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*Addison's Disease
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 7 2909-2922
Copyright © 2001 by The Endocrine Society

Special Features

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

Address correspondence and requests for reprints to: Noel K. Maclaren, M.D., Weill Medical College of Cornell University, 1300 York Avenue, Room LC-623, New York, New York 10021. E-mail: nkmaclaren{at}aol.com

Abstract

Whereas it is now more than 150 yr since T. Addison first described the clinical and pathological features of adrenal failure (1 ), the disease remains underdiagnosed, leading to unnecessary morbidity and mortality. Over the past decade, there have been important advances in elucidating the pathogeneses and underlying genetics of the individual forms of the disease. This review emphasizes the multiple etiologies and the diagnostic steps to be taken with consideration to age at onset and gender and summarizes new genetic insights in the disease.

ADRENAL INSUFFICIENCY, OR Addison’s disease, can present as a life-threatening crises, because it is frequently unrecognized in its early stages. A relatively uncommon disease in Western countries at an estimated prevalence rate near 120 per million (2), a survey of patients with Addison’s disease who are members of the National Adrenal Disease Foundation revealed that 60% had sought medical attention from two or more physicians before the correct diagnosis was ever considered. No figures are available on the number of undiagnosed patients succumbing to adrenal insufficiency. Thus, physicians are advised to keep a high index of suspicion of adrenal insufficiency in unexplained illnesses. Adrenal insufficiency can present with ill-defined fatigue and weakness. It can mimic a gastrointestinal disorder or a psychiatric disease, especially depression. Adrenal insufficiency may cause persistent vomiting, anorexia, hypoglycemia, poor weight gain in a child, or unexplained weight loss in an adult, malaise, fatigue, muscular weakness, unexplained isotonic or hyponatremic dehydration, hyperkalemia, hypotension, hypoglycemia and especially generalized hyperpigmentation (Table 1Go). In our experience, the development of tiredness with muscular weakness, in particular, can be important clues as to the underlying diagnosis. The "muddy" hyperpigmentation in Addison’s disease is due to the elevation of MSH and ACTH, caused by the compensatory activation of hypothalamic-pituitary axis. However, in rare cases, a defect of melanocyte response can result in the absence of hyperpigmentation (3).


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  		Table 1. Clinical features of Addison’s disease

 
Etiologies of Addison’s Disease

Whereas primary adrenal insufficiency last century was most commonly due to tuberculosis, autoimmune disease currently accounts for most of the cases presenting outside 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 steroidogenesis (Fig. 1Go). Congenital adrenal hypoplasia (AHC), mutations of steroidogenic factor-1 (SF-1), and ACTH unresponsiveness can all lead to adrenal dysgenesis/hypoplasia, albeit the latter usually results in isolated deficiency of gluco-corticoids. Autoimmune polyglandular syndrome (APS), adrenoleukodystrophy (ALD), adrenal hemorrhage, adrenal metastases, infections, and amyloidoses can all lead to destruction of adrenal gland. Congenital adrenal hyperplasia (CAH), mitochondrial disorders, the Smith-Lemli-Opitz syndrome (SMOS), an enzyme deficiency in cholesterol metabolism, can all lead to impaired steroidogenesis. The relative frequencies of these different disorders varies markedly according to the age and gender of the patients at their clinical presentation (Figs. 2Go and 3Go and Table 2Go). At birth, adrenal hemorrhage from anoxia/sepsis is most common, adrenal insufficiency from CAH usually presents in neonates, and in older children it often occurs as part of an autoimmune poly-glandular syndrome or APS. In boys, adrenoleukodystrophy, DAX-1-related disorders are increasingly recognized, whereas adults have increasing incidences of infectious and metastatic adrenal failures.



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  		Figure 1. Etiologies of Addison’s disease. DAX-1, Dosage-sensitive sex reversal-adrenal hypoplasia gene 1; ACTHR, ACTH receptor (melanocortin-2 receptor) gene.

 


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  		Figure 2. Causes of Addison’s disease in boys. A/R, Autosomal-recessive.

 


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  		Figure 3. Causes of Addison’s disease in girls.

 

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  		Table 2. Genetic etiology of adrenal insufficiency

 
Adrenal dysgenesis

Adrenal development and congenital hypoplasia. Development of adrenal gland depends on multiple interacting genes. Currently an understanding of this complex process is just beginning. The role of the nuclear hormone receptor gene superfamily such as SF-1 (4), the dosage-sensitive sex reversal-adrenal hypoplasia gene 1 on Xp21 (DAX-1) (5), and the ACTH receptor (melanocortin-2 receptor) gene (6) are now known to be important for normal development of adrenal cortex. Mutations in DAX-1, a nuclear hormone receptor gene, are associated with adrenal hypoplasia and hypogonadism. DAX-1 protein is expressed in the developing urogenital ridge, ovary, testis, adrenal cortex, hypothalamus, and anterior pituitary gland, sites in which it colocalizes with SF-1 (7).

SF-1

SF-1, essential for the development of the adrenal cortex, gonads, and ventro-medial nucleus of the hypothalamus, is a product of the fushi tarazu factor-1 (FTZ1-F1) gene, mapping to 9q33 and belonging to nuclear receptor superfamily 5, group A, member 1 (NR5A1) (8). SF-1 response elements are found in the promoters of the genes for the {alpha}-subunits of the pituitary glycoprotein hormones, müllerian-inhibiting substance, and the promoter of the DAX-1 gene (4). In addition, SF-1 is a transcription factor that regulates gene expression of the CYP steroid hydroxylases [21-hydroxylase (21-OH), the aldosterone synthase isoenzyme of steroid 11-ß-hydroxylase], cholesterol side-chain cleavage (SCC) enzyme CYP11A, 3-ß-hydrosteroid dehydrogenase, aromatase, and steroidogenic acute regulatory protein (StAR) and is essential for development of the adrenal cortex. In contrast, natural mutations in the rabbit gene encoding cholesterol SCC precludes the biosynthesis of all endogenous steroid hormones but does not inhibit the formation of either adrenal glands or gonads (9). These two nuclear receptors (SF-1 and DAX-1) may act as coregulators and be components of a regulatory cascade required for normal gonadal, adrenal, and hypothalamus development. Mice lacking SF-1 fail to develop gonads, adrenals, and hypothalamus (10). Recently, a 46 XY male pseudohermaphrodite presented at birth with primary adrenal insufficiency (11). Normal müllerian structures were found on ultrasound, and no androgenic response was elucidated after human CG stimulation. On histology of the gonads, there were poorly differentiated tubules and connective tissue streaks. Within the FTZ1-f1-gene, a 2-bp mutation was identified in exon 3, which encodes part of the DNA-binding domain of SF-1 (11). The patient demonstrated the critical role of SF-1 in adrenal and male gonadal differentiation. Another 46 XX female patient who presented at 14 months with adrenal insufficiency with normal sized uterus and ovaries, and normal LH and FSH levels, had a heterozygous mutation in SF-1 gene, indicating that SF-1 is probably not necessary for normal female gonadal development, although it has a crucial role in adrenal formation in both sexes (12).

AHC

AHC, a rare familial condition in which the adrenal corticies have arrested development, occurs in about 1 of 12,500 births (13). The disorder can present as four clinical forms of primary adrenal insufficiency: 1) a sporadic form associated with pituitary hypoplasia (14); 2) an autosomal recessive form with a distinct miniature adult adrenal morphology, characterized by small glands with a permanent cortical zone but a diminished fetal zone. The genetic basis of the recessive form of AHC is unknown (14); 3) an X-linked cytomegalic form associated with hypogonadotropic hypogonadism (15); and 4) an X-linked form associated with glycerol kinase deficiency (16).

The X-linked cytomegalic form associated with hypogonadotropic hypogonadism results from mutations of a DAX-1 gene. The secretion of other pituitary hormones is not impaired. Whereas presentation of adrenal insufficiency is from birth, there is great variability of presentations. Phenotypically, AHC can present in several forms that do not correlate with genotype. Thus, isolated adrenal insufficiency in infancy, isolated adrenal insufficiency later in life, isolated hypogonadotropic hypogonadism, adrenal insufficiency and hypogonadotropic hypogonadism, delayed-onset adrenal insufficiency from 2–9 yr of age with incomplete hypogonadotropic hypogonadism, and delayed puberty in females all may result. Cryptorchidism may also occur. Initial loss of mineralocorticoid functions with preserved cortisol responses and a transient recovery period is possible. Hypogonadism results from combined hypothalamic, pituitary, and Sertoli cell defects (15). DAX-1 function may be required for spermatogenesis, independent of its actions in the hypothalamus and pituitary. To complicate the issue, an active hypothalamic-pituitary-gonadal axis during first months of life and even first years of life has been reported in six affected children (17, 18, 19, 20), with prolonged activation of the axis, and even two cases with early central precocious puberty seen. Unexpectedly, patients with AHC have adequate functions to support the mini-puberty of infancy but cannot support normal adolescent puberty, revealing a loss of function over time or else different mechanisms for the mini-puberty of infancy from that of adolescent puberty (17, 18). A delayed puberty in females heterozygous for the DAX-1 gene mutation has been reported, as has an isolated hypogonadotropic hypogonadism in a female due to homozygous DAX-1 mutation (21). Some females who are shown not to be carriers for DAX-1 mutations may still be at potential risk of having affected sons because of gonadal mosaicism.

Adrenal hypoplasia as part of contiguous gene deletion syndrome

An X-linked form of adrenal insufficiency, associated with glycerol kinase deficiency is characterized by psychomotor retardation, muscular dystrophy, characteristic facies with hyperthelorism, alternating strabismus, and drooping mouth. Additional phenotypic features can include testicular abnormalities (anorchia or cryptorchidism), short stature, and osteoporosis. Time of presentation can vary from birth through childhood. About 100 patients from 78 unrelated families have been reported, and all but 1 patient were male. The genetic locus was mapped to Xp21 and variants of contiguous gene deletion syndrome (glycerol kinase deficiency, Duchenne muscular dystrophy, ornithine transcarbamylase deficiency, and mental retardation) can be seen. The gene order has been determined from the centomere is -OTC-DMD-GK-DAX-1-DSS, whereas patients with contiguous gene deletion syndrome have features of each of the individual genes involved (Fig. 4Go). All patients have loss of the GK locus together with one or more closely flanking genes, most frequently AHC and DMD. Larger deletions, extending to include the ornithine transcarbamylase deficiency have been also described (16).



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  		Figure 4. Contiguous gene deletion syndrome. DAX-1, Dosage-sensitive sex reversal-adrenal hypoplasia gene 1; GKD, glycerol-kinase deficiency; DMD/BMD, Duchenne/Becker muscular dystrophy; Il1RAPL-1, gene for interleukin 1 receptor family; OTCD, ornitine transcarbamoylase deficiency.

 
Familial glucocorticoid deficiency (FGD)

Corticotropin resistance syndrome or FGD can present as an FGD or as Allgrove’s syndrome (triple A syndrome). FGD is a rare autosomal recessive disorder in which cortisol and androgen secretions are deficient and unresponsive to ACTH stimulation. The disease usually manifests within the first year of life but may present in infancy or later childhood. Inactivating mutations of the G protein-coupled ACTH receptor (melanocortin-2 receptor) are found in 40% of FGD kindreds (FGD type-1), however, no such mutations are identifiable in the remaining 60% of cases (FGD type-2). FGD type-1 mutations result in a failure of adrenocortical organization with absent zona fasciculatae and reticularae. Aldosterone secretion is normal or only partially deficient, and responds to postural stimuli and volume depletion. Phenotypically FGD type-1 patients are significantly taller than type-2 patients (6).

Allgrove’s syndrome (triple A) is characterized by the triad of ACTH resistance, achalasia, and alacrimia. Presenting in the first decade of life, it is frequently associated with progressive neurological dysfunction, polyneuropathy, deafness, mental retardation, and hyperkeratosis of palms and soles. Mineralocorticoid deficiency develops in about 15% of cases. It is an autosomal recessive disorder mapping to 12q13, but the gene has yet to be identified. No ACTH receptor mutations have been found in Allgrove’s syndrome (6).

Adrenal destruction

Autoimmune Addison’s disease. Autoimmune Addison’s disease is a major part of type-1 and -2 APS (APS-1 and APS-2). The definition of the type of APS is clinically important in predicting the potential occurrence of the other associated diseases both in patients and family members.

APS-1 is defined by the presence of three principle components of the disease: chronic mucocutaneous candidiasis or moniliasis, acquired hypoparathyroidism, and autoimmune [adrenal autoantibody (AA) positive] Addison’s disease, albeit chronic active hepatitis, malabsorption/chronic diarrhea and alopecia universalis are common while girls are invariably hypogonadal by puberty. APS-1 affects males and females equally and often first manifests during infancy or early childhood. APS-1 is a rare recessive disease that has the highest incidences in genetically isolated populations, such as Iranian Jews (1 in 600–9,000; Ref. 22), Finns (1 in 25,000; Ref. 23), and Sardinians (24), where founder effects are probable. Chronic mucocutaneous candidiasis caused by the infection of Candida albicans is usually the initial feature, almost always involving the mouth, and later the nails. Hypoparathyroidism usually occurs next, but hypocalcemia can be masked by untreated Addison’s disease and only become declared by steroid replacement therapy (25). Juvenile onset pernicious anemia, vitiligo, anterior hypophysitis, celiac disease, and myositis can be additional features, with less frequent immune-mediated (type-1) diabetes (IMD), thyroid autoimmunity, and ectodermal dysplasias, especially among affected Finns.

APS-2 is defined by autoimmune Addison’s disease together with autoimmune thyroid disease (Schmidt’s syndrome) and/or IMD (Carpenter’s syndrome). APS-3 is autoimmune thyroid disease in association with atrophic gastritis/pernicious anemia, vitiligo, and/or IMD, but not Addison’s disease (25). APS-2/3 have strong female biases and can occur at any age, but with adult peak onsets of about 30 yr. Whereas the order of appearance of the clinical components of the disease can vary, the multiple prodromal autoimmunities are often ongoing simultaneously. Autoimmune Addison’s disease can develop slowly over many years before symptoms appear, making screening of patients with IMD and autoimmune thyroiditis for AAs valuable for early identification of the disease. Some 1 in 200–300 patients with IMD will develop antibody-positive Addison’s disease. Autoantibodies to 21-OH occur in 2% of patients with IMD and 3% of patients with Grave’s disease (26). Celiac disease, primary hypogonadism, chronic active hepatitis, and myasthenia gravis infrequently occur in APS-2.

The presence of circulating autoantibodies to endocrine antigens is a serologic characteristic of Addison’s disease and other components of the APS (Table 3Go).


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

 
After the appearance of antibodies to the adrenal cortex and/or to 21-hydroxylase (21-OHA), the first evidence of adrenal insufficiency is usually an increase in PRA after patients have been recumbent for more than 0.5 h. The raised renin level is due to a failing zona glomerulosa with salt loss, with low-normal or low plasma aldosterone concentrations (27). Zona fasciculata dysfunction can become evident months to years later, first by raised afternoon serum ACTH levels, then by decreasing serum cortisol responses to (ACTH) stimulation, and finally by decreasing basal serum cortisol concentrations and the appearance of symptoms (Fig. 5Go). Thus, these autoantibodies are useful markers for the prediction of the development of Addison’s disease, particularly 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). Component antigens for SCA have been recognized to be other P450 enzymes, 17-{alpha}-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.



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  		Figure 5. Natural history of Addison’s disease. ACA, Adrenal cell antibody; P450SCC, side chain cleavage enzyme.

 
Cell-mediated immune processes are important autoimmune 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-{gamma}, interleukin 2, and tumor necrosis factor {alpha}, whereas Th2 cells secrete interleukins 4, 5, and 10. A polarized Th2 response is associated with Graves’ disease, and Th1 with IMD. APS-1 result from biased Th2 immune responses to self-antigens and defective protective Th1 responses against invasion of yeast C. albicans (26).

A major advance in understanding the genetic susceptibility of the APS was made evident when the gene responsible for APS-1 was independently isolated and described as the autoimmune regulator (AIRE) (33, 34). The AIRE gene consists of 14 exons spanning 11.9 kb of genomic DNA, which maps to the long arm of chromosome 21 (21q22.3). The AIRE gene is expressed as messenger RNA (mRNA) in thymus, lymph nodes, pancreas, adrenal cortex, and peripheral blood mononuclear cells. The AIRE protein contains two zinc finger (PHD-finger) and three LXXLL motifs that facilitate the interaction of different proteins with nuclear receptors, and a proline-rich region typical of a nuclear transcription factor. More than 20 different mutations in the AIRE gene have been detected in APS-1 patients with various ethnic backgrounds. R257X (exon 6) is the dominant mutation for Finnish and North Italian patients, whereas 1094del13 (exon 8) is a dominant mutation for British and American Caucasians and R139X (exon 3) is the dominant mutation in Sardinian patients with APS-1. There are no clear correlations between the mutations in the AIRE gene and APS-1 phenotypes reported. However, patients with the same AIRE mutation often present with different components of the diseases of the APS-1, suggesting roles for environmental factors and background (epistatic) genes. The gene encoding the cytotoxic T lymphocyte antigen-4 (CTLA-4) plays an important role in the down-regulation of T-cell activity whereas CTLA-4 polymorphisms have been associated with Addison’s disease (35). The future research directions will be investigation of the role of AIRE protein in maintaining normal self-tolerance. It may be that the AIRE gene is involved in negative selection of self-reactive T-cell clones in the thymus and thereby in maintaining self-tolerance. Whatever its immunological functions, a recessive mutation of the AIRE gene inevitably results in widespread autoimmunities.

In our experience however, the AIRE gene is not involved in patients with isolated Addison’s disease or APS-2, whereas obligatory heterozygote parents of children with APS-1 display neither the autoantibodies nor the component diseases of their offspring. Whereas APS-1 is not influenced by HLA phenotype, APS-2/3 pedigrees by contrast express an autosomal dominant-like pattern of inheritance with an incomplete penentrance, strongly influenced by HLA-DR/DQ phenotype. Thus, IMD and islet cell autoimmunity is related to the DRB1*0401 or 0405/DQA1*0301/DQB1*0302 and DRB1*03/DQA1*0501/DQB1*0201 haplotypes whereas DRB1*0403, DRB1*0406 and DQB1*0602 are dominantly protective. Hashimoto’s thyroiditis is associated with DQB1*0301 while Graves disease is associated with DRB3*0201 and DRB1*07 is protective (36). Addison’s disease in the context of APS-2 is associated with DR3 haplotypes, whereas in unpublished studies of our own vitiligo seemed to be associated with DRB1*1301, albeit this needs confirmation.

ALD

Defective ß-oxidation of very long chain fatty acids (VLCFAs; chain length of 24 carbons and above) in ALD results in adrenal insufficiency and a progressive demyelination within the central nervous system. ALD affects 1 in 20,000 males. Whereas VLCFA levels in plasma are already increased at birth in affected siblings, ALD does not usually present clinically before 3 yr of age (37). The responsible ALD gene mapping to Xq28, encodes the peroxisomal membrane adrenoleukodystrophy protein (ALDP) that belongs to the ATP-binding cassette superfamily of transporters. ALDP imports activated acyl-CoA derivatives (VLCFA-CoA) into peroxisomes where they are shortened through the ß-oxidation pathway (Fig. 6Go). Curiously, ALD knockout mice do not develop demyelination, probably because they have an ALD-related protein redundancy in their brains when compared with humans, which allow for other ATP-binding cassette transporters to compensate for the ALDP defect (38). Phenotypes in male patients range from the rapidly progressive the childhood form, affecting boys between 5–12 yr (40% of ALD), to milder forms of adreno-myeloneuropathy (30% of ALD) or isolated adrenal insufficiency (15% of ALD) (37). The well described albeit rare Sertoli-cell-only syndrome results from accumulation of VLCFA in Leydig cells of the testes, and presents with diminished libido, impotence and infertility. More then one clinical expression can appear within a single pedigree and there are no clear correlations between genotype and phenotype, even within the same kindred (37). In patients with isolated adrenal insufficiency, clinical neurological manifestations may appear years later. Diagnostically, plasma VLCFAs tests should be done in all males with adrenal insufficiency but no adrenal autoantibodies (28).



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  		Figure 6. Role of ALDP in ß-oxidation of VLCFA. PMP70, More distantly related ALDRP.

 
Some 1–3% of women who are heterozygous carriers of the disorder have been reported to develop neurological disability, whereas 1–1.5% eventually develop adrenal insufficiency (37). Other of these women develop isolated mineralocorticoid insufficiency, subclinical decreases in glucocorticoid reserves, low serum cortisol levels, and exaggerated serum ACTH responses to CRH. Prenatal diagnosis of ALD is possible using determinations of VLCFA in cultured cultured villus sampling cells and/or amnioitic fluid or by assay of ALDP by immunoblotting or immunofluorescence or by DNA analyses of the fetal cells and maternal leukocytes (39).

Lorenzo’s oil, a 4:1 mixture of glyceryl-troleate and glyceryl-trierucate, has shown little therapeutic benefit (37). Preliminary data suggest that lovastatin, a hydroxy-methylglutaryl coenzyme A CoA reductase inhibitor, and fenofibrate can lead to overexpression of adrenoleukodystrophy-related protein (ALDRP), but these therapies are controversial (40, 41). Bone marrow transplantations have been performed on more than 90 ALD patients with clinical benefits reported if done at an early stage of the disease (42). Gene therapy has been attempted to correct the defect in VLCFA by targeting expression of the ALD gene to hematopoietic stem cells (CD34+) (43). Pharmacological induction of ALDRP by butyric acid analogs, such as 4-phenylbutyrate should be evaluated, because in an initial report 4-phenylbutyrate treatment of fibroblasts from patients with X-linked adreno-leukodystrophy increased the expression of ALDRP, improved oxidation of VLCFAs, and reduced VLCFA levels (44).

Infectious Addison’s disease:

Infectious forms of the disease are relatively rare in the United States, however, in developing nations such as India, tuberculosis is the most common cause. Thus, in all instances of unexplained Addison’s disease, a purified protein derivative (of tuberculosis) skin test should be carried out. However, in India and other countries the test is not informative because bacille calmette guierin is widely given at birth, while contacts with infected persons may give positive tests even when active disease is quiescent. AIDS patients may have decreased adrenal reserve and are increasingly prone to have tuberculosis (45). Fungal diseases such as histoplasmosis and coccidio-mycosis are uncommon additional causes (46, 47).

Adrenal hemorrhage

In meningococcal septicemias, hemorrhage into the adrenal glands may complicate the clinical picture leading to circulatory collapse (Waterhouse-Freiderickson syndrome). Pseudomonas auregenosa may also be associated with adrenal hemorrhage (48). Asplenia is associated with higher frequency of adrenal hemorrhage in case of septicemia. Septic shock in newborns, especially in those who are small for dates, may result in adrenal hemorrhage with rhabdomyelysis and renal insufficiency. The antiphospholipid syndrome is also associated with adrenal hemorrhage (49).

Impaired steroidogenesis

CAH. CAH due to 21-OH deficiency is the most common cause of salt-wasting adrenal crisis in the first 2 weeks of life, with an incidence of 1 in 10,000–18,000 live births. Affected females have ambiguous, virilized genitalia and are usually diagnosed at birth. Males, however, often go undiagnosed until they present with a salt-wasting crises often 2–3 weeks after birth. Deficiency of 3ß-hydroxysteroid dehydrogenase deficiency or P450cc enzyme also can present with adrenal insufficiency in neonatal period, with affected boys presenting with ambiguous genitalia or as phenotypically females. CAH due to defects in aldosterone synthetase leading to isolated aldosterone deficiency are not associated with sexual ambiguity (Table 4Go, adapted from P. C. White and P. W. Speiser, 2000). Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females by dexamethasone to minimize genital virilization, when given before the seventh to eighth week of gestation (50).


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  		Table 4. Characteristics of different forms of CAH

 
Congenital lipoid adrenal hyperplasia (lipoid CAH)

Lipoid CAH is the most severe form of CAH, involving deficiencies of glucocorticoids, mineralocorticoids, and sex steroids. Lipoid CAH is caused by mutation in the StAR gene that maps to 8p11. Affected individuals are all phenotypically female regardless of karyotype. The LH-dependent StAR protein stimulates cytochrome P450SCC activity, enhancing cholesterol transport from the outer to the inner mitochondrial membranes. The two-hit model of lipoid CAH results from low initial levels of StAR-independent steroidogenesis, leading to a complete loss of steroid hormones due to cellular destruction by accumulated lipids. This explains the presence of androgen-dependent Wolffian duct remnants in 46,XY fetuses and the delayed onset of mineralocorticoid deficiency in many patients. The two-hit model also correctly predicted that affected 46,XX patintes would undergo spontaeous puberty, as seen in StAR knockout mice (51).

Mitochondrial forms of Addison’s disease

Adrenal insufficiency can result from a mitochondrial disorders, characterized by chronic lactic acidosis, myopathy, cataracts, and nerve deafness (52, 53, 54). Cases with the Kearns-Sayre syndrome form of mitochondrial myopathy, deafness, with large-scale deletions in mitochondrial DNA are often associated with endocrine dysfunctions, particularly short stature, hypogonadism, diabetes, hypoparathyroidism, hypothyroidism, and adrenal insufficiency (55, 56).

Defective cholesterol metabolism

Most cortisol is synthesized from cholesterol brought to the adrenals by circulating low-density lipoproteins (LDLs) or high-density lipoproteins. As a result, patients without LDLs, such as those with abetalipoproteinemia, or without LDL receptors, such as those with homozygous familial hypercholesterolemia, have moderately impaired serum cortisol responses to ACTH, although they maintain normal basal cortisol secretions and do not develop clinically significant adrenal insufficiency (57).

Smith-Lemli-Opitz syndrome (SLOS)

The syndrome results from mutations in the sterol {Delta}-7-reductase gene (DHCR7), which catalyzes the final step in cholesterol biosynthesis leading to primary adrenal insufficiency. The gene maps to 11q12-q13. SLOS can present with typical facial appearance, mental retardation, microcephaly, proximally placed thumbs, congenital cardiac abnormalities, syndactyly of the second and third toes, incomplete development of the male genitalia in boys, and photosensitivity. Three unrelated patients with SLOS presented with adrenal insufficiency and failure to masculinize. A primary defect in the fetal adrenals resulting in a combination of low maternal estriol levels, sex reversal, and large adrenal glands in the fetus with SLOS has been demonstrated. Preliminary studies suggest that cholesterol supplementation may be of benefit to patients with the SLOS (58).

Drugs

Several drugs may inhibit cortisol biosynthesis. The list includes aminoglutethimide (59), etomidate (60), ketoconazole (61), methyrapone (62), and suramin (63). Patients with limited pituitary or adrenal reserve are those most likely to develop drug-induced adrenal insufficiency. Drugs that accelerate cortisol metabolism are phenytoin, barbiturates, and rifampin (64).

Corticosteroid replacement therapy

In Addison’s disease, replacement of glucocorticoid and mineralocorticoid hormones are essential for health and indeed life, however, there is no clear indications for replacement of adrenal adrenogens such as dihydroepiandrosterone. We will not discuss the latter controversy here because we do not offer it to our patients. We will also not discuss the dangers of adrenal insufficiency due to too rapid withdrawl of long-term therapeutic glucocorticoid therapy here.

Corticosteroid and mineralocorticoid replacement therapies should suppress the excessive secretion of CRH, ACTH, and resting renin levels. The normal daily cortisol production rate has been shown to be 6–7 mg/m2/day in children and adolescents (65, 66). This rate translates to about 10–12 mg/m2·day of oral hydrocortisone, to allow for step-down losses from absorption, hepatic processing, and metabolic bioavailability. In children, the preferred cortisol replacement is hydrocortisone in doses 10–20 mg/m2·day in three divided doses. However, there are several difficulties in choosing the optimal dose. It is not possible to emulate natural circadian rhythm of cortisol since the natural peak starts with the onset of rapid eye movement sleep in early hours of the morning, and the peak blood level resulting from the morning dose of hydrocortisone on awakening, comes several hours late. This transient early morning adrenal insufficiency can account for the symptoms of fatigue, lassitude, mild nausea, or headache that are often present on awakening and that are relieved within 30–60 min after taking the morning dose of hydrocortisone (67). The same related problem occurs with difficulties in suppression of nocturnal ACTH secretion. The early morning adrenal insufficiency with the traditional regimen results in plasma ACTH concentrations that are much higher than normal for several hours in the early morning (68, 69), leading to persistent hyperpigmentation. Furthermore, because ACTH secretion may, thus, become inadequately inhibited on a chronic basis by incomplete glucocorticoid negative feedback inhibition, it may eventually become poorly suppressible, leading to the development of pituitary hyperplasia or, rarely, a corticotroph adenoma (70, 71, 72, 73, 74, 75, 76). Such morning peaks of ACTH can be ameliorated, by changing the bedtime dose of hydrocortisone to an equivalent dose of dexamethasone (77, 75). Because availability of orally ingested hydrocortisone is variable (78) the patient can be easily over-treated and under-treated. Whereas both situations are undesirable, under-treatment can be life-threatening. Patients can present with chronic fatigue, reduced resistance to illness, postural hypotension, and have risk of nocturnal hypoglycemia. Chronic, borderline under-replacement can predispose the patient to more severe crises in case of recurrent illness or accident, particularly if they are unable to absorb their replacement therapy because of gastrointestinal upset or chronic malabsorption as in APS-1. The FDA withdrew oral hydrocortisone suspension from the market because of poor absorption and under-treatment of children.

The problems of excess of corticosteroid replacement are well known. They include weight gain, high blood pressure, hyperglycemia, suppression of growth rate, easy bruising, cardiovascular risk, raised intraocular pressure, gastric ulcers, poor wound healing, striae of the skin, and osteoporosis (79). Peacey et al. (80) demonstrated increase in serum osteocalcin in response to glucocrticoid dose adjustment. The absence of signs of steroid excess in the context of necessity, increasing doses are suggestive of poor compliance, malabsorbtion or increased catabolism. Thyrotoxicosis is associated with increased breakdown of gluco- and mineralocorticoids as well as estradiol, whereas patients with an APS may be complicated by unrecognized celiac disease. In such cases, gliadin, reticulin, endomysial, and tissue transglutaminase and TSH receptor autoantibodies should be evaluated (81). It is important to be aware that the treatment of hypothyroidism in case of unrecognized adrenal insufficiency may trigger an adrenal crises.

Mineralococrticoid replacement is readily accomplished by fluorohydrocortisone (fluorinef, 0.05–0.2 mg daily). Hypertension, bradycardia, suppressed renin levels, and retardation in growth rate are clinical signs of over-treatment with mineralocorticoids (82, 83). Older children do not require daily supplements with salt, whereas infants should have sodium chloride supplement 1–2 g daily (1 g contains 17 mEq of sodium). The sodium content of the formulas or breast milk is only about 8 mEq/L, which is only enough for maintenance of sodium content in healthy infants. Fortunately, humans have a well developed sense of salt homeostasis, and salt craving commonly occurs when a patients is deficient of total body salt. Excess salt is often needed during the summer, because aldosterone affects the salt content of sweat, being higher in patients with adrenal insufficiency. Well-being, weight gain, blood pressure, growth rate, and skin pigmentation are the most useful clinical markers of adequacy of replacement therapy, whereas plasma ACTH and renin levels are useful in following patients on replacement therapy (79).

Stress management

Endogenous adrenal secretion in critically ill or perioperative patients with healthy adrenals is increased (84). In the case of Addison’s disease, in significant febrile illnesses the routine steroid doses should be tripled and administered over three divided daily doses. If a patient is unable to tolerate oral medication, im or iv hydrocotisone succinate (Solu-Cortef) should be given and patient hydrated iv. The patients and their families should have instructions for such instances. Every patient should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card that is supplied with it. Both should indicate the diagnosis, the daily medications and doses, and the physician to call in the event of an emergency. For major surgery, administration of iv hydrocortisone 100 mg/m2·day is necessary for 24 h peri- and postoperatively, before tapering over several days to a maintenance dose. It is unnecessary to give otherwise mineralocorticoids over such periods if the patient begins the operative period in adequate salt balance.

Summary

Addisonian crisis represents an endocrine emergency that requires a correct diagnosis with identification of the cause (Fig. 7Go), with prompt and appropriate salt and steroid replacements to save the patient. It is, however, unusual that the patient does not exhibit clear warning signs of this impending disaster long before the event. Thus, physicians should have a high index of suspicion in a variety of unexplained chronic symptoms and signs. Great advances have been made into understanding the many causes of the disease in the 150 yr since its first description by Addison, and such advances translate into better diagnostic algorithms (Fig. 7Go) and specific therapies than were previously possible.



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  		Figure 7. Diagnostic workup for adrenal insufficiency. ACA, Adrenal cell antibodies; SCA, steroid cell antibodies; HP, hypoparathyroidism; MC, mucocutaneous candidias; AT, autoimmune thyroiditis; IMD, immune mediated diabetes; AAD, autoimmune Addison’s disease; DAX-1, dosage-sensitive sex reversal-adrenal hypoplasia gene 1; GK, glycerol-kinase; DMD, Duchenne muscular dystrophy.

 

Acknowledgments

We thank the Genentech Growth Foundation for grant support, The Adrenal Foundation of America, and our patients for their participation and support in our studies.

Received January 26, 2001.

Revised March 26, 2001.

Accepted March 28, 2001.

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