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Clinical review 130: Addison's Disease

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0021-972X/01/$03.00/0 Vol. 86, No. 7
The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright © 2001 by The Endocrine Society

CLINICAL REVIEW 130

Addison’s Disease 2001
SVETLANA TEN, MARIA NEW, AND NOEL MACLAREN
Department of Pediatrics, Weill Medical College of Cornell University, New York, New York 10021

ABSTRACT elucidating the pathogeneses and underlying genetics of the individ-

Whereas it is now more than 150 yr since T. Addison first described ual forms of the disease. This review emphasizes the multiple etiol-
the clinical and pathological features of adrenal failure (1), the disease ogies and the diagnostic steps to be taken with consideration to age
remains underdiagnosed, leading to unnecessary morbidity and mor- at onset and gender and summarizes new genetic insights in the
tality. Over the past decade, there have been important advances in disease. (J Clin Endocrinol Metab 86: 2909 –2922, 2001)

A DRENAL INSUFFICIENCY, OR Addison’s disease,

can present as a life-threatening crises, because it is
frequently unrecognized in its early stages. A relatively
of the newborn period. The various etiologies of Addison’s
disease can be grouped into three categories: 1) adrenal
dysgenesis; 2) adrenal destruction; and 3) impaired ste-
uncommon disease in Western countries at an estimated roidogenesis (Fig. 1). Congenital adrenal hypoplasia
prevalence rate near 120 per million (2), a survey of pa- (AHC), mutations of steroidogenic factor-1 (SF-1), and
tients with Addison’s disease who are members of the ACTH unresponsiveness can all lead to adrenal dysgenesis/
National Adrenal Disease Foundation revealed that 60% hypoplasia, albeit the latter usually results in isolated defi-
had sought medical attention from two or more physicians ciency of gluco-corticoids. Autoimmune polyglandular syn-
before the correct diagnosis was ever considered. No fig- drome (APS), adrenoleukodystrophy (ALD), adrenal
ures are available on the number of undiagnosed patients hemorrhage, adrenal metastases, infections, and amyloid-
succumbing to adrenal insufficiency. Thus, physicians are oses can all lead to destruction of adrenal gland. Congenital
advised to keep a high index of suspicion of adrenal in- adrenal hyperplasia (CAH), mitochondrial disorders, the
sufficiency in unexplained illnesses. Adrenal insufficiency Smith-Lemli-Opitz syndrome (SMOS), an enzyme deficiency
can present with ill-defined fatigue and weakness. It can in cholesterol metabolism, can all lead to impaired steroi-
mimic a gastrointestinal disorder or a psychiatric disease, dogenesis. The relative frequencies of these different disor-
especially depression. Adrenal insufficiency may cause ders varies markedly according to the age and gender of the
persistent vomiting, anorexia, hypoglycemia, poor weight patients at their clinical presentation (Figs. 2 and 3 and Table
gain in a child, or unexplained weight loss in an adult,
2). At birth, adrenal hemorrhage from anoxia/sepsis is most
malaise, fatigue, muscular weakness, unexplained isotonic
common, adrenal insufficiency from CAH usually presents
or hyponatremic dehydration, hyperkalemia, hypoten-
in neonates, and in older children it often occurs as part of
sion, hypoglycemia and especially generalized hyperpig-
an autoimmune poly-glandular syndrome or APS. In boys,
mentation (Table 1). In our experience, the development of
adrenoleukodystrophy, DAX-1-related disorders are in-
tiredness with muscular weakness, in particular, can be
important clues as to the underlying diagnosis. The “mud- creasingly recognized, whereas adults have increasing inci-
dy” hyperpigmentation in Addison’s disease is due to the dences of infectious and metastatic adrenal failures.
elevation of MSH and ACTH, caused by the compensatory
activation of hypothalamic-pituitary axis. However, in
Adrenal dysgenesis
rare cases, a defect of melanocyte response can result in the
absence of hyperpigmentation (3). Adrenal development and congenital hypoplasia. Development of
adrenal gland depends on multiple interacting genes. Cur-
Etiologies of Addison’s Disease rently an understanding of this complex process is just be-
Whereas primary adrenal insufficiency last century was ginning. The role of the nuclear hormone receptor gene su-
most commonly due to tuberculosis, autoimmune disease perfamily such as SF-1 (4), the dosage-sensitive sex reversal-
currently accounts for most of the cases presenting outside adrenal hypoplasia gene 1 on Xp21 (DAX-1) (5), and the
ACTH receptor (melanocortin-2 receptor) gene (6) are now
Received January 26, 2001. Revision received March 26, 2001. Ac- known to be important for normal development of adrenal
cepted March 28, 2001. cortex. Mutations in DAX-1, a nuclear hormone receptor
Address correspondence and requests for reprints to: Noel K. Ma-
claren, M.D., Weill Medical College of Cornell University, 1300 York
gene, are associated with adrenal hypoplasia and hypogo-
Avenue, Room LC-623, New York, New York 10021. E-mail: nadism. DAX-1 protein is expressed in the developing uro-
nkmaclaren@aol.com. genital ridge, ovary, testis, adrenal cortex, hypothalamus,

2909

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2910 TEN ET AL. JCE & M • 2001
Vol. 86 • No. 7

TABLE 1. Clinical features of Addison’s disease

Symptoms Signs Biochemical abnormalities

Fatigue Postural hypotension High (supine) plasma renin and/or increased
nighttime ACTH levels
Muscular weakness Weight loss Low ACTH stimulated cortisol responses
Abdominal pain Generalized pigmentation, darkened skin At the time of crisis: normo- or hyponatremia,
creases, pigmented buccal mucosa and nail hyperkalemia, hypoglycemia
beds
Vomiting Associated vitiligo and/or goiter Eosinophilia
Diarrhea Lymphocytosis
Salt craving
Behavior changes
Headache
Sweating
Depression
Muscle and joint pain

FIG. 1. Etiologies of Addison’s disease.

DAX-1, Dosage-sensitive sex reversal-
adrenal hypoplasia gene 1; ACTHR,
ACTH receptor (melanocortin-2 recep-
tor) gene.

and anterior pituitary gland, sites in which it colocalizes with and is essential for development of the adrenal cortex. In
SF-1 (7). contrast, natural mutations in the rabbit gene encoding cho-
lesterol SCC precludes the biosynthesis of all endogenous
SF-1 steroid hormones but does not inhibit the formation of either
SF-1, essential for the development of the adrenal cortex, adrenal glands or gonads (9). These two nuclear receptors
gonads, and ventro-medial nucleus of the hypothalamus, (SF-1 and DAX-1) may act as coregulators and be compo-
is a product of the fushi tarazu factor-1 (FTZ1-F1) gene, nents of a regulatory cascade required for normal gonadal,
mapping to 9q33 and belonging to nuclear receptor super- adrenal, and hypothalamus development. Mice lacking SF-1
family 5, group A, member 1 (NR5A1) (8). SF-1 response fail to develop gonads, adrenals, and hypothalamus (10).
elements are found in the promoters of the genes for the Recently, a 46 XY male pseudohermaphrodite presented at
␣-subunits of the pituitary glycoprotein hormones, müllerian- birth with primary adrenal insufficiency (11). Normal mül-
inhibiting substance, and the promoter of the DAX-1 gene (4). lerian structures were found on ultrasound, and no andro-
In addition, SF-1 is a transcription factor that regulates gene genic response was elucidated after human CG stimulation.
expression of the CYP steroid hydroxylases [21-hydroxylase On histology of the gonads, there were poorly differentiated
(21-OH), the aldosterone synthase isoenzyme of steroid tubules and connective tissue streaks. Within the FTZ1-f1-
11-␤-hydroxylase], cholesterol side-chain cleavage (SCC) gene, a 2-bp mutation was identified in exon 3, which en-
enzyme CYP11A, 3-␤-hydrosteroid dehydrogenase, aro- codes part of the DNA-binding domain of SF-1 (11). The
matase, and steroidogenic acute regulatory protein (StAR) patient demonstrated the critical role of SF-1 in adrenal and

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 CLINICAL REVIEW 2911

FIG. 2. Causes of Addison’s disease in

boys. A/R, Autosomal-recessive.

male gonadal differentiation. Another 46 XX female patient later in life, isolated hypogonadotropic hypogonadism,
who presented at 14 months with adrenal insufficiency with adrenal insufficiency and hypogonadotropic hypogonad-
normal sized uterus and ovaries, and normal LH and FSH ism, delayed-onset adrenal insufficiency from 2–9 yr of age
levels, had a heterozygous mutation in SF-1 gene, indicating with incomplete hypogonadotropic hypogonadism, and
that SF-1 is probably not necessary for normal female go- delayed puberty in females all may result. Cryptorchidism
nadal development, although it has a crucial role in adrenal may also occur. Initial loss of mineralocorticoid functions
formation in both sexes (12). with preserved cortisol responses and a transient recovery
period is possible. Hypogonadism results from combined
AHC hypothalamic, pituitary, and Sertoli cell defects (15).
AHC, a rare familial condition in which the adrenal corticies DAX-1 function may be required for spermatogenesis, in-
have arrested development, occurs in about 1 of 12,500 births dependent of its actions in the hypothalamus and pitu-
(13). The disorder can present as four clinical forms of primary itary. To complicate the issue, an active hypothalamic-
adrenal insufficiency: 1) a sporadic form associated with pitu- pituitary-gonadal axis during first months of life and even
itary hypoplasia (14); 2) an autosomal recessive form with a first years of life has been reported in six affected children
distinct miniature adult adrenal morphology, characterized by (17–20), with prolonged activation of the axis, and even
small glands with a permanent cortical zone but a diminished two cases with early central precocious puberty seen. Un-
fetal zone. The genetic basis of the recessive form of AHC is expectedly, patients with AHC have adequate functions to
unknown (14); 3) an X-linked cytomegalic form associated with support the mini-puberty of infancy but cannot support
hypogonadotropic hypogonadism (15); and 4) an X-linked form normal adolescent puberty, revealing a loss of function
associated with glycerol kinase deficiency (16). over time or else different mechanisms for the mini-pu-
The X-linked cytomegalic form associated with hypogo- berty of infancy from that of adolescent puberty (17, 18).
nadotropic hypogonadism results from mutations of a A delayed puberty in females heterozygous for the DAX-1
DAX-1 gene. The secretion of other pituitary hormones is gene mutation has been reported, as has an isolated hy-
not impaired. Whereas presentation of adrenal insuffi- pogonadotropic hypogonadism in a female due to ho-
ciency is from birth, there is great variability of presen- mozygous DAX-1 mutation (21). Some females who are
tations. Phenotypically, AHC can present in several forms shown not to be carriers for DAX-1 mutations may still be
that do not correlate with genotype. Thus, isolated adrenal at potential risk of having affected sons because of gonadal
insufficiency in infancy, isolated adrenal insufficiency mosaicism.

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2912 TEN ET AL. JCE & M • 2001
Vol. 86 • No. 7

FIG. 3. Causes of Addison’s disease in

girls.

Adrenal hypoplasia as part of contiguous gene androgen secretions are deficient and unresponsive to ACTH
deletion syndrome stimulation. The disease usually manifests within the first
An X-linked form of adrenal insufficiency, associated with year of life but may present in infancy or later childhood.
glycerol kinase deficiency is characterized by psychomotor Inactivating mutations of the G protein-coupled ACTH re-
retardation, muscular dystrophy, characteristic facies with ceptor (melanocortin-2 receptor) are found in 40% of FGD
hyperthelorism, alternating strabismus, and drooping kindreds (FGD type-1), however, no such mutations are
mouth. Additional phenotypic features can include testicular identifiable in the remaining 60% of cases (FGD type-2). FGD
abnormalities (anorchia or cryptorchidism), short stature, type-1 mutations result in a failure of adrenocortical orga-
and osteoporosis. Time of presentation can vary from birth nization with absent zona fasciculatae and reticularae. Al-
through childhood. About 100 patients from 78 unrelated dosterone secretion is normal or only partially deficient, and
families have been reported, and all but 1 patient were male. responds to postural stimuli and volume depletion. Pheno-
The genetic locus was mapped to Xp21 and variants of con- typically FGD type-1 patients are significantly taller than
tiguous gene deletion syndrome (glycerol kinase deficiency, type-2 patients (6).
Duchenne muscular dystrophy, ornithine transcarbamylase Allgrove’s syndrome (triple A) is characterized by the triad
deficiency, and mental retardation) can be seen. The gene of ACTH resistance, achalasia, and alacrimia. Presenting in the
order has been determined from the centomere is -OTC- first decade of life, it is frequently associated with progressive
DMD-GK-DAX-1-DSS, whereas patients with contiguous neurological dysfunction, polyneuropathy, deafness, mental re-
gene deletion syndrome have features of each of the indi- tardation, and hyperkeratosis of palms and soles. Mineralo-
vidual genes involved (Fig. 4). All patients have loss of the corticoid deficiency develops in about 15% of cases. It is an
GK locus together with one or more closely flanking genes, autosomal recessive disorder mapping to 12q13, but the gene
most frequently AHC and DMD. Larger deletions, extending has yet to be identified. No ACTH receptor mutations have
to include the ornithine transcarbamylase deficiency have been found in Allgrove’s syndrome (6).
been also described (16).

Familial glucocorticoid deficiency (FGD) Adrenal destruction

Corticotropin resistance syndrome or FGD can present as Autoimmune Addison’s disease. Autoimmune Addison’s dis-
an FGD or as Allgrove’s syndrome (triple A syndrome). FGD ease is a major part of type-1 and -2 APS (APS-1 and APS-2).
is a rare autosomal recessive disorder in which cortisol and The definition of the type of APS is clinically important in

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 TABLE 2. Genetic etiology of adrenal insufficiency

Chromosomal Gluco- Mineralo-

Disease Incidence Defective gene Clinical features Androgens Other laboratory features
location corticords corticords
APS 1 1:9,000 – AIRE-1 gene 21q22 Adrenal insufficiency with 2 2 2 1 ACA, 21-OHA, SCA
25,000 hypoparathyroidism and mucocutaneus
candidiasis
APS 2 and isolated AAD 1:20,000 HLA 6p21 Adrenal insufficiency with IDM and 2 2 2 1 ACA, 21-OHA, SCA
CTLA-4 2q33 autoimmune thyroiditis
SF-1 Rare SF-1 9q33 In boys male pseudohermaphroditism, but 2 2 2
normal gonads development in girls
CAH 1:12,500 DAX-1 Xp21 Hypogonadism, no puberty 2 2 2
Contiguous gene deletion Rare DAX-GK-DMD Genomic deletion Hypertheloric appearance, with wide-set 2 2 2 Pseudotriglyceridemia,
syndrome between Xp21.3– eyes, alternating strabismus and a elevated glycerol in the
p21.2 drooping mouth serum, urine
FGD1 Rare ACTHR gene 18p11 Absence of mineralocorticoid deficiency, tall 2 Nl Nl 2 DHEAS, hypoglycemia
stature, lack of adrenarche
Triple A syndrome Rare Unknown 21q13 Achalasia, alacrimia, adrenal insufficiency 2 2in 15% Nl Hypoglycemia
CLINICAL REVIEW

ALD 1:20,000 ALDP Xq28 Progressive behavioral and neurological 2 2 2 VLCFA 1

deficits
Mitochondrial adrenal Rare mtDNA mtDNA Lactic acidosis, myopathy, cataracts, short 2 2 2 Lactate 1
insufficiency stature, sensorineural hearing loss,
metaphyseal dysplasia
SLOS 1:20,000 to Sterol delta-7- 11q12– q13 Ambiguity of male external genitalia, 2 2 2 High 7-dehydrocholesterol/
30,000 reductase gene failure of masculinization, polydactyly, cholesterol ratio
(DHCR7) 2/3 toe syndactyly, photosensitivity,
mental retardation
AAD, Autoimmune Addison’s disease; mtDNA, mitochondrial DNA; DHCR7, sterol ⌬-7-reductase gene.

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2913
2914 TEN ET AL. JCE & M • 2001
Vol. 86 • No. 7

FIG. 4. Contiguous gene deletion syn-

drome. DAX-1, Dosage-sensitive sex re-
versal-adrenal hypoplasia gene 1; GKD,
glycerol-kinase deficiency; DMD/BMD,
Duchenne/Becker muscular dystrophy;
Il1RAPL-1, gene for interleukin 1 re-
ceptor family; OTCD, ornitine transcar-
bamoylase deficiency.

predicting the potential occurrence of the other associated gastritis/pernicious anemia, vitiligo, and/or IMD, but not
diseases both in patients and family members. Addison’s disease (25). APS-2/3 have strong female biases
APS-1 is defined by the presence of three principle com- and can occur at any age, but with adult peak onsets of about
ponents of the disease: chronic mucocutaneous candidiasis 30 yr. Whereas the order of appearance of the clinical com-
or moniliasis, acquired hypoparathyroidism, and autoim- ponents of the disease can vary, the multiple prodromal
mune [adrenal autoantibody (AA) positive] Addison’s dis- autoimmunities are often ongoing simultaneously. Autoim-
ease, albeit chronic active hepatitis, malabsorption/chronic mune Addison’s disease can develop slowly over many years
diarrhea and alopecia universalis are common while girls are before symptoms appear, making screening of patients with
invariably hypogonadal by puberty. APS-1 affects males and IMD and autoimmune thyroiditis for AAs valuable for early
females equally and often first manifests during infancy or identification of the disease. Some 1 in 200 –300 patients with
early childhood. APS-1 is a rare recessive disease that has the IMD will develop antibody-positive Addison’s disease. Au-
highest incidences in genetically isolated populations, such toantibodies to 21-OH occur in 2% of patients with IMD and
as Iranian Jews (1 in 600 –9,000; Ref. 22), Finns (1 in 25,000; 3% of patients with Grave’s disease (26). Celiac disease, pri-
Ref. 23), and Sardinians (24), where founder effects are prob- mary hypogonadism, chronic active hepatitis, and myasthe-
able. Chronic mucocutaneous candidiasis caused by the in- nia gravis infrequently occur in APS-2.
fection of Candida albicans is usually the initial feature, almost The presence of circulating autoantibodies to endocrine
always involving the mouth, and later the nails. Hypopara- antigens is a serologic characteristic of Addison’s disease and
thyroidism usually occurs next, but hypocalcemia can be other components of the APS (Table 3).
masked by untreated Addison’s disease and only become After the appearance of antibodies to the adrenal cortex
declared by steroid replacement therapy (25). Juvenile onset and/or to 21-hydroxylase (21-OHA), the first evidence of
pernicious anemia, vitiligo, anterior hypophysitis, celiac dis- adrenal insufficiency is usually an increase in PRA after
ease, and myositis can be additional features, with less fre- patients have been recumbent for more than 0.5 h. The raised
quent immune-mediated (type-1) diabetes (IMD), thyroid renin level is due to a failing zona glomerulosa with salt loss,
autoimmunity, and ectodermal dysplasias, especially among with low-normal or low plasma aldosterone concentrations
affected Finns. (27). Zona fasciculata dysfunction can become evident
APS-2 is defined by autoimmune Addison’s disease to- months to years later, first by raised afternoon serum ACTH
gether with autoimmune thyroid disease (Schmidt’s syn- levels, then by decreasing serum cortisol responses to
drome) and/or IMD (Carpenter’s syndrome). APS-3 is au- (ACTH) stimulation, and finally by decreasing basal serum
toimmune thyroid disease in association with atrophic cortisol concentrations and the appearance of symptoms

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 CLINICAL REVIEW 2915

TABLE 3. Circulating antibodies to endocrine antigens in autoimmune polyglandular syndromes

Autoantigen Tissue/cells Reference

Addison’s disease 21-OH, P450 scc Enzymes of the adrenal cortex 27
17-OH 28
Hypogonadism, premature menopause CYP450 scc Ovary: granulosa/theca cells 29
17-OH Testis: Leydig cells
Placenta: syncytiotrophoblasts
Hashimoto’s thyroiditis/hypothyroidism Thyroid peroxidase Thyroid enzyme 30
Thyroglobulin Thyroid secreted protein 31
TSHr (blocking) Thyrocytes
Thyrocytes and extra ocular fat cells
Graves’ TSHr (stimulating)
Hypoparathyroidism Calcium sensing receptor Parathyroid/?other tissues 32
IMD GAD65 38KDa Pancreatic ␤ cells 33
IA-2, IA2␤ 34, 35
Insulin
L-aminoacid decarboxylase
Note antibody is seen as an ICA but
is not associated with diabetes in
APS-1
Vitiligo Tyrosinase Melanocyte 36
Alopecia areata Tyrosine hydroxylase Scalp cells 37
Pernicious anemia H⫹,K⫹ ATPase Gastric parietal cells 38, 39
Achlorhydria Intrinsic factor Gastric mucosa and chief cells
Chronic hepatitis active P450D6, 2C9 Hepatocytes 40, 41
P450 1A2 42, 43
Celiac disease Antigliadin Small intestine 44
Antiendomysial 45
Transglutaminase 46
Malabsorption Tryptophan hydroxylase Intestine chromaffin cells 47

FIG. 5. Natural history of Addison’s

disease. ACA, Adrenal cell antibody;
P450SCC, side chain cleavage enzyme.

(Fig. 5). Thus, these autoantibodies are useful markers for the
prediction of the development of Addison’s disease, partic-
ularly so for children (28). There are two types of antibodies
detected by microscopic immunofluorescence: AAs reacting
with only the adrenal cortex and steroidal cell antibodies
(SCAs) that react with all steroid hormone-producing cells.
One autoantigen is involved in reactions of AA is the protein
of P450 21-OH enzyme, with epitopes in the central segment
of the enzyme and the C-terminal portion (29, 30). Compo-
nent antigens for SCA have been recognized to be other P450
enzymes, 17-␣-hydroxylase (17-OH) (31) and SCC enzyme
(32). Almost all patients with both Addison’s disease and
gonadal failure have positive 17-OH and SCC antibodies and
APS-1.
Cell-mediated immune processes are important autoim-
mune adrenal insufficiency. Lymphocytic infiltrations of the
adrenal glands are associated with follicle formation and loss
of adrenocortical cells with scarring. The cellular defect in the
APS may be associated with abnormal balances in cytokine
production by T cells. The subgroups of T helper (Th) cells—
Th1 and Th2, natural killer cells (NK-T)—produce a different
profile of cytokines. Th1 cells secrete interferon-␥, interleukin
2, and tumor necrosis factor ␣, whereas Th2 cells secrete
interleukins 4, 5, and 10. A polarized Th2 response is asso-

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2916 TEN ET AL. JCE & M • 2001
Vol. 86 • No. 7

ciated with Graves’ disease, and Th1 with IMD. APS-1 result ALD
from biased Th2 immune responses to self-antigens and de- Defective ␤-oxidation of very long chain fatty acids
fective protective Th1 responses against invasion of yeast C. (VLCFAs; chain length of 24 carbons and above) in ALD
albicans (26). results in adrenal insufficiency and a progressive demye-
A major advance in understanding the genetic suscep- lination within the central nervous system. ALD affects 1 in
tibility of the APS was made evident when the gene 20,000 males. Whereas VLCFA levels in plasma are already
responsible for APS-1 was independently isolated and increased at birth in affected siblings, ALD does not usually
described as the autoimmune regulator (AIRE) (33, 34). present clinically before 3 yr of age (37). The responsible ALD
The AIRE gene consists of 14 exons spanning 11.9 kb of gene mapping to Xq28, encodes the peroxisomal membrane
genomic DNA, which maps to the long arm of chromo- adrenoleukodystrophy protein (ALDP) that belongs to the
some 21 (21q22.3). The AIRE gene is expressed as mes- ATP-binding cassette superfamily of transporters. ALDP im-
senger RNA (mRNA) in thymus, lymph nodes, pancreas, ports activated acyl-CoA derivatives (VLCFA-CoA) into per-
adrenal cortex, and peripheral blood mononuclear cells. oxisomes where they are shortened through the ␤-oxidation
The AIRE protein contains two zinc finger (PHD-finger) pathway (Fig. 6). Curiously, ALD knockout mice do not
and three LXXLL motifs that facilitate the interaction of develop demyelination, probably because they have an ALD-
different proteins with nuclear receptors, and a proline- related protein redundancy in their brains when compared
rich region typical of a nuclear transcription factor. More with humans, which allow for other ATP-binding cassette
than 20 different mutations in the AIRE gene have been transporters to compensate for the ALDP defect (38). Phe-
detected in APS-1 patients with various ethnic back- notypes in male patients range from the rapidly progressive
grounds. R257X (exon 6) is the dominant mutation for the childhood form, affecting boys between 5–12 yr (40% of
Finnish and North Italian patients, whereas 1094del13 ALD), to milder forms of adreno-myeloneuropathy (30% of
(exon 8) is a dominant mutation for British and American ALD) or isolated adrenal insufficiency (15% of ALD) (37).
Caucasians and R139X (exon 3) is the dominant mutation The well described albeit rare Sertoli-cell-only syndrome
in Sardinian patients with APS-1. There are no clear cor- results from accumulation of VLCFA in Leydig cells of the
relations between the mutations in the AIRE gene and testes, and presents with diminished libido, impotence and
APS-1 phenotypes reported. However, patients with the infertility. More then one clinical expression can appear
same AIRE mutation often present with different compo- within a single pedigree and there are no clear correlations
nents of the diseases of the APS-1, suggesting roles for between genotype and phenotype, even within the same
environmental factors and background (epistatic) genes. kindred (37). In patients with isolated adrenal insufficiency,
The gene encoding the cytotoxic T lymphocyte antigen-4 clinical neurological manifestations may appear years later.
(CTLA-4) plays an important role in the down-regulation Diagnostically, plasma VLCFAs tests should be done in all
of T-cell activity whereas CTLA-4 polymorphisms have males with adrenal insufficiency but no adrenal autoanti-
been associated with Addison’s disease (35). The future bodies (28).
Some 1–3% of women who are heterozygous carriers of
research directions will be investigation of the role of AIRE
the disorder have been reported to develop neurological
protein in maintaining normal self-tolerance. It may be
disability, whereas 1–1.5% eventually develop adrenal in-
that the AIRE gene is involved in negative selection of
sufficiency (37). Other of these women develop isolated
self-reactive T-cell clones in the thymus and thereby in
mineralocorticoid insufficiency, subclinical decreases in
maintaining self-tolerance. Whatever its immunological
glucocorticoid reserves, low serum cortisol levels, and
functions, a recessive mutation of the AIRE gene inevitably
exaggerated serum ACTH responses to CRH. Prenatal
results in widespread autoimmunities. diagnosis of ALD is possible using determinations of
In our experience however, the AIRE gene is not involved in VLCFA in cultured cultured villus sampling cells and/or
patients with isolated Addison’s disease or APS-2, whereas amnioitic fluid or by assay of ALDP by immunoblotting or
obligatory heterozygote parents of children with APS-1 display immunofluorescence or by DNA analyses of the fetal cells
neither the autoantibodies nor the component diseases of their and maternal leukocytes (39).
offspring. Whereas APS-1 is not influenced by HLA phenotype, Lorenzo’s oil, a 4:1 mixture of glyceryl-troleate and
APS-2/3 pedigrees by contrast express an autosomal dominant- glyceryl-trierucate, has shown little therapeutic benefit (37).
like pattern of inheritance with an incomplete penentrance, Preliminary data suggest that lovastatin, a hydroxy-methyl-
strongly influenced by HLA-DR/DQ phenotype. Thus, glutaryl coenzyme A CoA reductase inhibitor, and feno-
IMD and islet cell autoimmunity is related to the fibrate can lead to overexpression of adrenoleukodystrophy-
DRB1*0401or0405/DQA1*0301/DQB1*0302andDRB1*03/ related protein (ALDRP), but these therapies are controversial
DQA1*0501/DQB1*0201 haplotypes whereas DRB1*0403, (40, 41). Bone marrow transplantations have been performed on
DRB1*0406 and DQB1*0602 are dominantly protective. more than 90 ALD patients with clinical benefits reported if
Hashimoto’s thyroiditis is associated with DQB1*0301 done at an early stage of the disease (42). Gene therapy has been
while Graves disease is associated with DRB3*0201 and attempted to correct the defect in VLCFA by targeting expres-
DRB1*07 is protective (36). Addison’s disease in the con- sion of the ALD gene to hematopoietic stem cells (CD34⫹)
text of APS-2 is associated with DR3 haplotypes, whereas (43). Pharmacological induction of ALDRP by butyric acid
in unpublished studies of our own vitiligo seemed to be analogs, such as 4-phenylbutyrate should be evaluated,
associated with DRB1*1301, albeit this needs confirmation. because in an initial report 4-phenylbutyrate treatment of

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 CLINICAL REVIEW 2917

FIG. 6. Role of ALDP in ␤-oxidation of

VLCFA. PMP70, More distantly related
ALDRP.

fibroblasts from patients with X-linked adreno-leukodys- diagnosed at birth. Males, however, often go undiagnosed
trophy increased the expression of ALDRP, improved ox- until they present with a salt-wasting crises often 2–3 weeks
idation of VLCFAs, and reduced VLCFA levels (44). after birth. Deficiency of 3␤-hydroxysteroid dehydrogenase
deficiency or P450cc enzyme also can present with adrenal
Infectious Addison’s disease: insufficiency in neonatal period, with affected boys present-
Infectious forms of the disease are relatively rare in the ing with ambiguous genitalia or as phenotypically females.
United States, however, in developing nations such as India, CAH due to defects in aldosterone synthetase leading to
tuberculosis is the most common cause. Thus, in all instances isolated aldosterone deficiency are not associated with sex-
of unexplained Addison’s disease, a purified protein derivative ual ambiguity (Table 4, adapted from P. C. White and P. W.
(of tuberculosis) skin test should be carried out. However, in Speiser, 2000). Prenatal diagnosis by direct mutation detec-
India and other countries the test is not informative because tion permits prenatal treatment of affected females by dexa-
bacille calmette guierin is widely given at birth, while contacts methasone to minimize genital virilization, when given be-
with infected persons may give positive tests even when active fore the seventh to eighth week of gestation (50).
disease is quiescent. AIDS patients may have decreased adrenal Congenital lipoid adrenal hyperplasia (lipoid CAH)
reserve and are increasingly prone to have tuberculosis (45).
Fungal diseases such as histoplasmosis and coccidio-mycosis Lipoid CAH is the most severe form of CAH, involving
are uncommon additional causes (46, 47). deficiencies of glucocorticoids, mineralocorticoids, and
sex steroids. Lipoid CAH is caused by mutation in the
Adrenal hemorrhage StAR gene that maps to 8p11. Affected individuals are all
phenotypically female regardless of karyotype. The LH-
In meningococcal septicemias, hemorrhage into the adre- dependent StAR protein stimulates cytochrome P450SCC
nal glands may complicate the clinical picture leading to activity, enhancing cholesterol transport from the outer to
circulatory collapse (Waterhouse-Freiderickson syndrome). the inner mitochondrial membranes. The two-hit model of
Pseudomonas auregenosa may also be associated with ad- lipoid CAH results from low initial levels of StAR-
renal hemorrhage (48). Asplenia is associated with higher independent steroidogenesis, leading to a complete loss of
frequency of adrenal hemorrhage in case of septicemia. Sep- steroid hormones due to cellular destruction by accumu-
tic shock in newborns, especially in those who are small for lated lipids. This explains the presence of androgen-
dates, may result in adrenal hemorrhage with rhabdomy- dependent Wolffian duct remnants in 46,XY fetuses and
elysis and renal insufficiency. The antiphospholipid syn- the delayed onset of mineralocorticoid deficiency in many
drome is also associated with adrenal hemorrhage (49). patients. The two-hit model also correctly predicted that
affected 46,XX patintes would undergo spontaeous pu-
Impaired steroidogenesis
berty, as seen in StAR knockout mice (51).
CAH. CAH due to 21-OH deficiency is the most common
cause of salt-wasting adrenal crisis in the first 2 weeks of life, Mitochondrial forms of Addison’s disease
with an incidence of 1 in 10,000 –18,000 live births. Affected Adrenal insufficiency can result from a mitochondrial dis-
females have ambiguous, virilized genitalia and are usually orders, characterized by chronic lactic acidosis, myopathy,

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 2918

TABLE 4. Characteristics of different forms of CAH

Gene Chromosomal Gluco- Mineral- Electrolytes

Disease Incidence Characteristic feature Androgens Elevated metabolities
defect location corticoids corticoids during crises
CAH 21-hydroxylase 1:10,000 – CYP21 6p21.3 Ambiguous genitalia in 2 2 1 1 17-OHP Na 2
deficiency 18,000 girls, precocious K1
puberty in boys Acidosis ⫹
CAH 3␤-hydroxysteroid Rare HSD3B2 1p13.1 Ambiguous genitalia in 2 2 1in girls DHEA, 17⌬5Preg Na 2
dehydrogenase boys, mild in girls 2in boys K1
deficiency Acidosis ⫹
CAH 11 ␤-hydroxylase 1:100,000 CYP11␤1 8q24.3 Ambiguous genitalia in 2 1 1 DOC, 11-deoxycortisol Na 1
deficiency girls, elevated BP K2
Alcolosis ⫾
CAH 17 ␣-hydroxylase Rare CYP17 10q24.3 Ambiguous genitalia in Nl 1 2 DOC, corticosterone Na 1
deficiency boys, no puberty in K2
girls, elevated BP Alcolosis ⫾
Congenital lipoid Rare StAR 8p11.2 All affected patients are none
TEN ET AL.

2 2 2 Na 1
adrenal hyperplasia phenotypically female. K2
46 XX female can Acidosis
undergo normal
puberty, with the
development of
hypogonadism later
Aldosterone synthase Rare CYP11␤2 8q24.3 Failure to thrive, salt- Nl 2 Nl Corticosterone, ⫾ 18- Na 1
deficiency wasting hydroxycorticosterone K2
Alcolosis ⫾
17-OHP, 17-Hydroxyprogesterone; DOC, deoxycorticosterone; DHEA, dehydroepiandroesterone; 17⌬5Preg. 17-⌬5-hydroxypregnenolone; Nl, normal. The table is adapted from
White et al. (2000).

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Vol. 86 • No. 7
JCE & M • 2001
 CLINICAL REVIEW 2919

cataracts, and nerve deafness (52–54). Cases with the Kearns- adolescents (65, 66). This rate translates to about 10 –12 mg/
Sayre syndrome form of mitochondrial myopathy, deafness, m2䡠day of oral hydrocortisone, to allow for step-down losses
with large-scale deletions in mitochondrial DNA are often from absorption, hepatic processing, and metabolic bioavail-
associated with endocrine dysfunctions, particularly short ability. In children, the preferred cortisol replacement is hy-
stature, hypogonadism, diabetes, hypoparathyroidism, drocortisone in doses 10 –20 mg/m2䡠day in three divided
hypothyroidism, and adrenal insufficiency (55, 56). doses. However, there are several difficulties in choosing the
optimal dose. It is not possible to emulate natural circadian
Defective cholesterol metabolism rhythm of cortisol since the natural peak starts with the onset
of rapid eye movement sleep in early hours of the morning,
Most cortisol is synthesized from cholesterol brought to
and the peak blood level resulting from the morning dose of
the adrenals by circulating low-density lipoproteins (LDLs)
hydrocortisone on awakening, comes several hours late. This
or high-density lipoproteins. As a result, patients without
transient early morning adrenal insufficiency can account for
LDLs, such as those with abetalipoproteinemia, or without
the symptoms of fatigue, lassitude, mild nausea, or headache
LDL receptors, such as those with homozygous familial hy-
that are often present on awakening and that are relieved
percholesterolemia, have moderately impaired serum corti-
within 30 – 60 min after taking the morning dose of hydro-
sol responses to ACTH, although they maintain normal basal
cortisone (67). The same related problem occurs with diffi-
cortisol secretions and do not develop clinically significant
culties in suppression of nocturnal ACTH secretion. The
adrenal insufficiency (57).
early morning adrenal insufficiency with the traditional reg-
imen results in plasma ACTH concentrations that are much
Smith-Lemli-Opitz syndrome (SLOS) higher than normal for several hours in the early morning
The syndrome results from mutations in the sterol ⌬-7- (68, 69), leading to persistent hyperpigmentation. Further-
reductase gene (DHCR7), which catalyzes the final step in more, because ACTH secretion may, thus, become inade-
cholesterol biosynthesis leading to primary adrenal insuffi- quately inhibited on a chronic basis by incomplete glucocor-
ciency. The gene maps to 11q12-q13. SLOS can present with ticoid negative feedback inhibition, it may eventually
typical facial appearance, mental retardation, microcephaly, become poorly suppressible, leading to the development of
proximally placed thumbs, congenital cardiac abnormalities, pituitary hyperplasia or, rarely, a corticotroph adenoma (70 –
syndactyly of the second and third toes, incomplete devel- 76). Such morning peaks of ACTH can be ameliorated, by
opment of the male genitalia in boys, and photosensitivity. changing the bedtime dose of hydrocortisone to an equiva-
Three unrelated patients with SLOS presented with adrenal lent dose of dexamethasone (77, 75). Because availability of
insufficiency and failure to masculinize. A primary defect in orally ingested hydrocortisone is variable (78) the patient can
the fetal adrenals resulting in a combination of low maternal be easily over-treated and under-treated. Whereas both sit-
estriol levels, sex reversal, and large adrenal glands in the uations are undesirable, under-treatment can be life-threat-
fetus with SLOS has been demonstrated. Preliminary studies ening. Patients can present with chronic fatigue, reduced
suggest that cholesterol supplementation may be of benefit resistance to illness, postural hypotension, and have risk of
to patients with the SLOS (58). nocturnal hypoglycemia. Chronic, borderline under-replace-
ment can predispose the patient to more severe crises in case
Drugs of recurrent illness or accident, particularly if they are unable
to absorb their replacement therapy because of gastrointes-
Several drugs may inhibit cortisol biosynthesis. The list
tinal upset or chronic malabsorption as in APS-1. The FDA
includes aminoglutethimide (59), etomidate (60), ketocon-
withdrew oral hydrocortisone suspension from the market
azole (61), methyrapone (62), and suramin (63). Patients with
because of poor absorption and under-treatment of children.
limited pituitary or adrenal reserve are those most likely to
The problems of excess of corticosteroid replacement are
develop drug-induced adrenal insufficiency. Drugs that ac-
well known. They include weight gain, high blood pressure,
celerate cortisol metabolism are phenytoin, barbiturates, and
hyperglycemia, suppression of growth rate, easy bruising,
rifampin (64).
cardiovascular risk, raised intraocular pressure, gastric ul-
cers, poor wound healing, striae of the skin, and osteoporosis
Corticosteroid replacement therapy
(79). Peacey et al. (80) demonstrated increase in serum os-
In Addison’s disease, replacement of glucocorticoid and teocalcin in response to glucocrticoid dose adjustment. The
mineralocorticoid hormones are essential for health and in- absence of signs of steroid excess in the context of necessity,
deed life, however, there is no clear indications for replace- increasing doses are suggestive of poor compliance, malab-
ment of adrenal adrenogens such as dihydroepiandros- sorbtion or increased catabolism. Thyrotoxicosis is associ-
terone. We will not discuss the latter controversy here ated with increased breakdown of gluco- and mineralocor-
because we do not offer it to our patients. We will also not ticoids as well as estradiol, whereas patients with an APS
discuss the dangers of adrenal insufficiency due to too rapid may be complicated by unrecognized celiac disease. In such
withdrawl of long-term therapeutic glucocorticoid therapy cases, gliadin, reticulin, endomysial, and tissue transglutami-
here. nase and TSH receptor autoantibodies should be evaluated
Corticosteroid and mineralocorticoid replacement thera- (81). It is important to be aware that the treatment of hypo-
pies should suppress the excessive secretion of CRH, ACTH, thyroidism in case of unrecognized adrenal insufficiency
and resting renin levels. The normal daily cortisol production may trigger an adrenal crises.
rate has been shown to be 6 –7 mg/m2/day in children and Mineralococrticoid replacement is readily accomplished

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2920 TEN ET AL. JCE & M • 2001
Vol. 86 • No. 7

FIG. 7. Diagnostic workup for adrenal

insufficiency. ACA, Adrenal cell anti-
bodies; SCA, steroid cell antibodies; HP,
hypoparathyroidism; MC, mucocutane-
ous candidias; AT, autoimmune thy-
roiditis; IMD, immune mediated diabe-
tes; AAD, autoimmune Addison’s
disease; DAX-1, dosage-sensitive sex
reversal-adrenal hypoplasia gene 1;
GK, glycerol-kinase; DMD, Duchenne
muscular dystrophy.

by fluorohydrocortisone (fluorinef, 0.05– 0.2 mg daily). Hy- to give otherwise mineralocorticoids over such periods if the
pertension, bradycardia, suppressed renin levels, and retar- patient begins the operative period in adequate salt balance.
dation in growth rate are clinical signs of over-treatment with
mineralocorticoids (82, 83). Older children do not require Summary
daily supplements with salt, whereas infants should have Addisonian crisis represents an endocrine emergency that requires a
sodium chloride supplement 1–2 g daily (1 g contains 17 mEq correct diagnosis with identification of the cause (Fig. 7), with prompt
of sodium). The sodium content of the formulas or breast and appropriate salt and steroid replacements to save the patient. It is,
milk is only about 8 mEq/L, which is only enough for main- however, unusual that the patient does not exhibit clear warning signs
of this impending disaster long before the event. Thus, physicians
tenance of sodium content in healthy infants. Fortunately, should have a high index of suspicion in a variety of unexplained chronic
humans have a well developed sense of salt homeostasis, and symptoms and signs. Great advances have been made into understand-
salt craving commonly occurs when a patients is deficient of ing the many causes of the disease in the 150 yr since its first description
total body salt. Excess salt is often needed during the sum- by Addison, and such advances translate into better diagnostic algo-
mer, because aldosterone affects the salt content of sweat, rithms (Fig. 7) and specific therapies than were previously possible.
being higher in patients with adrenal insufficiency. Well-
Acknowledgments
being, weight gain, blood pressure, growth rate, and skin
pigmentation are the most useful clinical markers of ade- We thank the Genentech Growth Foundation for grant support, The
quacy of replacement therapy, whereas plasma ACTH and Adrenal Foundation of America, and our patients for their participation
and support in our studies.
renin levels are useful in following patients on replacement
therapy (79). References
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