
`Clinical manifestations in addition to adrenal insuffi ciency
`
`Associations with HLA-DR3-DQ2, HLA-DR4-DQ8, MICA,
`CTLA-4, PTPN22, CIITA, CLEC16A, vitamin D receptor
`AIRE gene mutations
`
`Associations with HLA-DR3, HLA-DR4, CTLA-4
`
`Associations with HLA-DR3, CTLA-4
`
`None
`
`Chronic mucocutaneous candidosis, hypoparathyroidism,
`other autoimmune diseases
`Thyroid autoimmune disease, type 1 diabetes, other
`autoimmune diseases
`Other autoimmune diseases (autoimmune gastritis, vitiligo,
`coeliac disease, alopecia), excluding thyroid disease and
`type 1 diabetes
`
`Tuberculosis
`HIV-1
`Histoplasmosis, cryptococcosis, coccidioidomycosis
`Treponema pallidum
`Trypanosoma brucei
`Meningococcal sepsis (Waterhouse-Friderichsen syndrome),
`primary antiphospholipid syndrome
`Mainly cancers of the lung, stomach, breast, and colon
`Primary adrenal lymphoma, amyloidosis,
`haemochromatosis
`Unresolved Cushing’s syndrome, bilateral adrenal masses,
`bilateral phaeochromocytoma
`
`Tuberculosis-associated manifestations in other organs
`Other AIDS-associated diseases
`Opportunistic infections
`Other syphilis-associated organ involvement
`Other trypanosomiasis-associated organ involvement
`Symptoms and signs of underlying disease
`
`Disease-associated clinical manifestations
`Disease-associated clinical manifestations
`
`Symptoms and signs of underlying disease
`
`Drug-induced adrenal insuffi ciency
`Anticoagulants (heparin, warfarin), tyrosine-kinase inhibitors
`(sunitinib)
`Aminoglutethimide
`Trilostane
`Ketoconazole, fl uconazole, etomidate
`
`Phenobarbital
`
`Phenytoin, rifampicin, troglitazone
`
`Haemorrhage
`
`Inhibition of P450 aromatase (CYP19A1)
`Inhibition of 3β-hydroxysteroid dehydrogenase type 2
`Inhibition of mitochondrial cytochrome P450-dependent
`enzymes (eg, CYP11A1, CYP11B1)
`Induction of P450-cytochrome enzymes (CYP2B1, CYP2B2),
`which increase cortisol metabolism
`Induction of P450-cytochrome enzymes (mainly CYP3A4),
`which increase cortisol metabolism
`
`None, unless related to drug
`
`None, unless related to drug
`None, unless related to drug
`None, unless related to drug
`
`None, unless related to drug
`
`None, unless related to drug
`
`(Table 1 continues on next page)
`
`2
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`www.thelancet.com Published online February 4, 2014 http://dx.doi.org/10.1016/S0140-6736(13)61684-0
`
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`Seminar
`
`Pathogenetic mechanisms
`
`Clinical manifestations in addition to adrenal insuffi ciency
`
`(Continued from previous page)
`Genetic disorders
`Adrenoleukodystrophy or adrenomyeloneuropathy
`
`ABCD1 and ABCD2 gene mutations
`
`Congenital adrenal hyperplasia
`21-hydroxylase defi ciency
`11β-hydroxylase defi ciency
`3β-hydroxysteroid dehydrogenase type 2 defi ciency
`17α-hydroxylase defi ciency
`P450 oxidoreductase defi ciency
`
`P450 side-chain cleavage defi ciency
`Congenital lipoid adrenal hyperplasia
`Smith-Lemli-Opitz syndrome
`
`Adrenal hypoplasia congenita
`X-linked
`Xp21 contiguous gene syndrome
`
`SF-1 linked
`IMAGe syndrome
`
`CYP21A2 gene mutations
`CYP11B1 gene mutations
`Mutations in 3β-HSD2 gene
`CYP17A1 gene mutations
`Mutations in gene for P450 oxidoreductase
`
`CYP11A1 gene mutations
`StAR gene mutations
`DHCR7 gene mutations
`
`NR0B1 gene mutations
`Deletion of genes for Duchenne muscular dystrophy,
`glycerol kinase, and NR0B1
`NR5A1 gene mutations
`CDKN1C gene mutations
`
`Kearns-Sayre syndrome
`
`Mitochondrial DNA deletions
`
`Wolman’s disease
`Sitosterolaemia (also known as phytosterolaemia)
`
`LIPA gene mutations
`ABCG5 and ABCG8 gene mutations
`
`Familial glucocorticoid defi ciency or corticotropin insensitivity syndromes
`Type 1
`MC2R gene mutations
`
`Type 2
`
`MRAP gene mutations
`
`Variant of familial glucocorticoid defi ciency
`
`MCM4 gene mutations
`
`Primary generalised glucocorticoid resistance or Chrousos
`syndrome28–31
`Triple A syndrome (Allgrove’s syndrome)
`
`Generalised, partial, target-tissue insensitivity to
`glucocorticoids
`AAAS gene mutations
`
`Weakness, spasticity, dementia, blindness, quadriparesis.
`Adrenomyeloneuropathy is a milder variant of
`adrenoleukodystrophy with slower progression
`
`Hyperandrogenism
`Hyperandrogenism, hypertension
`Ambiguous genitalia in boys, postnatal virilisation in girls
`Pubertal delay in both sexes, hypertension
`Skeletal malformation (Antley-Bixler syndrome), abnormal
`genitalia
`XY sex reversal
`XY sex reversal
`Craniofacial malformations, mental retardation, growth failure,
`hyponatraemia, hyperkalaemia, cholesterol defi ciency
`
`Hypogonadotropic hypogonadism in boys
`Duchenne muscular dystrophy, glycerol kinase defi ciency,
`psychomotor retardation
`XY sex reversal
`Intrauterine growth retardation, metaphyseal dysplasia,
`adrenal hypoplasia congenita and genital abnormalities
`External ophthalmoplegia, retinal degeneration, cardiac
`conduction defects, other endocrine disorders
`Bilateral adrenal calcifi cation, hepatosplenomegaly
`Xanthomata, arthritis, premature coronary artery disease,
`short stature, gonadal and adrenal failure
`
`Hyperpigmentation, tall stature, characteristic facial features,
`such as hypertelorism and frontal bossing, lethargy and muscle
`weakness but normal blood pressure
`Hyperpigmentation, normal height, hypoglycaemia, lethargy,
`and muscle weakness, but normal blood pressure
`Growth failure, increased chromosomal breakage, natural killer
`cell defi ciency
`Fatigue, hypoglycaemia, hypertension, hyperandrogenism
`
`Achalasia, alacrima, deafness, mental retardation, hyperkeratosis
`
`APS=autoimmune polyendocrinopathy syndrome. CTLA-4=cytotoxic T-lymphocyte antigen 4. ABCD=ATP-binding cassette, subfamily D. StAR=steroidogenic acute regulatory protein. DHCR7=7-
`dehydrocholesterol reductase. ABCG5=ATP-binding cassette, subfamily G, member 5. ABCG8=ATP-binding cassette, subfamily G, member 8. MC2R=melanocortin 2 receptor. MRAP=melanocortin 2 receptor
`accessory protein. MCM4=minichromosome maintenance complex component 4. AAAS=achalasia, adrenocortical insuffi ciency, alacrima syndrome.
`
`Table 1: Causes of primary adrenal insuffi ciency
`
`autoantibodies can be secondary to tissue destruction
`(fi gure 1).37,38 Furthermore, several genes that confer
`susceptibility to autoimmune Addison’s disease have
`been identifi ed. In addition to the MHC haplotypes DR3-
`DQ2 and DR4-DQ8, cytotoxic T-lymphocyte antigen 4,
`protein tyrosine-phosphatase non-receptor type 22, and
`the MHC class II transactivator have been associated
`with the condition.32–35,39–41 Now that large genome-wide
`screening projects are feasible, new susceptibility genes
`are likely to be identifi ed in the near future.32–35
`Primary adrenal insuffi ciency can also present in the
`context of autoimmune polyendocrinopathy syndromes.
`
`Autoimmune polyendocrinopathy syndrome type 1, which
`is also known as APECED (autoimmune polyendo-
`crinopathy, candidosis, ectodermal dystrophy) syndrome,
`is a rare, autosomal recessive disorder caused by mutations
`in the autoimmune regulator (AIRE) gene.32,42 It is most
`common among particular population groups—people
`from Sardinia and Finland and Iranian Jews—and is
`characterised by chronic mucocutaneous candidosis,
`adrenocortical insuffi ciency, hypo parathyroidism, hypo-
`plasia of the dental enamel, and nail dystrophy; other
`autoimmune disorders, such as type 1 diabetes and
`pernicious anaemia, can develop later in life.42,43 Antibodies
`
`www.thelancet.com Published online February 4, 2014 http://dx.doi.org/10.1016/S0140-6736(13)61684-0
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`3
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`Seminar
`
`Stress?
`Virus?
`Environment?
`
`Adrenocortical
`cells
`
`Uptake of
`antigens
`
`21-hydroxylase
`
`Interferon-γ
`
`Interleukin-2
`
`Activation of autoreactive
`cytotoxic T lymphocytes
`
`Granzymes
`Perforin
`
`CD8+
`
`Adrenocortical cells
`
`Interleukin-12
`
`Antigen
`presentation
`
`CD4+
`Th1
`
`Dendritic
`cell
`
`Costimulation
`
`Activation of
`autoreactive T cells
`
`Interferon-γ
`
`Lymphotoxin-α
`
`CD4+
`Th1
`
`Interferon-γ
`
`Production of IgG
`autoantibodies
`
`Activation of
`autoreactive B cells
`
`Adrenocortical cells
`
`TNFα
`Interleukin-1β
`
`Free radicals
`Superoxide
`
`Interferon-γ
`
`Macrophage
`
`Figure 1: Molecular immunopathogenesis of primary adrenal insuffi ciency
`A persistent subclinical viral infection or an aberrant response to infl ammatory stressors could cause adrenocortical cell apoptosis or necrosis, leading to dendritic-cell
`activation by cellular components, including peptides derived from 21-hydroxylase. After activation, dendritic cells transport and present adrenocortical antigens to
`CD4-positive T-helper-1 (Th1) cells within the local draining lymph node. Activated specifi c CD4-positive Th1 cells could provide help for the activation and clonal
`expansion of cytotoxic lymphocytes and autoreactive B cells producing anti-21-hydroxylase and other antibodies. The continuing progressive destruction of adrenal
`cortex is mediated by several diff erent mechanisms: direct cytotoxicity by apoptosis-inducing cytotoxic lymphocytes via perforin and granzyme B or by the FasL-Fas
`pathway; direct cytotoxicity by interferon-γ and lymphotoxin-α secreted by CD4-positive Th1 cells; autoantibody-induced activation of the complement system or
`antibody dependent cellular cytotoxicity; cytotoxic eff ects of infl ammatory cytokines (tumour necrosis factor-α [TNFα], interleukin-1β) and free radicals (nitric oxide,
`superoxide) released by monocytes and macrophages or by the adrenocortical cells themselves.
`
`against interferon-ω and interferon-α are both sensitive
`and specifi c for type 1 autoimmune polyendocrinopathy
`syndrome, and mutational analysis of the AIRE gene
`confi rms the diagnosis in more than 95% of cases.44 Type 2
`autoimmune
`polyendocrinopathy
`syndrome
`is
`characterised by autoimmune adrenal insuffi ciency and
`autoimmune thyroid disease, with or without type 1
`diabetes; it is more prevalent than the type 1 form. It is
`often associated with other autoimmune conditions,
`aff ects women more commonly than men, and generally
`presents in the fourth decade of life.32–34,43,45,46 Autoimmune
`polyendocrinopathy syndrome type 4 is a rare syndrome
`characterised by the association of autoimmune Addison’s
`disease with one or more minor component autoimmune
`diseases (eg, hypogonadism, atrophic gastritis, pernicious
`anaemia, coeliac disease, myasthenia gravis, vitiligo,
`alopecia, and hypophysitis) but excluding the major
`
`component disease characteristics of types 1 and 2 (chronic
`candidosis, hypoparathyroidism, thyroid autoimmune
`diseases, type 1 diabetes).45
`Table 1 lists several infectious, drug-induced, and other
`causes of primary adrenal insuffi ciency, then genetic
`disorders. Of the genetic causes, adrenoleukodystrophy,
`is an X-linked recessive disorder that aff ects one in
`20 000 men and boys and is caused by mutations in the
`ATP-binding cassette, subfamily D, member 1 (ABCD1)
`gene. These mutations prevent normal transport of very-
`long-chain
`fatty acids
`into peroxisomes,
`thereby
`preventing
`their
`β-oxidation
`and
`breakdown.
`Accumulation of abnormal amounts of these fatty acids
`in aff ected organs (CNS, Leydig cells of the testes, adrenal
`cortex) is thought to be the underlying pathological
`process. The clinical features include neurological
`impairment resulting from white-matter demyelination
`
`4
`
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`Seminar
`
`and primary adrenal insuffi ciency, which presents in
`infancy or childhood. The
`two major
`forms of
`adrenoleukodystrophy are the cerebral form (50% of
`cases; early childhood manifestation with
`rapid
`progression) and adrenomyeloneuropathy (35% of cases;
`onset in early adulthood with slow progression) in which
`demyelination is restricted to the spinal cord and
`peripheral nerves. Since adrenal insuffi ciency can be the
`initial clinical manifestation, adrenoleukodystrophy
`should be considered in young male patients with
`adrenal insuffi ciency and confi rmed biochemically by
`measurement of plasma concentrations of very-long-
`chain fatty acids.1–3,47
`Primary adrenal insuffi ciency occasionally presents
`acutely as a consequence of bilateral adrenal haemorrhage
`in patients with antiphospholipid syndrome. It is
`characterised by
`recurrent arterial and
`venous
`thrombosis, complications during pregnancy, and the
`presence of autoantibodies
`to phospholipids. The
`condition can be isolated or manifest in the context of
`connective tissue disorders or malignant disorders.48,49
`In children, the most common cause of primary
`adrenal insuffi ciency is congenital adrenal hyperplasia,
`a group of autosomal recessive disorders resulting from
`defi ciency of one of the enzymes needed for synthesis
`of cortisol in the adrenal cortex. The most common
`form is classic 21-hydroxylase defi ciency, a condition
`characterised by low synthesis of glucocorticoids and,
`in many cases, mineralocorticoids, adrenal hyper-
`androgenism, and impaired development and function
`of the adrenal medulla.50–52 More rare forms are caused
`by defi ciency of 11β-hydroxylase, 17α-hydroxylase,
`17,20-lyase, 3β-hydroxysteroid dehydrogenase, or P450
`oxidoreductase.
`
`Central adrenal insuffi ciency
`Secondary adrenal insuffi ciency results from any process
`that involves the pituitary gland and interferes with
`corticotropin secretion (table 2). The corticotropin
`defi ciency can be isolated or can occur in association
`with defi ciencies of other pituitary hormones. Isolated
`corticotropin defi ciency generally results from an
`autoimmune process, as shown by
`the frequent
`association with other autoimmune endocrine disorders
`(thyroiditis, type 1 diabetes).53,54 Genetic causes of
`corticotropin
`defi ciency
`include
`loss-of-function
`mutations in the genes encoding pro-opiomelanocortin
`gene and proprotein convertase subtilisin or kexin type 1
`inhibitor, which also result
`in early-onset severe
`obesity,53,55 as well as mutations in TPIT, a T-box factor
`that controls transcription of the pro-opiomelanocortin
`gene in corticotrophs only.53,56
`Tertiary adrenal insuffi ciency results from processes
`that involve the hypothalamus and interfere with
`secretion of corticotropin-releasing hormone, arginine
`vasopressin, or both (table 3). Suppression of the
`hypothalamic-pituitary-adrenal (HPA) axis by long-term
`
`administration of high doses of glucocorticoids is the
`most common cause. Therefore, in most cases, slow
`withdrawal of glucocorticoid treatment over 9–12 months
`is needed for full recovery of the HPA axis.26,57–59 Tertiary
`adrenal insuffi ciency also occurs in patients cured of
`Cushing’s syndrome, since the persistently high serum
`cortisol concentrations before treatment suppress the
`HPA axis in the same way as high exogenous doses of
`glucocorticoids.60–63 Finally, drugs such as mifepristone, a
`glucocorticoid receptor antagonist, antipsychotics, and
`antidepressants
`cause
`target-tissue
`resistance
`to
`glucocorticoids through impairment of glucocorticoid
`signal transduction.60
`
`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 insuffi ciency. Cortisol secretion from
`the zona
`fasciculata
`is primarily
`regulated by
`corticotropin, which is released from the anterior
`pituitary in response to the hypothalamic neuropeptides
`corticotropin-releasing
`hormone
`and
`arginine
`vasopressin.50,60,64 In healthy people, cortisol secretion is
`pulsatile, and circulating cortisol concentrations fl uctuate
`naturally in a circadian fashion, highest in the early
`morning (0600–0800 h) and lowest around midnight.60,64–67
`The adrenal androgens, androstenedione, dehydro-
`epiandrosterone, and the sulphate ester of dehydro-
`epiandrosterone, are synthesised in the innermost zona
`reticularis.50 Dehydroepiandrosterone and its sulphate
`show a characteristic, age-associated pattern, with very
`high concentrations in the neonatal period, a decline to
`very low concentrations during the fi rst few months of
`life, and a continuous increase starting between age 6
`and 10 years, termed adrenarche. Peak concentrations of
`these two hormones are achieved during the third decade
`of life; they then decline steadily from the fi fth decade
`(adrenopause) with concentrations decreasing to 10–20%
`of the maximum at around age 70 years. The age-related
`decline in dehydro epiandrosterone sulphate does not
`refl ect a general loss of adrenocortical output because
`cortisol concentrations are maintained and even slightly
`rise with age.50,68
`The clinical manifestations of primary adrenal
`insuffi ciency (table 4) result from defi ciency of all
`adrenocortical
`hormones
`(aldosterone,
`cortisol,
`androgens); they can also include signs of other
`concurrent autoimmune conditions. Most of
`the
`symptoms are non-specifi c and can delay diagnosis and
`treatment of the condition. Hypoglycaemia can be the
`presenting sign in children with adrenal insuffi ciency,
`and it can lead to deterioration of glycaemic control and
`
`www.thelancet.com Published online February 4, 2014 http://dx.doi.org/10.1016/S0140-6736(13)61684-0
`
`5
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2020, Page 5
`
`

`

`Pathogenetic mechanisms
`
`Clinical manifestations in addition to adrenal insuffi ciency
`
`Low corticotropin secretion
`
`Anterior or posterior pituitary hormone defi ciencies, or both,
`and associated symptoms
`
`Low corticotropin secretion
`
`Low corticotropin secretion
`
`Anterior or posterior pituitary hormone defi ciencies, or both,
`and primary disease-associated symptoms
`Anterior or posterior pituitary hormone defi ciencies, or both,
`and primary disease-associated symptoms
`
`Low corticotropin secretion
`
`Abrupt onset of severe headache, visual disturbance, nausea,
`vomiting; anterior or posterior pituitary hormone defi ciencies,
`or both, and primary disease-associated symptoms
`Peripartum abrupt onset of severe headache, visual disturbance,
`nausea, and vomiting; anterior or posterior pituitary hormone
`defi ciencies or both, and primary disease-associated symptoms
`
`Seminar
`
`Space-occupying lesions or trauma
`Pituitary tumours (adenomas, cysts, craniopharyngiomas,
`ependymomas, meningiomas, rarely carcinomas) or trauma
`(pituitary stalk lesions)
`Pituitary surgery or irradiation for pituitary tumours,
`tumours outside the HPA axis or leukaemia
`Infections or infi ltrative processes (lymphocytic hypophysitis,
`haemochromatosis, tuberculosis, meningitis, sarcoidosis,
`actinomycosis, histiocytosis X, Wegener’s granulomatosis)
`Pituitary apoplexy
`
`Sheehan’s syndrome (peripartum pituitary apoplexy and
`necrosis)
`
`Low corticotropin secretion
`
`Genetic disorders
`Transcription factors involved in pituitary development
`HESX homeobox 1
`
`Orthodentical homeobox 2
`
`LIM homeobox 4
`
`PROP paired-like homeobox 1
`
`SRY (sex-determining region Y)
`Box 3
`
`T-box 19
`Congenital pro-opiomelanocortin defi ciency
`
`Prader-Willi syndrome
`
`Table 2: Causes of secondary adrenal insuffi ciency
`
`HESX1 gene mutations
`
`Mutations in gene for
`orthodentical homeobox 2
`Mutations in gene for LIM
`homeobox 4
`Mutations in gene for PROP
`paired-like homeobox 1
`
`Panhypopituitarism; short stature, delayed puberty, cognitive
`changes, septo-optic dysplasia
`Panhypopituitarism; neonatal hypoglycaemia, pituitary
`hypoplasia, ectopic posterior pituitary gland
`Panhypopituitarism; growth hormone, thyrotropin, and
`corticotropin defi ciencies
`Panhypopituitarism; late-onset corticotropin defi ciency,
`occasionally enlarged sella turcica
`
`Mutations in gene for SRY
`(sex-determining region Y) box 3
`Mutations in gene for T-box 19
`Mutations in gene for
`pro-opiomelanocortin
`Deletion or silencing of genes in
`imprinting centre for the
`syndrome
`
`Panhypopituitarism; infundibular hypoplasia,
`hypopituitarism, mental retardation
`Congenital isolated corticotropin defi ciency
`Early-onset severe obesity, hyperphagia, red hair
`
`Hypotonia, obesity, mental retardation, hypogonadism
`
`Pathogenetic mechanisms
`
`Clinical manifestations in addition to adrenal
`insuffi ciency
`
`Space-occupying lesions or trauma
`Hypothalamic tumours (craniopharyngiomas or metastasis
`from lung or breast cancer)
`Hypothalamic surgery or irradiation for CNS or nasopharyngeal
`tumours
`Infections or infi ltrative processes (lymphocytic hypophysitis,
`haemochromatosis, tuberculosis, meningitis, sarcoidosis,
`actinomycosis, histiocytosis X, Wegener’s granulomatosis)
`Trauma, injury (fracture of skull base)
`
`Low CRH secretion
`
`Low CRH secretion
`
`Low CRH secretion
`
`Low CRH secretion
`
`Anterior or posterior pituitary hormone defi ciencies,
`or both, and primary disease-associated symptoms
`Anterior or posterior pituitary hormone defi ciencies,
`or both, and primary disease-associated symptoms
`Anterior or posterior pituitary hormone defi ciencies,
`or both, and primary disease-associated symptoms
`
`Anterior or posterior pituitary hormone defi ciencies,
`or both, and primary disease-associated symptoms
`
`Drug-induced adrenal insuffi ciency
`Glucocorticoid therapy (systemic or topical) or endogenous
`glucocorticoid hypersecretion (Cushing’s syndrome)
`Mifepristone
`
`Antipsychotics (chlorpromazine), antidepressants (imipramine)
`
`Low CRH and corticotropin secretion
`
`Primary disease-associated symptoms
`
`Tissue resistance to glucocorticoids
`through impairment of glucocorticoid
`signal transduction
`Inhibition of glucocorticoid-induced
`gene transcription
`
`If excessive it can cause severe glucocorticoid
`defi ciency; no other symptoms, unless related to drug
`
`None, unless related to drug
`
`HPA=hypothalamic–pituitary–adrenal. CRH=corticotropin-releasing hormone.
`
` Table 3: Causes of tertiary adrenal insuffi ciency
`
`6
`
`www.thelancet.com Published online February 4, 2014 http://dx.doi.org/10.1016/S0140-6736(13)61684-0
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2020, Page 6
`
`

`

`Seminar
`
`Measurement of serum free cortisol concentrations can
`off er additional information, although the assay is not
`generally available; salivary cortisol concentration might
`be a useful alternative.75
`In healthy people, serum cortisol concentrations are
`highest in the early morning, at 275–555 nmol/L
`(100–200 μg/L). A low serum cortisol concentration
`(<80 nmol/L [30 μg/L]) in a blood sample taken in the
`early morning strongly suggests adrenal insuffi ciency.76,77
`By contrast, a morning serum cortisol concentration of
`more than 415 nmol/L (150 μg/L) predicts a normal
`serum cortisol response to insulin-induced hypoglycaemia
`or a short corticotropin test in almost all patients.78,79
`Simultaneous measurements of cortisol and corticotropin
`concentrations identify most cases of primary adrenal
`insuffi ciency.
`Similarly, a salivary cortisol concentration at 0800 h of
`more than 16 nmol/L (5·8 μg/L) excludes adrenal
`
`
`
`Pathophysiological mechanism
`
`Prevalence (%)
`
`Anorexia, weight loss (in children failure to thrive)
`Gastric pain, nausea, vomiting
`(most common in primary adrenal insuffi ciency)
`Myalgia, joint pain
`Dizziness
`
`Symptoms
`Fatigue, lack of energy or stamina, reduced strength Glucocorticoid defi ciency,
`adrenal androgen defi ciency
`Glucocorticoid defi ciency
`Glucocorticoid defi ciency,
`mineralocorticoid defi ciency
`Glucocorticoid defi ciency
`Mineralocorticoid defi ciency,
`glucocorticoid defi ciency
`Mineralocorticoid defi ciency
`Adrenal androgen defi ciency
`Adrenal androgen defi ciency
`
`Salt craving (primary adrenal insuffi ciency only)
`Dry and itch