eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Adrenal Insufficiency

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

Updated: Feb 18, 2009

Introduction

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 called central adrenal insufficiency, occurs when a lack of secretion of corticotropin-releasing hormone (CRH) from the hypothalamus or of adrenocorticotropic hormone (ACTH) from the pituitary leads to hypofunction of the adrenal cortex.

Adrenal insufficiency can further be classified 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 is primarily regulated by the renin-angiotensin system. Increased serum potassium concentrations can also stimulate aldosterone secretion. Cortisol secretion is regulated by ACTH, which, in turn, is regulated by CRH from the hypothalamus. Serum cortisol inhibits the secretion of both CRH and ACTH to prevent excessive secretion of cortisol from the adrenal glands (see Media file 1).

ACTH partially regulates adrenal androgen secretion; other unknown factors contribute to this regulation as well. ACTH not only stimulates cortisol secretion but also promotes growth of the adrenal cortex in conjunction with growth factors such as insulin like growth factor (IGF)-1 and IGF-2.^{[1 ]}

Frequency

United States

Primary adrenal insufficiency is uncommon. By comparison, iatrogenic central adrenal insufficiency is a more frequent cause of morbidity and mortality, though its exact incidence is unknown. Adrenal insufficiency secondary to congenital adrenal hyperplasia occurs in approximately 1 per 16,000 infants.

International

Willis and Vince (1997) reported data from Coventry County, Great Britain where the prevalence of adrenal insufficiency is 110 cases per million persons of all ages.^{[2 ]}More than 90% of cases are attributed to autoimmune disease.

An Italian study provided statistics similar to those observed in Great Britain.^{[3 ]}The incidence in Italy is estimated to be 117 cases per million persons.

Worldwide, the most common cause of adrenal insufficiency is tuberculosis (TB). The calculated incidence of adrenal insufficiency caused by TB is approximately 5 or 6 cases per million persons per year.

Mortality/Morbidity

Adrenal insufficiency may be difficult to differentiate from other conditions (eg, chronic fatigue syndrome, depression) if its onset is gradual.^{[4,5 ]}Hyperpigmentation may be seen in primary adrenal insufficiency due to ACTH overproduction by the pituitary. The ACTH molecule contains the sequence for alpha-melanocyte-stimulating hormone (MSH), which stimulates melanocytes.

Salt craving is a symptom typical of patients with dysfunction of the zona glomerulosa. Salt craving may be the first sign of autoimmune adrenal destruction.

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

Hyponatremia with or without hyperkalemia is common in patients with primary adrenal insufficiency, and it is due to deficient aldosterone secretion. Hyponatremia is occasionally found in patients with central or secondary adrenal insufficiency. The presumed cause is water retention due to increased secretion of vasopressin.^{[6 ]}

Adrenal insufficiency is a potentially fatal disease if it is 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 female individuals than in male individuals. Adrenal insufficiency due to adrenoleukodystrophy is limited to male individuals because it is X linked. A form of congenital adrenal hypoplasia due to a defect in DAX1 is also X-linked and, therefore, is confined to males. Secondary forms of adrenal insufficiency such as those due to a deficiency of ACTH or CRH, or a defect in the ACTH receptor, are equally common among male and female individuals.

Age

Autoimmune adrenal insufficiency is more common in adults than in children. Congenital causes, such as congenital adrenal hyperplasia, congenital adrenal hypoplasia, and defects in the ACTH receptor, most commonly become apparent in childhood.

Clinical

History

• In infants, acute adrenal insufficiency may occur in the context of serious illness (eg, sepsis), prolonged and difficult labor, or traumatic delivery.
• Infections such as tuberculosis (TB), meningococcemia, or any severe septicemia may result in adrenal insufficiency.
• Antiphospholipid syndrome occasionally results in acute adrenal insufficiency secondary to bilateral adrenal hemorrhage.^{[7 ]}
• Adrenal insufficiency may occur without concomitant illness when it is due to congenital adrenal hyperplasia or congenital adrenal hypoplasia.
• Symptoms of hypoglycemia are common in small children.
• Altered mental status, even without hypoglycemia, is common in patients with acute adrenal insufficiency.
• Patients with chronic adrenal insufficiency usually have chronic fatigue, anorexia, nausea, vomiting, loss of appetite, weight loss, recurring abdominal pain, and a lack of energy.
  • Increased skin pigmentation and salt craving are common among individuals with chronic primary adrenal insufficiency.
  • Excess melanocyte-stimulating hormone (MSH) activity from adrenocorticotropic hormone (ACTH) causes the hyperpigmentation.
  • Hyperpigmentation is not noted in patients with secondary or central adrenal insufficiency due to ACTH or corticotropin-releasing hormone CRH deficiency because these conditions do not elevate serum ACTH concentrations.
  • If the defect lies in the pituitary or hypothalamus, aldosterone production is not altered because the renin-angiotensin system adequately stimulates the adrenal zona glomerulosa to ensure sufficient aldosterone concentrations and to prevent salt wasting.
• Patients who have recently received long-term pharmacologic doses of glucocorticoids are prone to develop symptoms of adrenal insufficiency when they are stressed because of an illness or trauma.
  • In this setting, adrenal insufficiency is due to chronic suppression of CRH and ACTH by exogenous glucocorticoids. As a consequence, patients are unable to mount an appropriate cortisol response to stress.
  • Patients in this situation are not hyperpigmented because ACTH concentrations are not elevated and they 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 how long the patient was exposed to pharmacologic glucocorticoids.
• In general, autoimmune adrenal insufficiency or adrenal insufficiency due to adrenoleukodystrophy (Online Mendelian Inheritance in Man [OMIM] 300100), chronic infections (eg, HIV infection, TB, fungal infection), or infiltrative lesions usually present with chronic symptoms (eg, fatigue, anorexia, abdominal pain).^{[8 ]} However an acute adrenal crisis may exacerbate the symptoms. (See also Adrenal Crisis and Adrenal Insufficiency and Adrenal Crisis.)

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 in a patient after a traumatic delivery.
• Patients with chronic adrenal insufficiency may have increased skin pigmentation, particularly in the areolae and genitalia, as well as any scars or moles. Recent scars are typically affected most often. Areas unexposed to sun (eg, palmar creases, axillae, areolae) are often hyperpigmented, which may help to distinguish hyperpigmentation from sun tan. The patient may also have pigmentary lines in the gums.
• Signs of weight loss may be evident. If the patient is not frankly hypotensive, he or she may have orthostatic hypotension.
• Some patients lose pubic and axillary hair 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, may present with adrenal calcifications. Adrenal calcifications may be seen on plain radiography or CT scanning 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 pharmacologic doses of glucocorticoids can suppress the CRH-ACTH-adrenal axis. The 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.
  • Recent treatment with megestrol acetate, an orexigenic agent, has also resulted in iatrogenic adrenal suppression. The mechanism is presumably related to the glucocorticoid properties of megestrol acetate.^{[9 ]}
  • Other causes of central adrenal insufficiency include congenital or acquired hypopituitarism and ACTH unresponsiveness. This unresponsiveness may be isolated (as in Familial Glucocorticoid Deficiency; OMIM 202200),^{[10,11 ]}or it may be associated with achalasia and alacrima (as in achalasia-addisonism-alacrima syndrome, or triple A syndrome [AAAS]; OMIM 231550).^{[12,13 ]}
• Acquired primary adrenal insufficiency
  • In developed countries, the most common cause is autoimmune destruction of the adrenal cortex.^{[14 ]}This disorder may occur in isolation or may be part of a polyglandular autoimmune disorder.
  • Patients with type 1 autoimmune polyglandular disease (OMIM 240300) usually present in the first decade of life with mucocutaneous candidiasis or hypoparathyroidism. Type 1 autoimmune polyglandular disease, an autosomal recessive disorder that involves the AIRE gene on chromosome 21, presents with all or some of the following features:
    • Chronic mucocutaneous candidiasis
    • Hypoparathyroidism
    • Adrenal failure
    • Gonadal failure
    • Vitiligo
    • Alopecia
    • Hypothyroidism
    • Type 1 diabetes mellitus
    • Pernicious anemia
    • Steatorrhea
  • Type 2 autoimmune polyglandular disease consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. Individuals with this condition generally present in the second or third decades of life, although some components of the syndrome may be present in the pediatric age group. Type 2 autoimmune polyglandular disease is transmitted as an autosomal disorder with variable penetrance.
  • Relatively uncommon causes of adrenal failure include the following:
    • Adrenal hemorrhage^{[7 ]}
    • Infections (eg, TB, HIV infection)
    • Neoplastic destruction
    • Metabolic disorders (eg, various forms of adrenal leukodystrophy,^{[15,16 ]}Wolman disease [OMIM 278000], Smith-Lemli-Opitz syndrome^{[17 ]})
    • Administration of the anesthetic agent etomidate^{[18 ]}
  • Hemochromatosis may cause either primary or secondary adrenal insufficiency. Among patients with thalassemia who have received multiple transfusions, iron deposition in the pituitary and/or adrenal glands may also cause adrenal insufficiency.
• Congenital primary adrenal insufficiency
  • Congenital disease may occur as a result of adrenal hypoplasia^{[19,20,21 ]}or hyperplasia.
  • Inherited as an X-linked disorder, adrenal hypoplasia congenita (OMIM 300200) is caused by deletion of the DAX1 gene on chromosome X.^{[22 ]}This is often part of a contiguous gene deletion that also involves the genes for glycerol kinase deficiency and dystrophin, resulting in elevations in serum glycerol (often measured using a triglyceride assay) and Duchenne muscular dystrophy. An alternate form, also X linked, is characterized by intrauterine growth retardation and skeletal and genital anomalies (ie, IMAGe syndrome; OMIM 300290). A third form of adrenal hypoplasia congenita is autosomal recessive (OMIM 240200).
  • Congenital adrenal hyperplasia results from a deficiency of one of several enzymes required for adrenal synthesis of cortisol. Symptoms of adrenal insufficiency most often develops with combined deficiencies of cortisol and aldosterone. The most prevalent form of congenital adrenal hyperplasia is caused by a deficiency in steroid 21-hydroxylase (OMIM 201910).
  • Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency caused by a mutation in the steroid acute regulatory protein (ie, STAR protein; OMIM 201710)^{[23 ]}or a mutation in the cholesterol side-chain cleavage gene (at the cytochrome P450 [CYP] 11A locus; OMIM 118485^{[24 ]}). This disease causes a defective synthesis of all adrenocortical hormones. In its complete form, the disease is lethal.
  • Mutations or deletions involving CYP oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17-hydroxylase, 21-hydroxylase, and 17-20 lyase activities. The result is adrenal insufficiency, which is often accompanied by skeletal dysplasia and primary hypogonadism.^{[25,26,27 ]}
• Relative adrenal insufficiency
  • The term relative adrenal insufficiency has been coined to describe patients with critical illness who do not appear to mount the cortisol response expected given the severity of their illness. 
  • Some patients have had adrenal insufficiency secondary to exposure to etomidate, an agent known to interfere with cortisol synthesis.^{[18 ]}Early reports indicated improvements in outcome when such patients were provided with glucocorticoids at stress doses. Subsequent studies have clearly confirmed the fact that a substantial number of patients with critical illness who have not been exposed to etomidate have low serum cortisol concentrations.^{[28 ]}Some studies have found that those with very high concentrations of cortisol have a worse prognosis and a higher complication rate of secondary sepsis or intestinal perforation. 
  • Controlled trials have failed to confirm the benefit of glucocorticoid replacement therapy. 
  • The current tools for the diagnosis of adrenal insufficiency are likely inadequate because they rely on measurement of total cortisol levels rather than free or unbound cortisol. 
  • Subjects with critical illness, particularly premature infants, often have low serum albumin and transcortin concentrations, leading to low total serum cortisol concentration. This issue needs to be revisited when sound methods for measurement of free cortisol become available. In the meantime, the authors and other critical care medicine specialists hold that provision of stress steroids in critically ill patients be reserved for those who have a preexisting or concurrent reason for adrenal insufficiency (ie, history of adrenal insufficiency, previous chronic glucocorticoid exposure, etomidate exposure) or those who have hypotension that is unresponsive to adequate fluid administration and catecholamines.^{[29,30 ]}

Differential Diagnoses

Other Problems to Be Considered

Adrenocorticotropic hormone (ACTH) receptor defect
Adrenoleukodystrophy and adrenomyeloneuropathy
Autoimmune polyglandular endocrinopathy syndromes
Infectious adrenalitis (eg, in association with HIV infection or tuberculosis [TB])
Adrenal hemorrhage
Lipoid adrenal hyperplasia
Wolman disease

Workup

Laboratory Studies

General considerations and tests

Clinical suspicion is important because the presentation of patients with adrenal insufficiency may be insidious and subtle.

When adrenal insufficiency is suspected, laboratory studies of the following measures help to establish the diagnosis:

• Electrolyte levels
• Fasting blood sugar concentration
• Serum adrenocorticotropic hormone (ACTH) concentration
• Plasma renin activity
• Serum cortisol concentration, preferably obtained before 8:00 am
• Serum aldosterone concentration

When hyponatremia or hyperkalemia is present, a simultaneous serum sample and spot urine or 24-hour urine measurement of sodium, potassium, and creatinine concentrations can be used to calculate the fractional excretion of sodium to determine whether inappropriate natriuresis is occurring. A plasma renin activity (PRA)–to–aldosterone ratio of more than 30 is suggestive of inadequate mineralocorticoid production.

Serum cortisol testing and the administration of cosyntropin

Interpret random serum cortisol concentrations in the context in which they were obtained. For example, adrenal insufficiency is unlikely in an otherwise healthy individual whose 8:00 am serum cortisol concentration is more than 10 mcg/dL. By contrast, a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient is suggestive of adrenal insufficiency, although some critically ill patients may have such cortisol concentrations due to lack of protein binding to cortisol (see Relative Adrenal Insufficiency).

Results diagnostic of adrenal insufficiency

A diagnosis of adrenal insufficiency is confirmed if the serum cortisol level is less than 18 mcg/dL in the presence of a markedly elevated serum ACTH concentration and plasma renin activity. Based on normative data of children of various ages, adrenal insufficiency is likely if the serum cortisol concentration is less than 18 mcg/dL 30-60 minutes after administration of 250 mcg of cosyntropin (synthetic ACTH 1-24).^{[31 ]}

These criteria may not apply to premature or low-birth-weight infants, who have low cortisol secretion and, most likely, decreased cortisol binding to carrier proteins.^{[32 ]} Therefore, the diagnosis of adrenal insufficiency in premature infants remains problematic.

If the serum cortisol level is low but the ACTH value is elevated, measurement of antiadrenal antibodies may be informative. Antibodies to one or more steroidogenic enzymes, particularly 21-hydroxylase, are often found in patients with autoimmune adrenal disease.

The best dose of cosyntropin to administer for a cosyntropin stimulation test remains controversial.^{[33,34,35,36 ]}The standard dose is 250 mcg intravenously. Low doses (1 mcg or 0.5 mcg/m²) have been used in the belief that the low-dose test is more sensitive for central adrenal insuffficiency.^{[37 ]}A recent meta-analysis suggests that the low dose cosyntropin stimulation test is superior, but the difference was small.^{[38 ]}This issue remains unresolved in the pediatric age group. Because dilution of cosyntropin to 1 mcg is cumbersome and prone to error, and because all doses above are probably supraphysiologic, the author generally uses the standard dose or empirically adjusts the dose for patient size to 25 mcg for an infant, 50 mcg for a young child, 100 mcg for an older child, and 250 mcg for an adolescent or adult.

When a patient's serum cortisol response to cosyntropin is subnormal but his or her serum ACTH level is not elevated, the possibility of central adrenal insufficiency should be considered. Other indications of pituitary dysfunction, such as prior glucocorticoid exposure (suggesting a suppressed hypothalamic-pituitary-adrenal axis) or evidence of other pituitary dysfunction (suggesting hypopituitarism) are helpful. In central adrenal insufficiency, a 3-day stimulation with ACTH produces a normal cortisol response, indicating intact adrenal glands and implying that the initial low cortisol response to cosyntropin was related to chronic ACTH deficiency.  ACTH gel (ACTHar Gel) is administered at 25 U/m² every 12 hours for 3 days. Plasma cortisol levels should increase to more than 40 mcg/dL in response. This procedure is now seldom performed.

Insulin-tolerance testing and metyrapone stimulation

If the patient has recent-onset (ie, <10 d) central adrenal insufficiency (eg, a patient who recently underwent surgery of the hypothalamus or pituitary regions), the relatively cumbersome and risky insulin-tolerance test or metyrapone stimulation test may be preferable to a cosyntropin challenge because the adrenal glands may not have had sufficient time to atrophy in the absence of ACTH stimulation. The insulin tolerance test is still considered the criterion standard.

An insulin-tolerance test requires an intravenous administration of insulin (usually regular insulin 0.05-0.15 U/kg) to induce a 50% reduction in blood sugar concentration. Cortisol and glucose concentrations are measured every 15 minutes for 60 minutes. The test is considered adequate if the blood sugars level decreases by at least 50%. In response to the hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 18-20 mcg/dL.

The insulin-tolerance test poses some risk of hypoglycemic seizure. Therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overtly symptomatic.

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

Test for antiadrenal antibodies

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

Corticotropin-releasing hormone stimulation test

The standard ovine corticotropin-releasing hormone (CRH) stimulation test (1 mcg/kg over 1 min) may be helpful in the differential diagnosis of adrenal insufficiency. A lack of a 2-fold increase in serum ACTH concentration indicates pituitary dysfunction. A 2-fold or greater rise in ACTH without a concomitant rise in serum cortisol to more than 18-20 mcg/dL implies primary adrenal insufficiency.^{[39 ]}Ovine CRH is difficult to obtain, and this test is mainly performed for research purposes.

Imaging Studies

CT scanning is the imaging study of choice and helps in identifying adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT scanning. Abdominal radiography may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease. Ultrasonography is a poor imaging modality for investigating the adrenal glands. Iodocholesterol scanning is not particularly useful.

Procedures

CT-guided fine-needle aspiration sometimes helps in diagnosing the etiology of infiltrative adrenal disease.

Histologic Findings

Histologic findings depend on the underlying cause. In cases of autoimmune adrenal failure, lymphocytic infiltration destroys the adrenal gland. Granulomatous changes in the adrenal glands indicate TB-related adrenal insufficiency. Neoplastic infiltrations are caused by metastatic tumors. Hemorrhagic adrenal insufficiency results in hemorrhagic destruction of the adrenal glands. Fungal disease produces the typical picture of fungal infiltrates. Atrophy of the adrenals characterizes ACTH deficiency or resistance. Hyperplasia of the adrenals is characteristic of defects in steroidogenesis.

Treatment

Medical Care

Patients with adrenal insufficiency are generally hypovolemic and may be hypoglycemic, hyponatremic, or hyperkalemic. Initial therapy consists of intravenously administered saline and dextrose.

If patients are hypotensive, a 20-mL/kg bolus of isotonic sodium chloride solution given over the first hour may be necessary to restore their blood pressure. The bolus may be repeated if the patient's blood pressure remains low.

After results for the patient's electrolyte, blood sugar, cortisol, and adrenocorticotropic hormone (ACTH) concentrations are obtained, administer glucocorticoids if adrenal insufficiency is suspected.

If a cosyntropin stimulation test is chosen, a single dose of dexamethasone may be administered without interfering with the cortisol response to cosyntropin.

Surgical Care

No surgical management is needed in most cases.

If a patient with adrenal insufficiency requires surgery, treat him or her with stress doses of glucocorticoids (eg, hydrocortisone 50-75 mg/m² given intramuscularly or intravenously when the patient is being transported from the floor to the operating room or in advance of the planned surgery).

During surgery, administer additional doses by giving either a hydrocortisone infusion at a dosage of 2-4 mg/m²/h or additional intravenous boluses of 10-25 mg/m² every 6 hours throughout the procedure. These dosage recommendations are empiric, not evidence based.

After surgery, continue the administration of hydrocortisone in the immediate postoperative period.

On the second and third postoperative days, the dosage 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 dosage 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 oral fludrocortisone in the postoperative period, stress doses of hydrocortisone may be continued for a prolonged period to provide adequate mineralocorticoid activity.

Consultations

Consult an endocrinologist if adrenal insufficiency is suspected.

Diet

Patients should eat an unrestricted diet. Patients with primary adrenal insufficiency should have ample access to salt because of the salt wasting that occurs if their condition is untreated. Infants with primary adrenal insufficiency often need 2-5 g of sodium chloride per day. The patient's caloric intake may need to be monitored. Restrict the patient's caloric intake if excess weight gain occurs and reevaluate the glucocorticoid dose because excess glucocorticoid administration stimulates appetite.

Activity

No restrictions are necessary after adequate replacement therapy is started. If patients exercise in warm climates, provide them with sufficient sodium chloride to prevent hyponatremia. Stress doses of glucocorticoids are generally not needed for exercise.

Medication

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 pharmacologic doses of glucocorticoids, which 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 or 20 mL/kg) over the first hour. Follow this with the typical continuous infusion of 3200 mL/m²/d or 200 mL per 100 calories of estimated energy expenditure at rest to restore intravascular volume.

Dextrose must be provided. If the patient is hypoglycemic, 2 mL/kg of 25% dextrose in water (D25W) or 4 mL/kg 10% dextrose in water (D10W) should correct hypoglycemia. Provide 5% dextrose in water (D5W) to prevent initial or further hypoglycemia.

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

After intravenous fluids are provided, administer stress doses of glucocorticoid. The recommended stress dosage of hydrocortisone is an initial dose of 50-75 mg/m² given intravenously, followed by 50-75 mg/m²/d divided in 4 intravenous doses. Hydrocortisone may be given intramuscularly if intravenous access is unavailable. However, intramuscular administration works slowly. 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 performing a diagnostic cosyntropin stimulation test. Methylprednisolone and dexamethasone have negligible mineralocorticoid effects. 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 a mineralocorticoid is currently available in the United States. However, if the patient has good GI function, fludrocortisone 0.1-0.2 mg may be orally 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 adrenal insufficiency and the need to allow the child to grow at a normal rate since excess replacement with glucocorticoid diminishes growth velocity. Individualize the dosage for each patient. The range for hydrocortisone is 7-20 mg/m²/d given orally in 2 or 3 divided doses.

Hydrocortisone is available in 5-mg, 10-mg, and 20-mg tablets. Hydrocortisone is recommended for long-term therapy because of its relatively low potency, which eases the titration of appropriate doses.

In a large patient, prednisone or dexamethasone may be substituted. Estimated equivalencies are as follows; however, individual sensitivity to these drugs widely varies:^{[40 ]}

• 1 mg of prednisone = 4-6 mg of hydrocortisone
• 1 mg of dexamethasone = 50-100 mg of 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 the dose of glucocorticoid for each patient on the basis of clinical criteria (eg, absence of symptoms of glucocorticoid deficiency, excessive weight gain and normal growth). In the author's experience, plasma adrenocorticotropic hormone (ACTH) concentrations provide little guidance for adjusting doses of glucocorticoids. Growth pattern and symptoms of salt craving, blood pressure, plasma renin activity, and electrolytes help in adjusting doses of fludrocortisone.

Supplementation of patients with primary adrenal insufficiency with dehydroepiandrosterone has not proven to be beneficial.^{[41,42 ]}

Stress and illness

An important physiologic response to stress is an increase in ACTH-mediated cortisol production. Patients with adrenal insufficiency are unable to mount this response, regardless of the reason, and they must be given stress doses of glucocorticoid.

When a febrile illness occurs or when a patient requires a surgical or stressful procedure, triple the dosage. If a patient is vomiting or listless, administer parenteral glucocorticoid (hydrocortisone 50-75 mg/m² given intramuscularly or intravenously or equivalent methylprednisolone 10-15 mg/m² or dexamethasone 1-1.5 mg/m²). Repeat the dose every 6-8 hours until patient recovers because hydrocortisone succinate has a short duration of action.

Injectable glucocorticoid must be provided to all patients with adrenal insufficiency. The patient and caretaker must be instructed in its administration, the indications for its use and the life saving importance of its administration.

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

Glucocorticoid or mineralocorticoid replacement is not contraindicated when needed. This therapy is involved in few drug-drug interactions. Preferred glucocorticoids during pregnancy are hydrocortisone or prednisone because the placenta inactivates them and prevents thereby prevents exposing the fetus to excess glucocorticoids. In contrast, dexamethasone and betamethasone readily crosses the placenta and can suppress fetal adrenal function.

Because cortisol from the adrenal cortex stimulates phenylethanolamine N -methyltransferase, the last step in epinephrine synthesis, in the adrenal medulla, patients with congenital cortisol deficiency have deficient epinephrine responses to stress, a condition not amenable to replacement therapy.^{[43,44 ]}

Mineralocorticoids

Mineralocorticoids are used as replacement therapy in aldosterone deficiency and as prophylaxis against hyponatremia and hyperkalemia in patients with primary adrenal insufficiency.

Fludrocortisone (Florinef)

Drug of choice (DOC) for mineralocorticoid replacement therapy if zona glomerulosa of adrenal cortex does not produce aldosterone. Allows patient to achieve normal sodium homeostasis. Available only PO. If patient cannot tolerate PO, parenteral hydrocortisone can provide mineralocorticoid effect. Infant may require sodium chloride supplements because their diets often provide insufficient sodium.

Dosing

Adult

0.1-0.2 mg/d PO qd or divided bid

Pediatric

0.05-0.2 mg/d PO

Interactions

Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause sodium retention, hypokalemia, and hypertension; use cautiously in patients with hypertension and in patients taking potassium-depleting diuretics and digoxin; gradually taper dose when discontinuing

Glucocorticoids

Glucocorticoids give patients with adrenal insufficiency the equivalent of the body's missing cortisol produced by the adrenal cortex under normal conditions and under stress. Dexamethasone and betamethasone cross the placenta to an appreciable degree; therefore, they should not be used in pregnant women unless they are specifically indicated (ie, to aid maturation of the fetal lung or to suppress fetal adrenal function).

Hydrocortisone (Hydrocortone, A-Hydrocort)

DOC because of mineralocorticoid activity and glucocorticoid effects. Equivalent to adrenal product (ie, cortisol). Has short half-life; therefore, does not inhibit growth to same degree as more potent, longer-acting synthetic glucocorticoids (eg, prednisone, methylprednisolone, dexamethasone). Because of short action, must be administered PO bid/tid; usually given q6h when administered IV.
In healthy person, mean cortisol secretion is about 7-10 mg/m²/d. Aim of replacement therapy is to supply only as much as needed. Target is best judged subjectively on basis of patient's own sense of well-being.
Dose requirements are greater PO than parenterally because some hydrocortisone is inactivated as it passes through liver. Equivalent low doses can be derived for prednisone, methylprednisolone, and dexamethasone (which have about 4, 5, and 40-50 times the potency of hydrocortisone, respectively).

Dosing

Adult

10-20 mg/m²/d PO q6h

Pediatric

Dosing guidelines somewhat lower than those in adults, except in patients with congenital adrenal hyperplasia
Congenital adrenal hyperplasia: Typical mean dosage is 15 mg/m²/d; ACTH often refractory to suppression with low doses of glucocorticoid; dosages >20 mg/m²/d may lead to growth suppression; very low doses allow for unchecked secretion of adrenal androgens and adverse growth consequences

Interactions

Live-virus immunization may be undertaken in patients receiving corticosteroids as replacement therapy for Addison disease; phenytoin, phenobarbital, ephedrine, and rifampin may increase hepatic clearance of steroids (increased doses required); frequently check prothrombin time (PT) in patients receiving glucocorticoids and coumarin anticoagulants because steroids may inhibit (or, in rare cases, enhance) response to these anticoagulants; when administered with potassium-depleting diuretics, closely observe patients for possible hypokalemia

Contraindications

Documented hypersensitivity; pharmacologic doses generally contraindicated in viral, fungal, or TB infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Dexamethasone (Decadron)

Provides glucocorticoid activity. At pharmacologic doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reducing capillary permeability. May be used for allergic and inflammatory conditions.

Dosing

Adult

1/40 the dose of hydrocortisone; adjust dosage to clinical response

Pediatric

Older children: 1/50-1/75 the dose of hydrocortisone; physiologic replacement dosage is 0.6-0.75 mg/m²/d PO divided q6-12h; titrate up or down on basis of clinical response

Interactions

Effects decrease with coadministration of barbiturates, phenytoin and rifampin; decreases effect of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of several 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

Methylprednisolone (Medrol, Solu-Medrol)

Provides glucocorticoid activity. At pharmacologic doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability. Available in liquid form, unlike hydrocortisone.

Dosing

Adult

Physiologic replacement: 2-3 mg/m²/d initially; titrate up or down on basis of clinical response

Pediatric

Not established but may be used if hydrocortisone use problematic.
Physiologic replacement: 2-3 mg/m²/d initially; titrate up or down depending on clinical response

Interactions

Coadministration with digoxin may increase digitalis toxicity due to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia if concurrently taking diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or TB infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Possible complications of glucocorticoids include hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections

Prednisone (Liquid Pred, Prednisone Intensol Concentrate, Deltasone)

Provides glucocorticoid activity. At pharmacologic doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability. Available in liquid form.

Dosing

Adult

Physiologic replacement: 2-4 mg/m²/d initially; titrate up or down depending on clinical response

Pediatric

Not established but may be used if hydrocortisone problematic
Physiologic replacement: 2-4 mg/m²/d initially; titrate up or down depending on clinical response

Interactions

Coadministration with digoxin may increase digitalis toxicity due to hypokalemia; phenobarbital, phenytoin and rifampin may decrease levels (adjust dosage); monitor patients for hypokalemia if concurrently taking diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or TB infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Possible complications of glucocorticoids include hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections

Follow-up

Further Outpatient Care

• Monitor the adequacy of dosing in patients with adrenal insufficiency who receive long-term glucocorticoid therapy.
  • Too little glucocorticoid causes symptoms of adrenal insufficiency, such as anorexia, nausea, vomiting, abdominal pain, asthenia, poor weight gain, and weight loss.
  • Too much glucocorticoid causes excessive weight gain, cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure.
  • In children, growth failure is a sensitive indicator of exposure to excessive glucocorticoids.
• If adrenal insufficiency has an autoimmune etiology, monitor patients for the development of associated autoimmune phenomena, such as hypoparathyroidism, hypogonadism, vitiligo, pernicious anemia, thyroid dysfunction, and diabetes mellitus.

Inpatient & Outpatient Medications

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

Deterrence/Prevention

• Iatrogenic adrenal insufficiency due to glucocorticoid therapy can be prevented by giving the patient dosages below his or her physiologic requirements.
• Treatment with alternate-day oral prednisone, or with topical or inhaled glucocorticoids, can reduce the risk of iatrogenic adrenal insufficiency.

Complications

• Hypotension, shock, hypoglycemia, and death are the primary complications of adrenal insufficiency.
• Complications of excessive glucocorticoids include the following:
  • Growth failure
  • Obesity
  • Striae
  • Osteoporosis
  • Muscle weakness
  • Hypertension
  • Hyperglycemia
  • Cataracts
• Daily oral glucocorticoid therapy may provide iatrogenic suppression of the hypothalamic-pituitary-adrenal axis within 2 weeks. Effects can last for weeks to months, depending on the duration of exposure to pharmacologic doses of glucocorticoids.
• Complications of excessive administration of mineralocorticoids include hypertension and hypokalemia.

Prognosis

• The prognosis for an untreated patient is poor. Death is a common outcome unless replacement steroid therapy is begun.
• 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. Include education about how to administer an injectable glucocorticoid when the patient is vomiting or unable to take oral stress doses. Periodically reinforce this information because caretakers are often reluctant to inject medications.
• Advise patients and their caretakers to immediately seek medical help if the patient becomes ill.

Miscellaneous

Medicolegal 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 tuberculosis (TB) and HIV infection, can impair adrenal function.
  • The possibility of central adrenal insufficiency must be investigated, identified, and treated in all patients who have undergone pituitary surgery, irradiation, or prolonged treatment with glucocorticoids.
• Advise patients to wear or carry a medical alert tag or card at all times to help them receive appropriate emergency care if they are found unconscious.

Special Concerns

• Dosage requirements may increase during pregnancy.

Multimedia

Media file 1: Regulation of the adrenal cortex.

Media file 2: Left photograph shows hyperpigmentation on the dorsum of the hand before the treatment of primary adrenal insufficiency. Right photograph shows normal pigmentation after treatment.

Media file 3: Left photograph shows a patient with Addison disease who has prominent pigmentation in areas not exposed to the sun, such as the palmar creases. Right photograph shows normal pigmentation after treatment.

Media file 4: Left photograph shows vitiligo in a patient with autoimmune adrenalitis. Right photograph shows an area of hyperpigmentation surrounding the vitiligo.

Media file 5: Left photomicrograph shows autoimmune adrenalitis. Right photomicrograph shows tuberculous adrenalitis. Note the caseous granuloma.

Media file 6: CT scan shows enlarged adrenal glands in a patient with early active autoimmune adrenalitis. Patients with chronic disease present with the opposite picture of hypotrophic adrenals.

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Keywords

Addison disease, Addison's disease, adrenal crisis, adrenal insufficiency and adrenal crisis, glucocorticoid deficiency, familial glucocorticoid deficiency, hypoadrenalism, adrenal hypoplasia, hypocortisolism, adrenals, adrenal glands, adrenal failure, hormonal insufficiency, glucocorticoids, mineralocorticoids, androgens, primary adrenal insufficiency, secondary adrenal insufficiency, central adrenal insufficiency, dysfunctional adrenal gland

CRH, corticotropin-releasing hormone, adrenocorticotropic hormone, corticotropic hormone, ACTH, hypofunction of the adrenal cortex, congenital adrenal insufficiency, acquired adrenal insufficiency, tuberculosis, TB, autoimmune adrenal insufficiency, adrenal hypoplasia congenita, AHC, congenital adrenal hypoplasia, congenital adrenal hyperplasia, CAH

Contributor Information and Disclosures

Author

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
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital
Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

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