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Predisposing Factors for Adrenal Insufficiency

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Predisposing Factors for Adrenal Insufficiency The new england journal of medicine review article CURRENT CONCEPTS Predisposing Factors for Adrenal Insufficiency Stefan R. Bornstein, M.D. From the Department of Medicine, Tech- drenal insufficiency — the clinical manifestation of deficient nical University of Dresden, Dresden, Ger- production or action of glucocorticoids — is a life-threatening disorder that many. Address reprint requests to Dr. Bornstein at the Department of Medicine, may result from either primary adrenal failure or secondary adrenal disease Technical University of Dresden, Fetscher- A 1,2 due to impairment of the hypothalamic–pituitary axis. This article focuses on pro- str. 74, 01307 Dresden, Germany, or at viding the practicing clinician with new insights into predisposing factors for adre- [email protected]. nal insufficiency. When and during what situations should a clinician suspect ad- N Engl J Med 2009;360:2328-39. renal insufficiency? What genetic disorders, infections, and medications should be Copyright © 2009 Massachusetts Medical Society. considered? What are the current views on the underlying mechanisms? The cardinal clinical symptoms of adrenocortical insufficiency, as first described by Thomas Addison in 1855,3 include weakness, fatigue, anorexia, and abdominal pain, with orthostatic hypotension, salt craving, and characteristic hyperpigmenta- tion of the skin occurring with primary adrenal failure. The acute syndrome con- stitutes a medical emergency since it may result in a severe hypotensive crisis and clouded sensorium, together with pain in the muscles, joints, or abdomen and fever.1,2 In the diagnostic workup for the disorder, the capacity of the adrenal cortex to respond to corticotropin is tested with the use of the standard short corticotropin test, which measures the serum cortisol level before and 30 or 60 minutes after an intravenous or intramuscular injection of 250 μg of corticotropin.4 An increase in the serum cortisol level to peak concentrations above 500 nmol per liter (18 μg per deciliter) indicates a normal response. The adrenal responsiveness to an exogenous corticotropin challenge is impaired in most cases of secondary adrenal disease. With mild secondary adrenal insufficiency, however, the hypothalamic–pituitary– adrenal axis may appear intact, with a normal response to a corticotropin chal- lenge. Recent evidence suggests that the 1-μg corticotropin stimulation test is more sensitive than the 250-μg corticotropin test for establishing the diagnosis of sec- ondary adrenal insufficiency.5 Once adrenal insufficiency is diagnosed, glucocorticoid replacement is initiated in two or three daily doses; one half to two thirds of the daily dose (15 to 25 mg of hydrocortisone) is given in the morning, in line with the physiologic cortisol-secre- tion pattern. Mineralocorticoid replacement (0.05 to 0.2 mg of fludrocortisone daily as a morning dose) is required only in the case of primary adrenal insufficiency, and dehydroepiandrosterone replacement (25 to 50 mg) remains an optional treatment.1,2 Management of an acute adrenal crisis consists of immediate intravenous ad- ministration of 100 mg of hydrocortisone, followed by 100 to 200 mg of hydrocor- tisone every 24 hours and a continuous infusion of larger volumes of physiologic saline solution (initially 1 liter per hour) under continuous cardiac monitoring. Timely diagnosis and clinical management of this condition are critical, and physicians in all areas of medicine should be aware of the causes, signs, and symptoms that her- ald adrenal insufficiency. 2328 n engl j med 360;22 nejm.org may 28, 2009 Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on June 22, 2010 . Copyright © 2009 Massachusetts Medical Society. All rights reserved. current concepts may present with late-onset adrenal insufficien- Hereditary Disorders 12-14 Associated with Adrenal cy. Congenital adrenal hypoplasia is usually Insufficiency manifested in early childhood but may not be ap- parent until adolescence or early adulthood.14 Hereditary factors are increasingly recognized as Adrenoleukodystrophy and adrenomyeloneu- playing a critical role in the regulation of the ropathy are two phenotypes of an X-linked reces- hypothalamic–pituitary–adrenal axis.6 Genes that sive disorder that affects 1 in 20,000 males. This have been identif ied as having such a role include disorder is characterized by spastic paralysis as those that encode receptors, transcription factors, well as adrenal insufficiency.1,2,15 Adrenoleuko- and enzymes involved in hormone synthesis or in dystrophy begins in infancy or childhood, whereas the regulation of pituitary-gland, adrenal-gland, adrenomyeloneuropathy usually begins in adoles- or target-cell function (Table 1). In addition, certain cence or early adulthood and has a milder and forms of autoimmune adrenalitis have hereditary slower progression. It is important to realize, how- components, either with an autosomal recessive ever, that adrenal insufficiency may be the only pattern of inheritance (autoimmune polyglandu- sign of the disorder; the diagnosis may be con- lar syndrome 1) or with an autosomal dominant firmed by measurement of very-long-chain fatty pattern involving incomplete penetrance (autoim- acids. This disorder accounts for up to 10% of all mune polyglandular syndrome 2). cases of adrenal insufficiency. Congenital adrenal hyperplasia due to 21- Like hereditary disorders of the adrenal gland, hydroxylase deficiency7 is one of the more com- most genetic defects affecting the pituitary gland mon causes of hereditary adrenal disorders, with cause symptoms early in life; however, once again, the classic form having an overall incidence of clinicians should be aware that the signs and 1 case in 15,000 live births. The carrier frequency symptoms of some of these disorders have a late of classic congenital adrenal hyperplasia is ap- onset. For example, mutations in the gene encod- proximately 1 in 60 persons. Patients with classic ing the pituitary transcription factor paired-like congenital adrenal hyperplasia usually present in homeobox 1 (PROP1) cause a progressive deterio- early childhood with a moderate form known as ration of anterior pituitary function, including simple-virilizing congenital adrenal hyperplasia or adrenal insuff iciency, which necessitates replace- with a severe form that causes salt wasting and ment therapy with hydrocortisone in affected virilization. Nonclassic congenital adrenal hyper- patients at a mean age of 18 years.13 Further- plasia occurs in adolescent girls and women, who more, secondary adrenal insufficiency has been present with hirsutism and infertility. noted in up to 60% of patients with the Prader– Although congenital adrenal hyperplasia is a Willi syndrome.16 The Prader–Willi syndrome is common disorder, pitfalls in coping with stressful the most common cause of obesity related to a situations and preventing an adrenal crisis are in- syndrome (with a prevalence of 1 case in 10,000 frequently considered in routine clinical practice7,8; to 20,000 obese persons) and is associated with in addition, the importance of educating parents a very high rate of sudden death (3%). Hydro- about the management of the disorder can be un- cortisone treatment during the acute illness has derappreciated. Clinicians should take time to ex- been recommended in patients with this syn- plain to the child and his or her family that the drome unless adrenal insufficiency can be ruled daily glucocorticoid regimen must not be inter- out.16 rupted by illness. Missed doses during a minor It has been suggested that numerous other malaise such as a viral infection, particularly one genes play critical roles in the development and that causes vomiting or diarrhea, can lead to shock function of the adrenal and pituitary glands in and death. To prevent this, patients should be in- animal models. Putative genes include morpho- structed to increase the doses of glucocorticoids gens such as wingless and sonic hedgehog,17 during illness, surgery, or other forms of severe growth factors, toll-like receptors, and scavenger stress. molecules involved in cholesterol transport and Most genetic disorders associated with adrenal oxidative stress.18,19 The adrenal stress response insufficiency have characteristic clinical features is impaired in mice with toll-like receptor 2 or that become evident early in life1,2,9-11 (Table 1). 4 deficiency.19 Polymorphisms in the same re- However, persons with some genetic disorders ceptors occur in humans at rates of up to 10%.20 n engl j med 360;22 nejm.org may 28, 2009 2329 Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on June 22, 2010 . Copyright © 2009 Massachusetts Medical Society. All rights reserved. 2330 Table 1. Genetic Defects Associated with Adrenal Insufficiency. Downloaded fromwww.nejm.org atLIBRARIES OFTHEUNIV OFCOLORADO onJune22, 2010. Primary Adrenal Insufficiency Gene No.* Disorder Clinical Characteristics Enzymes in steroidogenesis and cholesterol metabolism 21-Hydroxylase (CYP21A2) 1589 Congenital adrenal hyperplasia Ambiguous genitalia, hirsutism, presence or absence of salt Copyright © 2009 Massachusetts Medical Society. All rightsreserved. wasting 3 Beta-hydroxysteroid dehydrogenase type II 3284 Congenital adrenal hyperplasia Ambiguous genitalia, premature pubarche, hirsutism, pres- (HSD3B2) ence or absence of salt wasting Steroid 11-beta-hydroxylase (CYP11B1) 1584 Congenital adrenal hyperplasia Virilization, impaired cortisol synthesis, hypertension
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