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 hyperpigmentation of the skin occurring with primary adrenal failure. The acute syndrome constitutes 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 challenge. Recent evidence suggests that the 1-μg corticotropin stimulation test is more sensitive than the 250-μg corticotropin test for establishing the diagnosis of secondary 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-secretion 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 administration of 100 mg of hydrocortisone, followed by 100 to 200 mg of hydrocortisone 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.

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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

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Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on June 22, 2010 . Copyright © 2009 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Clinical Clinical Characteristics short stature, gonadal and adrenal failure adrenal and gonadal stature, short short stature, gonadal and adrenal failure adrenal and gonadal stature, short conduction defects; other endocrine disorders endocrine other defects; conduction renal insufficiency, gonadal anomalies gonadal insufficiency, renal cy without adrenal hyperplasia adrenal without cy growth failure growth Bixler syndrome), impaired steroidogenesis impaired syndrome), Bixler ence or absence of salt wasting salt of absence or ence level deoxycorticosterone high to wasting Xanthomata, premature coronary artery disease, arthritis, disease, artery coronary premature Xanthomata, Xanthomata, premature coronary artery disease, arthritis, disease, artery coronary premature Xanthomata, Bilateral adrenal calcification, hepatosplenomegaly calcification, adrenal Bilateral External ophthalmoplegia, retinal degeneration, and cardiac and degeneration, retinal ophthalmoplegia, External Intrauterine growth retardation, metaphyseal dysplasia, ad- dysplasia, metaphyseal retardation, growth Intrauterine Hypogonadotropic hypogonadism in males in hypogonadism Hypogonadotropic dysgenesis gonadal with females, in karyotype XY 46, Hyponatremia, hyperkalemia, cholesterol deficiency cholesterol hyperkalemia, Hyponatremia, Abnormal genitalia, skeletal malformation (the Antley– (the malformation skeletal genitalia, Abnormal Ambiguous genitalia, premature pubarche, hirsutism, pres- hirsutism, pubarche, premature genitalia, Ambiguous due hypertension synthesis, cortisol impaired Virilization, infantilism sexual amenorrhea, primary Hypertension, Ambiguous genitalia, hirsutism, presence or absence of salt of absence or presence hirsutism, genitalia, Ambiguous Disorder olemia) olemia) physeal dysplasia, adrenal hypoplasia adrenal dysplasia, physeal abnormalities genital and congenita, syndrome (IMAGE) Kearns–Sayre syndrome Kearns–Sayre 190hypoplasia adrenal Congenital 3988disease Wolman’s 2516hypoplasia adrenal Congenital 1717syndrome Smith–Lemli–Opitz 1583deficiencyside-chain–cleavage P450 insufficien- adrenal late-onset or early-onset Clitoromegaly, 6770hyperplasiaadrenal lipoid Congenital deficiency, mineralocorticoid and glucocorticoid Severe 15841586hyperplasia adrenal Congenital 5447hyperplasia adrenal Congenital hyperplasia adrenal Congenital 15893284hyperplasia adrenal Congenital hyperplasia adrenal Congenital 64241phytoster- as known (also Sitosterolemia 64240phytoster- as known (also Sitosterolemia 64589meta retardation, growth Intrauterine Gene No.* ber 8 ( ABCG8 ) 8 ber ber 5 ( ABCG5 ) 5 ber esterase ( LIPA ) esterase (steroidogenic factor 1) ( NR5A1 ) 1) factor (steroidogenic ( NR0B1 ) ( HSD3B2 ) ATP-binding cassette, subfamily G (WHITE), mem- (WHITE), G subfamily cassette, ATP-binding ATP-binding cassette, subfamily G (WHITE), mem- (WHITE), G subfamily cassette, ATP-binding Nuclear receptor subfamily 5, group A, member 1 member A, group 5, subfamily receptor Nuclear X chromosome on located but unknown, Gene Nuclear receptor subfamily 0, group B, member 1 member B, group 0, subfamily receptor Nuclear 7-Dehydrocholesterol reductase ( DHCR7 ) reductase 7-Dehydrocholesterol P-450 (cytochrome) side-chain cleavage ( CYP11A1 ) cleavage side-chain (cytochrome) P-450 Steroidogenic acute regulatory protein ( STAR ) protein regulatory acute Steroidogenic Steroid 11-beta-hydroxylase ( CYP11B1 ) 11-beta-hydroxylase Steroid ( CYP17A1 ) 17-alpha-hydroxylase Steroid ( POR ) oxidoreductase (cytochrome) P-450 3 Beta-hydroxysteroid dehydrogenase type II type dehydrogenase Beta-hydroxysteroid 3 21-Hydroxylase ( CYP21A2 ) 21-Hydroxylase Sterol secretion Sterol Storage disease — lipase A, lysosomal acid, cholesterol acid, lysosomal A, lipase — disease Storage Mitochondrial abnormality (gene unknown) (gene abnormality Mitochondrial Transcription factors Transcription Enzymes in steroidogenesis and cholesterol metabolism cholesterol and steroidogenesis in Enzymes Genetic Defects Associated with Adrenal Insufficiency. Adrenal with Associated Defects Genetic 1. Table Insufficiency Adrenal Primary

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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 sella turcica sella of mental retardation mental of deficiencies delayed puberty, other signs of pituitary failure pituitary of signs other puberty, delayed gland pituitary rior kodystrophy, with slower progression slower with kodystrophy, adrenal insufficiency may be the only sign of adrenoleu- of sign only the be may insufficiency adrenal kodystrophy cutaneous candidiasis cutaneous retardation, hyperkeratosis retardation, and muscle weakness but normal blood pressure blood normal but weakness muscle and as hypertelorism and frontal bossing, lethargy and mus- and lethargy bossing, frontal and hypertelorism as pressure blood normal but weakness cle Hypotonia, mental retardation, obesity, and hypogonadism and obesity, retardation, mental Hypotonia, Early-onset obesity, red hair, pigmentation hair, red obesity, Early-onset Low or absent cortisol production cortisol absent or Low Late-onset corticotropin deficiency, occasionally enlarged occasionally deficiency, corticotropin Late-onset Infundibular hypoplasia, hypopituitarism, varying degrees varying hypopituitarism, hypoplasia, Infundibular Growth hormone, thyrotropin, and corticotropin corticotropin and thyrotropin, hormone, Growth Short stature, cognitive alterations, septo-optic dysplasia, septo-optic alterations, cognitive stature, Short poste- ectopic hypoplasia, pituitary hypoglycemia, Neonatal Adrenomyeloneuropathy is a milder variant of adrenoleu- of variant milder a is Adrenomyeloneuropathy Addison’s disease, thyroid disease, type 1 diabetes mellitus diabetes 1 type disease, thyroid disease, Addison’s quadriparesis; blindness, dementia, spasticity, Weakness, Adrenal insufficiency, hypoparathyroidism, chronic muco- chronic hypoparathyroidism, insufficiency, Adrenal Achalasia, alacrima, adrenal insufficiency, deafness, mental deafness, insufficiency, adrenal alacrima, Achalasia, syndrome deficiency eloneuropathy type 2 type eloneuropathy type 1 type Polyendocrine autoimmune syndrome autoimmune Polyendocrine 215adrenomy- or Adrenoleukodystrophy 225adrenomy- or Adrenoleukodystrophy 326syndrome autoimmune Polyendocrine 3653syndrome Prader–Willi 5443deficiency (POMC) Proopiomelanocortin 9095adrenocorticotrophic isolated Congenital 5626 Panhypopituitarism 6658 Panhypopituitarism 5015 Panhypopituitarism 8820 Panhypopituitarism 8086syndrome Triple-A 41581deficiency glucocorticoid Familial such features, facial height, increased Hyperpigmentation, 89884 Panhypopituitarism 562462deficiency glucocorticoid Familial lethargy hypoglycemia, height, normal Hyperpigmentation, drome (nonprotein coding) ( IPW ) coding) (nonprotein drome ( POMC ) ( ABCD1 ) ( ABCD2 ) the CD28/CTLA4 region on chromosome 2q33 chromosome on region CD28/CTLA4 the (Allgrove, triple-A) ( AAAS ) triple-A) (Allgrove, mone) ( MC2R ) mone) T-box 19 ( TBX19 ) 19 T-box PROP paired-like homeobox 1 ( PROP1 ) 1 homeobox paired-like PROP SRY (sex-determining region Y)-box 3 ( SOX3 ) 3 Y)-box region (sex-determining SRY Orthodenticle homeobox 2 ( OTX2 ) 2 homeobox Orthodenticle ( LHX4 ) 4 homeobox LIM HESX homeobox 1 ( HESX1 ) 1 homeobox HESX ATP-binding cassette, subfamily D (ALD), member 1 member (ALD), D subfamily cassette, ATP-binding ATP-binding cassette, subfamily D (ALD), member 2 member (ALD), D subfamily cassette, ATP-binding Gene unknown, but appears to be associated with associated be to appears but unknown, Gene Autoimmune regulator ( AIRE ) regulator Autoimmune Achalasia, adrenocortical insufficiency, alacrima insufficiency, adrenocortical Achalasia, Melanocortin 2 receptor accessory protein ( MRAP ) protein accessory receptor 2 Melanocortin Melanocortin 2 receptor (adrenocorticotropic hor- (adrenocorticotropic receptor 2 Melanocortin Imprinting center — imprinted in Prader–Willi syn- Prader–Willi in imprinted — center Imprinting Corticotropin synthesis — proopiomelanocortin — synthesis Corticotropin Pituitary insufficiency Pituitary factors Transcription Peroxisomal abnormalities Peroxisomal Autoimmune adrenalitis Autoimmune Corticotropin-receptor and signaling and Corticotropin-receptor * Gene numbers are from the gene database of the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov/).

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Whether mutations and gene polymorphisms in- There has been an increased incidence of adre- volving these factors predispose affected persons nal dysfunction, particularly among patients who to adrenal insufficiency requires clarification. are receiving antifungal therapies. Such therapies (e.g., ketoconazole) are known to interfere with Drugs as Predisposing Factors glucocorticoid synthesis and are therefore also for Glucocorticoid Deficiency used, in doses of 400 to 800 mg per day, to treat hypercortisolism. Although some of the newer Drugs may cause glucocorticoid deficiency at hy- antifungal compounds (e.g., itraconazole and flu- pothalamic, pituitary, and adrenal levels as well conazole) have fewer adrenostatic effects, adrenal as at the sites of the glucocorticoid receptor, its insufficiency that occurs after treatment with high signaling pathway, and peripheral glucocorticoid doses has been reported.24 These compounds may metabolism (Table 2). Suppression of the hypo- therefore confer a predisposition to adrenal insuf- thalamic–pituitary–adrenal axis by exogenous glu- ficiency during states of increased glucocorticoid cocorticoid treatment is the most common cause requirement, such as severe stress in any kind of of an impaired adrenal response. According to critical illness. current estimates, nearly 1% of people in the gen- Etomidate, a commonly used, potent hypnotic eral population (2.5% of those who are more than agent, can also lower cortisol levels, even after a 70 years of age) are treated with long-term regi- single injection of the drug.25 Therefore, in the mens of glucocorticoids for inflammation related case of any critically ill patient, the clinician should to chronic disease.21 Since the proportion of elderly specifically ask about the use of etomidate; if the persons in the population is increasing, this fig- patient is receiving etomidate, the clinician should ure is likely to rise. consider adding glucocorticoid therapy.26 To avoid an unexpected adrenal crisis in per- It is prudent to monitor adrenal function dur- sons admitted to the hospital on an emergency ing severe stress in patients who are receiving basis, physicians should not only ask whether the novel tyrosine kinase–targeting drugs, since some patient has been taking glucocorticoids but should of these compounds (e.g., sunitinib) have been also be aware of the many obscure situations in- shown in studies in animals to cause adrenal dys- volving the use of glucocorticoids. Patients may function and hemorrhage.27 The underlying mech- be unaware of or reluctant to report exposure to anism may be related to the fact that vascular glucocorticoids. These may include athletes, pa- endothelial growth factor–receptor antagonists tients with cancer, patients with orthopedic con- impair endothelial integrity, which may then lead ditions, and persons receiving adrenal extracts to hemorrhage in the highly vascularized adrenal from sites on the Internet for what has been gland during stress. termed the “adrenal fatigue syndrome.” A lack of Finally, since growing numbers of chronically awareness that continuous use of topical gluco- ill patients take multiple drugs, clinicians must corticoids can suppress adrenal function is another consider the additive effect of a combination of widespread problem in daily practice. Concomitant drugs with antiglucocorticoid effects. Recent com- use of glucocorticoids with inhibitors (e.g., itra- prehensive toxicologic in vitro assays have shown conazole, diltiazem, mibefradil, and even grape- that increasing numbers of environmental com- fruit juice) of CYP3A4, the most abundant drug- pounds have the capability to impair adrenal ste- metabolizing cytochrome P450 enzyme, prolongs roidogenesis. Such compounds range from endo- the biologic half-life of the glucocorticoid, there- crine disruptors (e.g., phytoestrogen flavonoids) by markedly enhancing its effect in suppressing to widely used insecticides (e.g., lindane). The ef- adrenal function.22 In addition to glucocorticoids, fect on adrenal function in humans, however, has other steroid compounds such as megestrol ac- yet to be determined.28 etate and medroxyprogesterone inhibit the hypothalamic–pituitary–adrenal axis. Consideration of Diseases the Clinician Should the integrity of the hypothalamic–pituitary–adre- Consider nal axis will also be important when the new selective glucocorticoid-receptor activators come into Diseases that cause outright adrenal insufficiency common use.23 are rare. In addition to the genetic defects men-

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Table 2. Drug-Related Glucocorticoid Insufficiency.

Mechanism Drugs Primary adrenal insufficiency Hemorrhage Anticoagulants (heparin, warfarin), tyrosine kinase inhibitors (sunitinib) Inhibition of cortisol-synthesis enzyme P-450 aromatase (CYP19A1) Aminoglutethimide 3 Beta hydroxysteroid-dehydrogenase type 2 Trilostane (HSD3B2) Mitochondrial cytochrome P-450–dependent Ketoconazole enzymes (e.g., CYP11A1, CYP11B1) Fluconazole Etomidate Activation of cortisol metabolism Enzyme induction of P-450 cytochromes (CYP2B1 Phenobarbital and CYP2B2), which reduces corticosteroid levels Induction of drug-metabolizing cytochrome P-450 Phenytoin, rifampin, troglitazone enzymes (primarily CYP3A4) Secondary adrenal insufficiency Suppression of corticotropin-releasing hormone and Glucocorticoid therapy (systemic or topical), fluticasone, corticotropin synthesis megestrol acetate, medroxyprogesterone, ketorolac tromethamine, opiate drugs Peripheral resistance to glucocorticoids Interaction with glucocorticoid receptor Mifepristone Inhibition of glucocorticoid-induced gene tran Antipsychotic drugs (chlorpromazine), antidepressant scription drugs (imipramine) tioned above, pituitary tumors, hemorrhage, infec- In the Western world, glucocorticoid deficiency tions, and autoimmune disease are the most com- due to autoimmune disease accounts for up to 80% mon causes of complete adrenal insufficiency.1,2 of the cases of primary adrenal failure.1,2 Patients There is evidence that the Waterhouse–Frider- with autoimmune diseases, as well as some of ichsen syndrome, a meningococcal sepsis syn- their family members, frequently have multiple drome involving bilateral adrenal hemorrhage, is organ-specific endocrine disorders as part of an not limited to meningococcal infection, but may autoimmune polyglandular syndrome. Autoim- occur after infection with staphylococci or other mune thyroid disease is the most commonly pathogens.29,30 Considering the steady increase in observed organ manifestation, whereas vitiligo, methicillin-resistant Staphylococcus aureus and op- primary gonadal failure, atrophic gastritis, and portunistic infections, such causes of adrenal in- type 1 diabetes are less common.1,2 Latent or sub- sufficiency should be kept in mind. clinical forms may be more frequent than hith- Tuberculous adrenalitis was once the most fre- erto assumed.32 Consequently, the possibility of quent cause of primary adrenal insufficiency, and adrenal dysregulation should be considered in all this remains the case in many developing coun- patients who have any form of autoimmune en- tries. In recent years, there has been a resurgence docrine or metabolic disorder (Fig. 1). of tuberculous adrenalitis as a result of the in- The diagnosis of adrenal insufficiency is also creasing number of patients with the acquired frequently overlooked in inpatients with hypona- immunodeficiency syndrome. Adrenalitis due to tremia.33 Up to 20% of patients with normo cytomegalovirus infection is especially common in volemic hyponatremia have secondary adrenal inpatients with the human immunodeficiency virus sufficiency that is due in most cases to the empty infection, and apart from numerous opportunis- sella syndrome, Sheehan’s syndrome, or pituitary tic pathogens, antifungal therapy may further tumors. In these patients, plasma antidiuretic hor- compromise adrenal function in these persons.31 mone levels are elevated, most likely owing to a

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failure of endogenous glucocorticoid to suppress Mechanisms of adrenal suppression in sepsis the hormone. Hydrocortisone-replacement thera- remain largely unclear; however, cytokines such py leads to rapid normalization of serum sodium as tumor necrosis factor-α or other peptides de- levels.33 rived from blood cells — known as corticostatins Another underdiagnosed clinical problem is — that may compete with corticotropin on its re- hypopituitarism due to brain injury. Pituitary dys- ceptor 42 influence adrenal regulation during in- function occurs in up to 30% of patients with flammation, induce tissue resistance to glucocor- trauma to the brain and may not appear until ticoids, or have both effects.43 In order for an months or years after the traumatic incident.34 adrenocortical cell to respond adequately to the severe stress of inflammation, intraadrenal cell– 42 Glucocorticoid Insufficiency cell communication needs to be intact. This in- Related to Critical Illness volves a close crosstalk of adrenocortical cells with chromaffin cells, as well as endothelial cells and Disease processes that cause a predisposition to intraadrenal immune cells.42 As summarized in adrenal failure during periods of increased stress Figure 2, it has been suggested that neuropeptides, appear to be more frequent than previously as- neurotransmitters, oxidative stress, altered adrenal sumed. Terms such as “relative adrenal insufficien- blood flow, and substrate deficiency due to low cy” and, more accurately, “critical illness–related lipoprotein cholesterol levels and drug interactions corticosteroid insufficiency” have been used to affect adrenal integrity.42,44,45 Septicemia itself and characterize these conditions. medications used during its treatment (Table 2) Recently, expert panels and consensus confer- may interfere with receptor signaling associated ences involving intensivists, pulmonologists, and with the membrane microdomains, with the ma- endocrinologists have examined the clinical rel- chinery of cholesterol transport and storage, with evance of adrenal insufficiency and have provided enzymes involved in steroidogenesis, and with the recommendations for diagnosis and manage- mitochondrial function that is critical for steroido- ment.35 The syndrome has been defined as inad- genesis.46 Furthermore, impaired blood supply to equate glucocorticoid activity in relation to the se- the pars distalis may induce pituitary ischemia, verity of the patient’s illness and has been most necrosis, or both during septic shock, and an in- prominently investigated in cases of sepsis and creased accumulation of nitric oxide, superoxide, septic shock.36-39 The best test currently available or central neuropeptides or prostaglandins con- for establishing the diagnosis is the 1-μg corti- tributes to a decrease in hypothalamic–pituitary cotropin stimulation test, in which cortisol levels hormones in patients with sepsis (Fig. 2). are measured 30 minutes after stimulation, with The clinical consequences of impaired adrenal a level of less than 25 μg per deciliter (690 nmol function in patients with sepsis remain unclear. per liter) or an increment over baseline of less than A recent large, multicenter, randomized, double- 9 μg per deciliter (250 nmol per liter) representing blind, placebo-controlled trial showed that al- an inadequate adrenal response. An inadequate though hydrocortisone does help to reverse septic response to corticotropin testing occurs in up to shock, it does not improve survival.39 Therefore, 60% of patients with sepsis38; however, declining general use of glucocorticoids in patients with cortisol-binding globulin levels in patients with sepsis does not appear to be warranted. A clearer sepsis may moderate the impairment of active understanding of the relevant causes of adrenal free-cortisol production. To better define this syn- insufficiency in patients with sepsis and a more drome, endocrine testing for adrenal insuff iciency refined definition of subgroups that may benefit in patients with sepsis or other critical illnesses from glucocorticoid therapy are required. Addi- must be improved. Confounding factors such as tional factors that may contribute to the conflict- variability in sampling and cortisol assays, including results include the severity of the sepsis, the ing interfering antibodies, need to be considered. duration of therapy, and the use or nonuse of Measurement of free cortisol or widespread im- fludrocortisone39 to treat hypoaldosteronism. It is plementation of more accurate mass spectrometry imperative that we gain a better understanding of methods might help to overcome these analytic both the true pattern of cortisol secretion during limitations.40,41 critical illness and the pharmacokinetics of vari-

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Endocrine Chronic Mental Risk Congenital Infectious Coagulation Liver Tissue autoimmune Trauma inflammatory Tumors disorders, groups abnormalities diseases disorders disease infiltration disorders disorders addictions

Short stature Hashimoto’s Head trauma Rheumatoid HIV-1–cyto- Waterhouse– Hepatitis Pituitary and Adrenal Anxiety Disorders of disease Bleeding arthritis megalovirus Friderichsen Liver failure adrenal Amyloidosis disorders infection syndrome in tumors sexual Diabetes Burns Asthma Liver trans- Hemo- Atypical differentiation mellitus Tuberculosis sepsis Metastases chromatosis depression Pregnancy Crohn’s plantation Hirsutism type 1 disease Candidiasis Thrombo- with low (bilateral Sarcoidosis Anti- Clinical Pernicious Surgical cytopenia lipoproteins lymphoma, depressants Obesity in Allergies Histo- signs and anemia trauma Drug-related and adrenal renal cancer) Pituitary congenital plasmosis Alcohol patient adrenal exhaustion History of adrenal and Vitiligo in Sports Histiocytosis history hemorrhage syndrome hypophy- pituitary autoimmune Wegener’s (e.g., with sectomy disorders polyglandular granulomatosis syndromes heparin) History of Sarcoidosis Antiphospho- bilateral lipid adrenal- syndrome ectomy or causing removal of adrenal incidentaloma hemorrhage History of irradiation

Be aware of Be aware of Check for Check for Check for Be aware of Consider Check for Consider Be aware late onset of thyroid steroid use intranasal, antifungal non- masking by craniospinal additional of HPA-axis adrenal hormone in elite intraarticular, therapies or meningo- immuno- irradiation in suppression by dys- insufficiency triggering athletes and topical rifampin coccal suppressive leukemia and steroid therapy regulation adrenal crisis use of or steroids infections steroid other brain Consider Rule out steroids and causing therapy tumors pituitary Addison’s novel Waterhouse– Additional apoplexy disease in selective Friderichsen consider- (Sheehan’s Consider patients gluco- syndrome ations syndrome) palliation of with corticoid- in pregnancy breast and anorexia receptor endometrial nervosa Check for agonists cancer with use of megestrol perioperative acetate or etomidate use of other steroid in tumor therapy

Consider nonspecific symptoms: fatigue, hypotension, malaise, vomiting, abdominal pain, fever of unknown origin, failure to thrive, hemodynamic complications in patients in critical condition (fluid resistance in shock, poor response to vasopressors)

Suspect impaired HPA-axis; initiate diagnostic workup and hydrocortisone treatment

Figure 1. Clinical Checklist for Adrenal Insufficiency. COLOR FIGURE The figure shows a practical chart for identifying adrenal insufficiency among persons in 10 major risk groups withDraft a potential 5 predispo-5/11/09 sition to clinical or subclinical adrenal insufficiency. The corresponding list of patient history and clinical signs shouldAuthor raiseBornstein awareness about a possible adrenal dysfunction, particularly in the critically ill patient, and allow timely initiation of therapy.Fig HPA# denotes1 hypothalamic–pituitary–adrenal. Title Table 3 ME DE Campion Artist Knoper AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully Issue date 5/28/09 n engl j med 360;22 nejm.org may 28, 2009 2335 The new england journal of medicine

ous hydrocortisone-replacement therapies. Finally, Figure 2 (facing page). Current Concepts of Immune– the adverse effects of glucocorticoid replacement Endocrine and Metabolic Factors Involved in Glucocor- on insulin resistance, protein catabolism, and im- ticoid Dysregulation in Critical Illness. munosuppression may be aggravated by high-fat Cytokines, chemokines, and adipokines derived from parenteral nutrition in critically ill patients, since immune cells and fat cells and bacterial and viral tox- lipids have recently been shown to increase the ins mediated by toll-like receptors modify pituitary– action of glucocorticoids.47 adrenal hormone synthesis and glucocorticoid tissue sensitivity and the activation of peripheral cortisol me- On the basis of available evidence, current rec- tabolism. Similarly, the function of the hypothalamic– ommendations, and good clinical practice, and pituitary–adrenal axis is influenced by blood flow, irrespective of the results of adrenal testing, mod- endothelial factors, neurotransmitters, and neuropep- erate doses of hydrocortisone (200 to 300 mg per tides. Furthermore, synthesis of pituitary and adrenal day) should be given soon after the onset of septic hormones requires a large supply of vitamins, antioxi- dants, and cholesterol. Impairment and dysregulation shock in patients who remain hypotensive despite of any of these pathways will disrupt the integrity of the adequate administration of fluids and vasopres- hypothalamic–pituitary–adrenal axis and may lead to a sor agents.35,36,39 Current evidence is insufficient disturbed adrenal stress response. An electron micro- to recommend the replacement of other steroids graph shows the vesicular mitochondria of an adreno- that are suppressed in patients with sepsis, in- cortical cell in a normal mouse and in a mouse with suppressed corticosterone responses due to the ad- cluding mineralocorticoids and adrenal andro- ministration of dexamethasone (Panels A and B, re- gens.1,48,49 spectively; uranyl acetate and lead citrate staining). In addition to impairment of adrenal glucocor- The number and conformational structure of internal ticoid regulation, hypoaldosteronism occurs fre- mitochondrial membranes correlate with the steroido- quently in critically ill patients. This condition genic capacity of an adrenocortical cell. Animal models with a defect in steroid production frequently show al- probably does not result from a selective effect on terations in vesicular mitochondria, with reduction and the adrenal zona glomerulosa or aldosterone syn- tubular transformation of internal membranes.19,42 thase; rather, it seems likely that the same mech- Staining of histologic sections of adrenal glands with anisms that lead to glucocorticoid insufficiency Sudan black shows the storage of lipid droplets in account for the hypoaldosteronism. Future stud- the adrenal cortex of rats in an unstressed state and 2 hours after stimulation with corticotropin-releasing ies will need to address these mechanisms. The hormone (Panels C and D, respectively). Since choles- role of mineralocorticoid supplementation in the terol constitutes the substrate for steroidogenesis, treatment of critically ill patients is already being there is a rapid disappearance of cholesterol-storing investigated in ongoing multicenter trials. liposomes after activation of the hypothalamic–pitu- Several randomized studies have assessed the itary–adrenal axis (Panel D), illustrating the requirement of an external cholesterol supply for the adrenal role of glucocorticoid treatment in patients with gland. CRH denotes corticotropin-releasing hormone, acute lung injury or the acute respiratory distress HDL denotes high-density lipoprotein, LDL low-density syndrome.50,51 A consistent finding in these stud- lipoprotein, and TNF tumor necrosis factor. ies was that such treatment resulted in an acceler- ated resolution of the disorders.35 In addition, coids in liver-transplant recipients has masked the preliminary data suggest that glucocorticoids have syndrome. Patients with liver diseases have very a beneficial effect in patients with severe pancrea- low lipoprotein levels, and a substrate shortage titis52 and in those who have undergone trauma may therefore lead to an adrenal exhaustion syn- with hemorrhagic shock, as well as in patients who drome. However, a reduction in total cortisol may have just undergone cardiac surgery53 and those reflect a decrease in cortisol-binding globulin who are being weaned from mechanical venti- rather than a decrease in free cortisol. Never- lation.54 theless, patients with liver diseases should be It has become evident that patients with liver carefully monitored for symptoms and signs of diseases have adrenal disturbances. Signs of adre- adrenal insufficiency and may benefit from glu- nal insufficiency are present in 33% of patients cocorticoid-replacement therapy.55 with acute liver failure, 65% of patients with chronic liver disease and sepsis, and 92% of pa- Conclusion tients who have undergone a liver transplanta- tion.45 Consequently, the term “hepato–adrenal In 1855, Thomas Addison concluded that “my ex- syndrome” has been introduced. It has been sug- perience, though necessarily limited, leads to a gested that immunosuppression with glucocorti- belief that [adrenal insufficiency] is by no means

2336 n engl j med 360;22 nejm.org may 28, 2009

Hypothalamus CRH

Pituitary TNF-α, interleukin-6, Immune cells Corticotropin corticostatins

Neurotransmitters, Exogenous steroids neuropeptides Innervation Endothelial- Vasculature derived factors Nitric oxide

Adipocyte-derived factors (e.g., leptin) Adipose tissue

Pathogens Cholesterol supply

Adrenal Bacterial gland Liver toxins HDL Toll-like receptors LDL

Glucocorticoid receptor and signaling Glucocorticoid and downstream metabolism Peripheral cells

A B C D

Cortex

Cortex Medulla

Medulla

COLOR FIGURE of very rare occurrence and that were we better this disease and better able to manage it withDraft a 8 5/11/09 acquainted with its symptoms and progress, we simple glucocorticoid-replacement regimen; Authorhow- Bornstein should probably succeed in detecting many cases, ever, clinicians must be aware of the growingFig #list 2 Title Predisposing Factors which in the present state of our knowledge may of causes and predisposing factors involved in for Adrenal Insufficiency 3 ME be entirely overlooked or misunderstood.” Today, the development of this life-threatening disorder.DE Campion we are better acquainted with the symptoms of A simplified checklist of groups that are Artistat in- Knoper AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully n engl j med 360;22 nejm.org may 28, 2009 2337 Issue date 5/28/09 The new england journal of medicine

creased risk for adrenal impairment may help to Supported by grants from Deutsche Forschungsgemeinschaft (BO 1141/8-1 and SFB 655 – TP A6), from the Sander Foundation, raise awareness among clinicians (Fig. 1). This in- and from the Center for Regenerative Therapies Dresden. formation is important, since timely and adequate No potential conflict of interest relevant to this article was hydrocortisone replacement in patients with acute reported. I thank Dr. Graeme Eisenhofer, Kathy Eisenhofer, Dr. Wiebke adrenal insufficiency represents a lifesaving and Arlt, and Dr. Monika Ehrhart-Bornstein for their careful reading effective solution in medical emergencies. of the manuscript.

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