AUTHOR INFORMATION

Section 1 of 12

Authored by Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook

Coauthored by Phyllis Speiser, MD, Professor, Department of Pediatrics, New York University School of Medicine; Chief, Division of Pediatric Endocrinology, Schneider Children's Hospital

Thomas A Wilson, MD, is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa

Edited by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry B Bercu, MD, Professor, Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Therapeutics, University of South Florida; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital

Author's Email:	Thomas A Wilson, MD
Editor's Email:	Karl S Roth, MD

eMedicine Journal, April 7 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 12

Background: Adrenal insufficiency can be classified as primary or secondary. Primary adrenal insufficiency occurs when the adrenal gland itself is dysfunctional. Secondary adrenal insufficiency, also termed central adrenal insufficiency, occurs when lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus or adrenocorticotropic hormone (ACTH) secretion from the pituitary is responsible for hypofunction of the adrenal cortex. Adrenal insufficiency can be classified further as congenital or acquired.

Pathophysiology: The adrenal cortex is divided into 3 major anatomic zones: the zona glomerulosa, which produces aldosterone, and the zonae fasciculata and reticularis, which together produce cortisol and adrenal androgens. A fetal zone, unique to primates, produces dehydroepiandrosterone, a precursor of both androgens and estrogens. This zone involutes within the first few months of postnatal life.

Aldosterone secretion primarily is regulated by the renin-angiotensin system, but it also is stimulated by increased serum potassium concentrations. Cortisol secretion is regulated by ACTH, which, in turn, is regulated by CRH from the hypothalamus. Serum cortisol inhibits secretion of CRH and ACTH, thus preventing excessive secretion of cortisol from the adrenal glands. Adrenal androgen secretion is regulated partially by ACTH but also by other unknown factors. ACTH not only stimulates cortisol secretion, it also promotes growth of the adrenal cortex in conjunction with growth factors such as insulinlike growth factor (IGF)-1 and IGF-2.

Frequency:

• In the US: Primary adrenal insufficiency is uncommon. Iatrogenic central adrenal insufficiency is a more frequent cause of morbidity and mortality, although exact incidence is unknown. Adrenal insufficiency secondary to congenital adrenal hyperplasia (CAH) has an incidence of approximately 1 case per 16,000 infants.

• Internationally: In Great Britain, the prevalence of adrenal insufficiency is 110 cases per million persons of all ages. More than 90% of cases are attributed to autoimmune disease. An Italian study provides similar statistics. Worldwide, the most common cause is tuberculosis (TB). The calculated incidence is approximately 5-6 cases per million persons per year.

Mortality/Morbidity: Adrenal insufficiency may be difficult to differentiate from other conditions, such as chronic fatigue syndrome and depression, if onset is gradual. Hyperpigmentation may be seen in primary adrenal insufficiency due to the elevated ACTH overproduced by the pituitary. The ACTH molecule contains the alpha-melanocyte-stimulating hormone (MSH) sequence, which stimulates melanocytes. Salt craving is another symptom typical of patients with zona glomerulosa dysfunction and may be the first sign of autoimmune adrenal destruction.

Patients with chronic adrenal insufficiency often complain of fatigue, anorexia, asthenia, weight loss, abdominal pain, nausea, vomiting, and weakness. Patients may have hypoglycemia and most have hypotension. Orthostatic changes in BP and pulse are cardinal signs of adrenal insufficiency.

Hyponatremia with or without hyperkalemia is common in primary adrenal insufficiency due to deficient aldosterone secretion. Hyponatremia occasionally is seen in central or secondary adrenal insufficiency, presumably due to water retention from increased vasopressin secretion.

Adrenal insufficiency is a potentially fatal disease if unrecognized and untreated. Death usually results from hypotension or cardiac arrhythmia secondary to hyperkalemia.

Race: Adrenal insufficiency exhibits no racial predilection.

Sex:

• Autoimmune adrenal insufficiency is more common in females than males.

• Adrenal insufficiency due to adrenoleukodystrophy is limited to males because it is X-linked, as is a form of congenital adrenal hypoplasia, termed adrenal hypoplasia congenita (AHC). Both conditions are relatively rare.

• Secondary adrenal insufficiency due to a deficiency of ACTH or CRH, or to a lack of ACTH receptors, is equally common among males and females.

Age: Autoimmune adrenal insufficiency is more common in adults than in children. Congenital causes, such as CAH, congenital adrenal hypoplasia, and defects in the ACTH receptor, are more commonly recognized in childhood.

CLINICAL

Section 3 of 12

History:

• Acute adrenal insufficiency in infants may occur in the context of a serious illness such as sepsis, as the result of prolonged and difficult labor, or from a traumatic delivery. Older children and adults also may have a history of infectious illness, particularly TB or meningococcemia, although any type of severe sepsis may trigger adrenal insufficiency. The condition may be seen without concomitant illnesses when it is due to CAH or AHC. Antiphospholipid syndrome occasionally results in acute adrenal insufficiency secondary to bilateral adrenal hemorrhage.



• Autoimmune adrenal insufficiency or adrenal insufficiency due to adrenoleukodystrophy (Online Mendelian Inheritance in Man [OMIM] *300100), chronic infections (eg, HIV, TB, fungi) or infiltrative lesions generally present with chronic symptoms (eg, fatigue, anorexia, abdominal pain), which may be exacerbated by an acute adrenal crisis.



• Patients with chronic adrenal insufficiency usually complain of chronic fatigue, anorexia, nausea, vomiting, loss of appetite, weight loss, recurring abdominal pain, and lack of energy.



• Symptoms of hypoglycemia are common in small children. Altered mental status, even without hypoglycemia, is common with acute adrenal insufficiency.



• Increased skin pigmentation and salt craving are common in chronic primary adrenal insufficiency. These symptoms are not seen in patients with secondary or central adrenal insufficiency resulting from ACTH or CRH deficiency, since these conditions do not elevate serum ACTH concentrations. Excess MSH activity causes hyperpigmentation. If the defect lies in the pituitary or hypothalamus, no defect exists in aldosterone production because the renin-angiotensin system adequately stimulates the adrenal zona glomerulosa to ensure sufficient aldosterone concentrations and to prevent salt wasting.



• Patients who have been on long-term pharmacologic doses of glucocorticoids in the recent past are prone to develop symptoms of adrenal insufficiency when they are stressed by an illness or trauma. In this situation, adrenal insufficiency is due to chronic suppression of CRH and ACTH by exogenous glucocorticoids, and these patients consequently are unable to mount an appropriate cortisol response to stress. These patients do not waste sodium because their renin-angiotensin system maintains aldosterone secretion. Recovery of the hypothalamic-pituitary-adrenal axis may take weeks to months and is related to duration of pharmacological glucocorticoid exposure.

Physical:

• Patients with acute adrenal insufficiency generally present with acute dehydration, hypotension, hypoglycemia, or altered mental status. These signs usually occur in an acutely ill patient with sepsis or disseminated intravascular coagulation or following a traumatic delivery.



• Patients with chronic adrenal insufficiency may demonstrate increased skin pigmentation, particularly in areolae, genitalia, scars, and moles. Typically, recent scars are affected more than those preceding onset. Areas unexposed to sun (eg, palmar creases, axillae, areolae) often are hyperpigmented. The patient also may have pigmentary lines in the gums. Signs of weight loss may be evident. If not frankly hypotensive, the patient may demonstrate orthostatic hypotension. Some patients also may lose pubic and axillary hair (but not become totally alopecic) because adrenal androgens support growth of body hair in these areas.



• Wolman disease (OMIM *278000), an autosomal recessive disorder caused by a deficiency of lysosomal acid lipase, generally is accompanied by hepatosplenomegaly and adrenal calcifications, which may be seen on plain radiographs or CT scan of the adrenal glands.

Causes:

• Central adrenal insufficiency


• • Most cases are iatrogenic, caused by long-term administration of glucocorticoids. A mere 2 weeks' exposure to pharmacological doses of glucocorticoids can cause CRH-ACTH-adrenal axis suppression. Suppression can be so great that acute withdrawal or stress may prevent the axis from responding with sufficient cortisol production to prevent an acute adrenal crisis. Recently, treatment with megesterol acetate, an orixegenic agent, has resulted in iatrogenic adrenal suppression, presumably through glucocorticoid properties of megesterol acetate.
  
  
  
  • Other causes include congenital and acquired hypopituitarism and ACTH unresponsiveness. This may be either isolated (OMIM *202200) or associated with achalasia and alacrima (triple A syndrome [AAAS]; OMIM *#231550).
  
  
  
• Acquired primary adrenal insufficiency


• • In developed countries, the most common cause is autoimmune destruction of the adrenal cortex. This disorder may exist in isolation or may be part of a polyglandular autoimmune disorder.

  • Type 1 autoimmune polyglandular disease (OMIM *240300) presents in the first decade of life and is transmitted as an autosomal recessive disorder with all or some of the following:
    • Adrenal failure
      
    • Hypoparathyroidism
      
    • Hypothyroidism
      
    • Gonadal failure
      
    • Diabetes mellitus type 1
      
    • Vitiligo
      
    • Alopecia
      
    • Pernicious anemia
      
    • Chronic mucocutaneous candidiasis
      
  
  
  
  • Type 2 autoimmune polyglandular disease consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. This condition presents in the second and third decades of life and is transmitted as an autosomal disorder with variable penetrance.

  • Less common causes of adrenal failure include the following:
    • Adrenal hemorrhage
      
    • Infections (eg, TB, HIV)
      
    • Neoplastic destruction
      
    • Metabolic disorders (eg, various forms of adrenal leukodystrophy, Wolman disease [OMIM *278000], Smith-Lemli-Opitz syndrome)
      
  
  
  
  • Hemachromatosis may cause either primary or secondary adrenal insufficiency. Iron deposition in the pituitary and/or adrenal glands in multiply transfused patients with thalassemia patients also may cause adrenal insufficiency.
  
  
  
• Congenital primary adrenal insufficiency


• • Congenital disease may occur from adrenal hypoplasia or hyperplasia.
  
  
  
  • Adrenal hypoplasia congenita (AHC), inherited as an X-linked disorder (OMIM 300200), is caused by deletion of the DAX1 gene on chromosome X and often is part of a contiguous gene deletion that involves glycerol kinase deficiency, Duchenne muscular dystrophy, and hypogonadotropic hypogonadism. An alternate form, also X-linked, has been described characterized by intrauterine growth retardation and skeletal and genital anomalies (IMAGE syndrome; OMIM 300290). A third form of AHC is autosomal recessive (OMIM 240200).
  
  
  
  • CAH results from a deficiency of 1 of several enzymes required for adrenal synthesis of cortisol. Adrenal insufficiency most often develops with combined deficiencies of cortisol and aldosterone. The most prevalent form of CAH is caused by a steroid 21-hydroxylase deficiency (OMIM *201910).
  
  
  
  • Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency caused either by a mutation in the steroid acute regulatory protein (STAR; OMIM #201710) or a mutation in the cholesterol side chain cleavage gene (CYP11A; OMIM #118485). This disease causes a defective synthesis of all adrenocortical hormones and, in its complete form, is lethal.
  
  
  
  • Mutations or deletions of P450 oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17 hydroxylase, 21 hydroxylase, and 17-20 lyase activities resulting in adrenal insufficiency often accompanied by primary hypogonadism.
  
  
  

DIFFERENTIALS

Section 4 of 12

3-Beta-Hydroxysteroid Dehydrogenase Deficiency
Adrenal Hypoplasia
Birth Trauma
Chronic Fatigue Syndrome
Congenital Adrenal Hyperplasia
Familial Glucocorticoid Deficiency
Hypopituitarism
Pseudohypoaldosteronism

Other Problems to be Considered:

ACTH receptor defect (familial glucocorticoid deficiency)
Adrenal hypoplasia congenita
Adrenoleukodystrophy and adrenomyeloneuropathy
Autoimmune polyglandular endocrinopathy syndromes
Congenital adrenal hyperplasia
Infectious adrenalitis (HIV, TB)
Lipoid adrenal hyperplasia
Wolman disease

WORKUP

Section 5 of 12

Lab Studies:

• Clinical suspicion is important because presentation of the disorder may be insidious and subtle. When adrenal insufficiency is suspected, the following laboratory studies help establish the diagnosis:


• • Electrolytes

  • Fasting blood sugar

  • Serum ACTH

  • Plasma renin activity

  • Serum cortisol

  • Serum aldosterone
  
  
  
• When hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine, along with a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring.
  • Interpret random serum cortisol concentrations within the context from which they were obtained. (For example, adrenal insufficiency is unlikely in an otherwise healthy individual with an 8:00 am serum cortisol concentration more than 10 mcg/dL. Yet a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient highly suggests adrenal insufficiency.)

  • A diagnosis of adrenal insufficiency is confirmed by a serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity, or a concentration lower than that level obtained 60 minutes following cosyntropin administration.

  • Diagnosis also is confirmed when serum cortisol concentrations fail to increase to more than 18-20 mcg/dL by 60 minutes following cosyntropin administration.

  • Note that these guidelines do not apply to premature and low birth weight infants, who have much lower cortisol secretion.



• If serum cortisol is low with elevated ACTH, measure antiadrenal antibodies. Antibodies to 1 or more steroidogenic enzymes, particularly 21-hydroxylase, often are found in autoimmune adrenal disease.



• Cosyntropin administration is controversial because whether the best dose is the standard 250 mcg, the 1 mcg, or the low 0.5 mcg/m² is unresolved, particularly in the pediatric age group. The standard dose, therefore, is suggested. The common preparation of cosyntropin makes it cumbersome to deliver 1 mcg or less, and both doses seem supraphysiological.



• When serum cortisol response to cosyntropin is subnormal, but serum ACTH is not elevated, confirm the possibility of central adrenal insufficiency. In this context, a 6-hour or 3-day treatment with ACTH can produce a normal cortisol response, confirming that initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. The dose of ACTH for the 6-hour test is 25 IU administered IV over the 6 hours. If the 3-day test is chosen, administer 25 mg/m² of ACTH gel IM every 12 hours for the 3 days. Plasma cortisol should increase to more than 40 mcg/dL in response to either of these tests. Alternatively, 24-hour urinary 17-hydroxysteroid concentrations should increase 5-10 fold in response to the 3-day ACTH stimulation test.



• If the patient has recent onset (ie, <10 d) of central adrenal insufficiency (as in a recent surgery in the hypothalamus or pituitary regions), resorting to a more cumbersome and risk-bearing insulin tolerance test or metyrapone stimulation test may be preferable. These conditions are the only real indication for performing these tests in a patient with adrenal insufficiency



• An insulin tolerance test requires IV administration of insulin (usually 0.05-0.15 units regular insulin/kg) to induce a 50% drop in blood sugar. Measure cortisol and glucose concentrations every 15 minutes for 60 minutes. The test is considered adequate if the blood sugar drops by at least 50%. In response to this hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 20 mcg/dL. This test involves some risk of hypoglycemic seizure; therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overly symptomatic.



• Standard metyrapone stimulation tests involve administering 300 mg/m² metyrapone in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, the last enzyme step in cortisol synthesis, the cortisol precursor 11-deoxycortisol increases in the plasma. A normal response is a rise in 11-deoxycortisol concentrations to more than 10.5 mcg/dL 4 hours following the last dose of metyrapone or a 2- to 3-fold increase in 24-hour urinary 17-hydroxycorticosteroid concentrations (which include tetrahydro compound S [urinary metabolite of 11-deoxycortisol]), on the day or day following metyrapone administration. This test is cumbersome and carries some risk of inducing an adrenal crisis.



• When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If the test results for antiadrenal antibodies are negative, search for another etiology such as TB, adrenal hemorrhage, or adrenoleukodystrophy.



• The standard ovine or human CRH stimulation test is reliable in the diagnosis and differential diagnosis of adrenal insufficiency.


• • Patients with glucocorticoid deficiency of any etiology have subnormal cortisol responses.
  
  
  
  • Patients with primary glucocorticoid deficiency have elevated ACTH concentrations basally and after CRH administration.
  
  
  
  • Patients with secondary glucocorticoid deficiency have low ACTH levels throughout the test if they suffer from a primary pituitary deficiency, or these patients have exaggerated responses if their problem is tertiary.
  
  
  

Imaging Studies:

• CT is the imaging study of choice and helps identify adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT.



• Abdominal radiographs may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease.



• Ultrasonography is a poor imaging modality for investigation of the adrenal glands.



• Iodocholesterol scanning is not particularly useful.

Procedures:

• CT-guided fine-needle aspiration sometimes helps diagnose the etiology of infiltrative adrenal diseases.

TREATMENT

Section 6 of 12

Medical Care:

• Patients generally are hypovolemic, and they may be hypoglycemic, hyponatremic, or hyperkalemic. Initial therapy consists of IV saline and dextrose.



• If hypotensive, a 20 mL/kg bolus of isotonic sodium chloride solution over the first hour may be necessary to restore BP. The bolus may be repeated if BP remains low.



• Once electrolytes, blood sugar, cortisol, and ACTH concentrations are obtained, treat patients suspected of having adrenal insufficiency with glucocorticoids.



• If the physician proceeds with a cosyntropin stimulation test, dexamethasone may be administered prior to cosyntropin without interfering with results. Short-term dexamethasone administration does not interfere with cortisol response or with cortisol assay.

Surgical Care:

• No surgical management is needed in most cases.



• Treat patients with adrenal insufficiency requiring surgery with stress doses of glucocorticoids (eg, 50-75 mg/m² hydrocortisone IM or IV "on call" prior to surgery).


• • Treat the patient with additional hydrocortisone during the procedure, using either a hydrocortisone drip of 2-4 mg/m²/h or as an additional push of 10-25 mg/m² IV every 6 hours throughout the procedure.
  
  
  
  • Continue hydrocortisone administration in the immediate postoperative period.
  
  
  
  • On the second and third postoperative day, the dose of hydrocortisone can be decreased by 50% each day to a minimum of the patient's usual daily requirement if the patient is recovering well and has no complications.
  
  
  
  • By the fourth postoperative day, the usual daily dose of steroids may be resumed if the patient is recovering satisfactorily. If complications occur, stress doses of glucocorticoids must be continued.
  
  
  
  • Fludrocortisone may be withheld on the day of surgery and while the patient is receiving stress doses of hydrocortisone. If the patient is unable to take PO fludrocortisone in the postoperative period, stress doses of hydrocortisone may be continued for a longer period to provide adequate mineralocorticoid activity.
  
  
  

Consultations: Consult an endocrinologist if adrenal insufficiency is suspected.

Diet:

• Patients should be on an unrestricted diet.



• Patients with primary adrenal insufficiency should have ample access to salt because they excrete too much salt if untreated.



• Infants with primary adrenal insufficiency often need 2-5 g/d of sodium chloride.



• Caloric intake may need monitoring. Restrict caloric intake if excess weight gain occurs because glucocorticoids stimulate appetite.

Activity:

• No restrictions are necessary once adequate replacement therapy is instituted.



• Provide patients who exercise in warm climates with sufficient sodium chloride to prevent hyponatremia.

MEDICATION

Section 7 of 12

Glucocorticoid replacement is required in all forms of adrenal insufficiency. Mineralocorticoid replacement is required only in primary adrenal insufficiency because aldosterone secretion is reduced in primary adrenal insufficiency but not in secondary (central) adrenal insufficiency. Treat an acute adrenal crisis (eg, hypotension, hypoglycemia) with pharmacological doses of glucocorticoids; this treatment can be in the form of hydrocortisone, methylprednisolone, or dexamethasone.

Acute adrenal insufficiency

In a hypotensive patient, rapidly administer isotonic sodium chloride solution (eg, 450 mL/m², 20 mL/kg) over the first hour and follow with a typical continued infusion rate of 3200 mL/m²/d or 200 mL/kg/100 calories of estimated resting-energy expenditure to restore intravascular volume.

Dextrose must be provided. If the patient is hypoglycemic, 2-4 mL/kg of 25% dextrose in water (D25W) corrects hypoglycemia. Provide 5% dextrose in water (D5W) to prevent further or initial hypoglycemia.

Potassium generally is not needed in acute situations, especially in patients with primary adrenal insufficiency who often are hyperkalemic.

Once IV fluids are provided, administer stress dosing of glucocorticoid. The recommended stress dose of hydrocortisone is 50-75 mg/m² IV initial dose, followed by 50-75 mg/m²/d IV divided in 4 doses. Hydrocortisone may be given IM if no IV access exists, but IM administration works slower. Comparable stress doses of methylprednisolone are 10-15 mg/m² and dexamethasone 1-1.5 mg/m².

Dexamethasone is preferable for patients with suspected but unproved adrenal insufficiency because the physician can simultaneously treat the patient while carrying out a diagnostic cosyntropin stimulation test. Methylprednisolone and dexamethasone have negligible mineralocorticoid effect. Large doses of hydrocortisone (ie, even double or triple the stress doses previously mentioned) are preferred if the patient is hypovolemic, hyponatremic, or hyperkalemic. No parenteral form of mineralocorticoid currently is available in the United States, but if the patient has good GI function, fludrocortisone 0.1-0.2 mg may be administered.

Long-term medical therapy

In a child with adrenal insufficiency, long-term glucocorticoid replacement must be balanced between the need to prevent symptoms of the adrenal insufficiency and the need to allow the child to grow at a normal rate while preventing symptoms of glucocorticoid excess. Individualize the dosage for each patient; the range for hydrocortisone is 7-20 mg/m²/d PO in 2-3 divided doses. Hydrocortisone is available in 5-, 10-, and 20-mg tablets. Hydrocortisone is recommended for long-term therapy because of its lower potency, which permits easier titration of appropriate doses. In a large patient, prednisone or dexamethasone may be substituted. Estimated equivalency is as follows:

• 1 mg prednisone = 4-10 mg hydrocortisone

• 1 mg dexamethasone = 50-100 mg hydrocortisone

Patients with primary adrenal insufficiency who also have mineralocorticoid deficiency require fludrocortisone at 0.1-0.2 mg/d. Young patients must be given adequate access to sodium chloride (2-5 g/d) to counteract salt wasting.

Adjust glucocorticoid dose for each patient based on clinical criteria (eg, absence of glucocorticoid deficiency symptoms, excessive and normal growth). The author's experience has shown that plasma ACTH concentrations provide little guidance for glucocorticoid dose adjustments. Growth pattern and symptoms of salt craving, BP, plasma renin activity, and electrolytes help adjust fludrocortisone dosages.

Stress and illness

An important physiological response to stress is an increase in cortisol production mediated by ACTH. Patients with adrenal insufficiency are unable to mount this response, regardless of etiology, and must be administered stress doses of glucocorticoid. When a febrile illness occurs or the patient requires a surgical or stressful procedure, triple the dosage. If the patient is vomiting or listless, administer parenteral glucocorticoid (hydrocortisone 50-75 mg/m² IM/IV or equivalent methylprednisolone [10-15 mg/m²] or dexamethasone [1-1.5 mg/m²]). Repeat the dose every 6-8 hours until patient has recovered because hydrocortisone succinate has a short duration of action.

Injectable glucocorticoid must be provided to all patients with adrenal insufficiency; provision should include instructions to the patient and caretaker about its use and importance.

Mineralocorticoid therapy does not need to be tripled during periods of illness and physical stress.

No contraindications exist to glucocorticoid or mineralocorticoid replacement when needed, and this therapy involves few drug-drug interactions. The preferred glucocorticoids during pregnancy are hydrocortisone or prednisone because the placenta inactivates them. In contrast, dexamethasone readily crosses the placenta and suppresses fetal adrenal function.

Drug Category: Glucocorticoids -- Supplies the adrenal insufficiency patient with the equivalent of the body's missing cortisol produced by the adrenal cortex under both normal conditions, and under stress. Dexamethasone and betamethasone cross the placenta to an appreciable degree, and therefore should not be used in pregnant women, unless specifically indicated (ie, for maturation of fetal lung or suppression of fetal adrenal function).

Drug Name	Hydrocortisone (Hydrocortone, A-Hydrocort) -- DOC because of mineralocorticoid activity and glucocorticoid effects. Equivalent to the adrenal product, cortisol. Has a short half-life and as such does not inhibit growth to the same degree as the more potent, longer-acting synthetic glucocorticoids (eg, prednisone, methylprednisolone, dexamethasone). Because it is short acting, hydrocortisone must be administered PO bid/tid or usually q6h when administered IV. In a healthy person, the average cortisol secretion is about 7-10 mg/m2/d, the aim of replacement therapy is to supply only as much as the patient needs; this is best judged subjectively by the patient's own sense of well-being. PO dose requirements are greater than parenterally administered dose requirements because some hydrocortisone is inactivated as it passes through the liver. Equivalent low doses can be derived for prednisone (about 4 times the potency of hydrocortisone), methylprednisolone (about 5 times the potency of hydrocortisone) and dexamethasone (about 40-50 times the potency of hydrocortisone).
Adult Dose	10-20 mg/m2/d PO q6h
Pediatric Dose	In children, similar dosing guidelines apply, except in congenital adrenal hyperplasia (CAH); in that disorder, ACTH is often refractory to suppression at low glucocorticoid doses, so that the average treatment dose is more typically ~15 mg/m2/d; doses >20 mg/m2/d may lead to growth suppression in any patient; very low doses allow unchecked secretion of adrenal androgens in CAH, also with adverse growth consequences
Contraindications	Documented hypersensitivity; pharmacological doses generally are contraindicated in viral, fungal, or tubercular infections
Interactions	Live virus immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy for Addison disease; phenytoin, phenobarbital, ephedrine, and rifampin may increase hepatic clearance of steroids, requiring higher dosages; PT should be checked frequently in patients receiving glucocorticoids and coumarin anticoagulants, since steroids may inhibit (or rarely enhance) response to these anticoagulants; when administered together with potassium-depleting diuretics, observe patients closely for possible hypokalemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Regularly observe patients taking steroids for potential development of iatrogenic Cushing syndrome; closely monitor children for growth; caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

Drug Name	Dexamethasone (Decadron) -- Provides glucocorticoid activity. In pharmacological doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. May be used for allergic and inflammatory conditions.
Adult Dose	Equivalent to 1/40 of hydrocortisone dose; adjust dose according to clinical response
Pediatric Dose	Older children: Equivalent to 1/40 of hydrocortisone dose; physiologic replacement dose is 0.6-0.75 mg/m2/d PO divided q6-12h; titrate up or down based upon clinical response
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor for signs of adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Name	Methylprednisolone (Medrol, Solu-Medrol) -- Provides glucocorticoid activity. In pharmacological doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Available in liquid form, unlike hydrocortisone, and may be used if hydrocortisone use is problematic.
Adult Dose	Physiological replacement therapy: Start with 2-3 mg/m2/d and titrate up or down based upon clinical response
Pediatric Dose	Not established, but may be used if hydrocortisone use is problematic. Initial starting dose for physiological replacement: 2-3 mg/m2/d, then titrate up or down depending upon clinical response
Contraindications	Documented hypersensitivity; viral, fungal or tubercular infections
Interactions	Coadministration with digoxin, may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking methylprednisolone concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Name	Prednisone (Liquid Pred, Prednisone Intensol Concentrate, Deltasone) -- Provides glucocorticoid activity. In pharmacological doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Adult Dose	For physiological replacement therapy, start with 2-4 mg/m2/d and titrate up or down depending upon clinical response
Pediatric Dose	Not established, but may be used if providing hydrocortisone is problematic since prednisone is available in liquid form, whereas hydrocortisone is not; Initial starting dose for physiological replacement: 2-4 mg/m2/d, then titrate up or down depending upon clinical response
Contraindications	Documented hypersensitivity; viral, fungal or tubercular infections
Interactions	Coadministration with digoxin, may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin and rifampin may decrease levels of prednisolone (adjust dose); monitor patients for hypokalemia when taking prednisone concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Category: Mineralocorticoids -- For replacement of aldosterone deficiency; to prevent hyponatremia and hyperkalemia in the patient with primary adrenal insufficiency.

Drug Name	Fludrocortisone (Florinef) -- DOC for mineralocorticoid replacement therapy if the adrenal cortex's zona glomerulosa does not produce aldosterone. This allows the patient to achieve normal sodium homeostasis. Available only in PO form. If the patient cannot tolerate PO medications, parenteral hydrocortisone can provide mineralocorticoid effect.
Adult Dose	0.1-0.2 mg/d PO qd or divided bid
Pediatric Dose	0.05-0.2 mg/d PO; infants' diets are often quite low in sodium, and they may also require sodium chloride supplements
Contraindications	Documented hypersensitivity; systemic fungal infections
Interactions	Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause sodium retention, hypokalemia, and hypertension; use cautiously in hypertensive subjects, patients on potassium-depleting diuretics and digoxin; taper dose gradually when therapy is discontinued

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• Monitor dosing adequacy for patients on long-term glucocorticoid therapy. Too little glucocorticoid causes symptoms of adrenal insufficiency (eg, anorexia, nausea, vomiting, abdominal pain, asthenia, poor weight gain, weight loss). Too much glucocorticoid causes excess weight gain, cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure. In children, growth failure is a sensitive indicator of exposure to excess glucocorticoids.



• If adrenal insufficiency has an autoimmune etiology, monitor patients for development of associated autoimmune phenomena (eg, hypoparathyroidism, hypogonadism, vitiligo, pernicious anemia, thyroid dysfunction, diabetes mellitus).

In/Out Patient Meds:

• In addition to the standard maintenance medications (see Medication) described above for patients with adrenal insufficiency, provide injectable hydrocortisone to patients and their family member for use when an impending adrenal crisis becomes apparent or when the patient cannot tolerate PO medications. An IM injection of hydrocortisone (eg, 25 mg for infants, 50 mg for children, 100 mg for adults) can be lifesaving in the interval prior to receiving professional medical care. If this is not possible, rectal hydrocortisone can be used until systemic glucocorticoids can be administered.

Deterrence/Prevention:

• Iatrogenic adrenal insufficiency from glucocorticoid therapy can be prevented by treating the patient with doses below physiological requirements. Treatment with alternate-day PO prednisone, or with topical or inhaled glucocorticoids can reduce the possibility of iatrogenic adrenal insufficiency.

Complications:

• Hypotension, shock, hypoglycemia, and death are the primary complications of adrenal insufficiency.



• Complications from excess glucocorticoids include the following:


• • Growth failure

  • Obesity

  • Striae

  • Osteoporosis

  • Muscle weakness

  • Hypertension

  • Hyperglycemia

  • Cataracts
  
  
  
• Daily PO glucocorticoid therapy may provide iatrogenic suppression of the hypothalamic-pituitary-adrenal axis within 2 weeks, which can last for weeks to months depending on the duration of exposure to pharmacological doses of glucocorticoids.



• Complications of excess mineralocorticoid administration include hypertension and hypokalemia.

Prognosis:

• An untreated patient's prognosis is poor; death is a common outcome unless replacement steroid therapy is instituted.



• With proper treatment and compliance, patients can live a normal life span without limitations.

Patient Education:

• Teach patients and their caretakers about the consequences and potential for death if adequate replacement therapy is not provided.



• Teach patients and their caretakers how to administer supplemental glucocorticoid in times of illness or traumatic stress, including how to administer injectable glucocorticoid when the patient is vomiting or unable to take PO stress doses. Periodically reinforce this information because caretakers often are reluctant to inject medications.



• Advise patients and their caretakers to seek medical help immediately if the patient becomes ill.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Physicians must consider adrenal insufficiency in the differential diagnosis of patients with suggestive symptoms such as chronic fatigue, anorexia, nausea, vomiting, diarrhea, unexplained weight loss, dehydration, hypoglycemia, and hypotension. Do not forget that chronic infections, such as HIV and TB, can impair adrenal function. The possibility of central adrenal insufficiency must be investigated, identified, and treated in all patients who have undergone pituitary surgery or radiation or prolonged treatment with glucocorticoids.



• Advise patients to wear or carry a medical alert tag or card at all times, so they may receive appropriate emergency care if they are found unconscious.

Special Concerns:

• Dose requirements may increase during pregnancy.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A patient presents to the ED of a northern US hospital in February because of recurring abdominal pain and vomiting. The record shows multiple previous visits for the same complaint and progressive weight loss. Physical examination reveals orthostatic hypotension. The patient's skin is unusually pigmented for the winter, and the patient has not been in the sun recently. Which of the following laboratory or radiographic findings should the ED physician expect?

A: Elevated serum amylase
B: Evidence of gall bladder disease
C: Small heart on chest radiographs
D: Hyponatremia and/or hyperkalemia
E: C and D

The correct answer is E: This patient has clinical symptoms and signs of chronic adrenal insufficiency. Adrenal insufficiency results in aldosterone deficiency, causing hyponatremia and hyperkalemia. The small heart is the result of intravascular volume depletion.

CME Question 2: A 16-year-old adolescent male presents to the ED with fever, petechiae, and purpura. He is hypotensive and appears ill. Blood cultures, electrolytes, and renal function tests are obtained. His dextrose stick is 30. Which of the following is the best treatment?

A: Antibiotics
B: IV fluids with isotonic sodium chloride solution
C: IV dextrose
D: Dexamethasone
E: All of the above

The correct answer is E: This patient most likely has meningococcal sepsis. Hypotension and hypoglycemia strongly suggest acute adrenal insufficiency, which is common in meningococcal infections. Treatment with IV fluids, dextrose, glucocorticoids, and antibiotics is essential.

Pearl Question 1 (T/F): A patient presents with hypotension, a low serum cortisol level, and an elevated serum adrenocorticotropic hormone (ACTH) level. The likely diagnosis is primary adrenal insufficiency.

The correct answer is True: The low serum cortisol and elevated serum ACTH levels confirm a diagnosis of primary adrenal insufficiency.

Pearl Question 2 (T/F): A patient with hypoglycemia and low levels of serum cortisol and adrenocorticotropic hormone (ACTH) later demonstrates a normal cortisol response to a 3-day ACTH stimulation test. The correct diagnosis is primary adrenal insufficiency.

The correct answer is False: The patient has central adrenal insufficiency, not primary adrenal insufficiency. In primary adrenal insufficiency, serum ACTH concentration is elevated, and the patient would not have a normal cortisol response to administered ACTH.

Pearl Question 3 (T/F): A patient with hypoparathyroidism from childhood presents with a history of recurring abdominal pain, nausea, intermittent vomiting, weight loss, hyperpigmentation, and hyponatremia. Adrenal insufficiency is the probable diagnosis.

The correct answer is True: The patient most likely has autoimmune polyglandular syndrome type 1, which includes hypoparathyroidism and adrenal insufficiency. Other likely conditions in this syndrome are chronic mucocutaneous candidiasis, ovarian failure, vitiligo, alopecia, pernicious anemia, and nail dystrophy.

Pearl Question 4 (T/F): A patient with severe hyponatremia and hyperkalemia from adrenal failure should be treated with fludrocortisone (in addition to dexamethasone or methylprednisolone) or with high doses of hydrocortisone.

The correct answer is True: Dexamethasone and methylprednisolone have little mineralocorticoid effect, so either fludrocortisone must be added, or high dose hydrocortisone must be administered to provide the mineralocorticoid effect necessary to correct the hyponatremia and hyperkalemia.

PICTURES

Section 11 of 12

Caption: Picture 1. The left photograph shows hyperpigmentation on the dorsal hand, preceding treatment of primary adrenal insufficiency. The right photograph shows normal pigmentation after treatment.
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Caption: Picture 2. Adrenal insufficiency. The left photograph shows prominent pigmentation in areas not exposed to the sun such as palmar creases in Addison disease. The right photograph shows normal pigmentation after treatment.
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Caption: Picture 3. Adrenal insufficiency. Vitiligo in a patient with autoimmune adrenalitis. Note area of hyperpigmentation surrounding vitiligo in right photograph.
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Caption: Picture 4. Illustration showing the hypothalamic-pituitary-adrenal axis under normal circumstances and in primary adrenal insufficiency.
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Caption: Picture 5. Adrenal insufficiency. The left photograph shows autoimmune adrenalitis; right photograph shows tuberculous adrenalitis (note caseous granuloma).
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Caption: Picture 6. Adrenal insufficiency. CT scan showing enlarged adrenals in early active autoimmune adrenalitis. Chronic cases present with the opposite picture of hypotrophic adrenals.
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BIBLIOGRAPHY

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