Pediatric Adrenal Insufficiency (Addison Disease)

The adrenal cortex is divided into 3 major anatomic zones. The zona glomerulosa produces aldosterone, and the zonae fasciculata and reticularis together produce cortisol and adrenal androgens. A fetal zone, unique to primates, produces dehydroepiandrosterone (DHEA), 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 adrenocorticotropic hormone (ACTH), which, in turn, is regulated by corticotropin-releasing hormone (CRH) from the hypothalamus. Serum cortisol inhibits the secretion of both CRH and ACTH to prevent excessive secretion of cortisol from the adrenal glands.

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 insulinlike growth factor (IGF)-1 and IGF-2.[5]

Iatrogenic central adrenal insufficiency as well as acquired and congenital primary adrenal insufficiency (Addison disease) are briefly discussed in this section.

Iatrogenic central adrenal insufficiency

Most cases of adrenal insufficiency (Addison disease) are iatrogenic, caused by long-term administration of glucocorticoids. A mere 2 weeks' exposure to pharmacologic doses of glucocorticoids can suppress the corticotropin-releasing hormone (CRH)–adrenocorticotropic hormone (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. Similar suppression can be seen in individuals on chronic high doses of inhalable glucocorticoids.[6]

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.[7]

A study by Gibb et al found that in four out of 48 patients on long-term opioid analgesia for chronic pain (8.3%), the basal morning plasma cortisol concentration was below 100 nmol/L (3.6 ng/dL), indicating that such treatment can suppress the hypothalamic-pituitary-adrenal axis in a clinically significant proportion of patients.[8]

Other causes of central adrenal insufficiency include congenital or acquired hypopituitarism and ACTH unresponsiveness.

A retrospective cohort study by Josephsen et al indicated that in extremely premature infants, combining budesonide with dexamethasone significantly increases the risk of presumed adrenal insufficiency (Addison disease). In infants with less than 28 weeks’ gestation, the incidence of presumed adrenal insufficiency was 20.8% in those who had received dexamethasone for the prevention of bronchopulmonary dysplasia, compared with 2.9% in those who did not. However, as used in intubated neonates who received a surfactant, an independent association with presumed adrenal insufficiency did not exist for dexamethasone after adjustment was made for gestational age, birthweight, and race. Nonetheless, in infants who had previously received budesonide/surfactant therapy, dexamethasone was independently associated with such insufficiency, the adjusted odds ratio being 5.38.[67]

Hypopituitarism with adrenal insufficiency can be a secondary manifestation of a sellar or suprasellar mass, an inflammatory or infiltrative process, surgery, or cranial irradiation. Congenital unresponsiveness to ACTH that can occur if the ACTH receptor is absent or altered can clinically mimic this condition. However serum ACTH concentrations can help to distinguish between the two.[9, 10]  ACTH unresponsiveness may be isolated (as in Familial Glucocorticoid Deficiency) (Online Mendelian Inheritance in Man database [OMIM] 202200),[9, 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 of adrenal insufficiency (Addison disease) is autoimmune destruction of the adrenal cortex.[14] This disorder may occur in isolation or may be part of a polyglandular autoimmune disorder (PGAD).

Patients with type 1 PGAD (OMIM 240300) usually present in the first decade of life with mucocutaneous candidiasis or hypoparathyroidism. This is an autosomal recessive disorder that involves the AIRE gene on chromosome 21 and 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 PGAD (Schmidt syndrome; OMIM 269200) 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 PGAD is transmitted as an autosomal disorder with variable penetrance. Addison disease should be considered in patients with type 1 diabetes and unexplained fatigue, hypotension, hypoglycemia, hyponatremia and hyperkalemia.

Other acquired causes of adrenal failure include the following:

• Adrenal hemorrhage[15]

• Infections (eg, tuberculosis [TB], human immunodeficiency virus [HIV] infection)

• Neoplastic destruction

• Metabolic disorders (eg, various forms of adrenal leukodystrophy [OMIM 300100],[16, 17] Wolman disease [OMIM 278000], Smith-Lemli-Opitz syndrome [OMIM 270400][18, 19] ) 

• Ketoconazole and related antifungals, as well as the anesthetic etomidate, can inhibit steroid synthesis, causing adrenal insufficiency[20, 10, 21]

• Mitotane, an agent used to treat adrenal carcinoma, results in adrenal insufficiency, due to direct toxic effects on the adrenal cortex[22]

Hemochromatosis may cause either primary (hereditary form OMIM 235200) or secondary adrenal insufficiency. Among patients with thalassemia or other forms of anemia who have received multiple transfusions, iron deposition in the pituitary and/or adrenal glands may also cause adrenal insufficiency.

Congenital primary adrenal insufficiency

Congenital Addison disease may occur as a result of adrenal hypoplasia[23, 24, 25] or hyperplasia.

Inherited as an X-linked disorder, adrenal hypoplasia congenita (OMIM 300200)—caused by deletion or mutation of the gene DAX1/NR0B1 (which encodes for the nuclear receptor DAX1) on chromosome Xp21.2—is additionally associated with hypogonadotrophic hypogonadism and primary defects in sperm production.[26] There is often 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. Deletion or mutation of the gene NR5A1, which encodes for the nuclear receptor steroidogenic factor 1, also results in congenital adrenal hypoplasia and may cause XY gonadal dysgenesis.[10] An alternate form of adrenal hypoplasia congenita, non-X linked, is characterized by intrauterine growth retardation and skeletal and genital anomalies (ie, IMAGe syndrome) (OMIM 614732). Still another type of adrenal hypoplasia congenita, an autosomal recessive form of uncertain etiology, has also been described (OMIM 240200).

Congenital adrenal hyperplasia results from a deficiency of one of several enzymes required for adrenal synthesis of cortisol. Symptoms of adrenal insufficiency (Addison disease) most often develop 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 (Addison disease) caused by a mutation in the steroid acute regulatory protein (ie, STAR protein) (OMIM 201710)[27] or a mutation in the cholesterol side-chain cleavage gene (at the cytochrome P450 [CYP] 11A locus) (OMIM 118485).[28] 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 (Addison disease), which is often accompanied by skeletal dysplasia, genital anomalies, and primary hypogonadism (OMIM 613571).[29, 30, 31]

Relative adrenal insufficiency

The term relative adrenal insufficiency (Addison disease) 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 developed adrenal insufficiency (Addison disease) after exposure to etomidate, an agent known to interfere with cortisol synthesis.[32] 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.[33] 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 in adults have failed to confirm the benefit of glucocorticoid replacement therapy.

Among critically ill children, a low incremental cortisol response to ACTH does not predict mortality.[34] There is still much controversy regarding how to best diagnose adrenal insufficiency in hospitalized children and adults, as well as whether and when to treat. Thus, the decision to treat a critically ill patient with glucocorticoids must be made on a case-by-case basis until further definitive evidence is available.[35]

Primary adrenal insufficiency (Addison disease) is uncommon in the United States. By comparison, iatrogenic central adrenal insufficiency is a more frequent cause of morbidity and mortality, although its exact incidence is unknown. Retrospective case review in one US urban center suggests that the prevalence of adrenal insufficiency in childhood is higher than previously suspected, approximately equivalent to that of congenital adrenal hyperplasia.[36] Adrenal insufficiency (Addison disease) secondary to congenital adrenal hyperplasia occurs in approximately 1 per 16,000 infants.

Willis and Vince collected data from Coventry County, Great Britain, where the prevalence of adrenal insufficiency (Addison disease) was similarly reported as 110 cases per million persons of all ages.[37] More than 90% of cases have been attributed to autoimmune disease. An Italian study provided statistics comparable to those observed in Great Britain:[38]  an estimated 117 cases per million persons. A study by Olafsson and Sigurjonsdottir estimated the prevalence of primary adrenal insufficiency in Iceland to be 22.1 per 100,000 population.[39]

Worldwide, the most common cause of adrenal insufficiency (Addison disease) is tuberculosis (TB), with a calculated incidence of this condition caused by TB at approximately 5-6 cases per million persons per year.

Although there does not appear to be a racial predilection, sex and age-related differences have been observed. Autoimmune adrenal insufficiency (Addison disease) is more common in female individuals than in male individuals and in adults than children, whereas 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/NR0B1 is also X-linked and, therefore, is confined to males. Secondary forms of adrenal insufficiency (Addison disease) such as those due to a deficiency of adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH), or a defect in the ACTH receptor, are equally common among male and female individuals.

Congenital causes, such as congenital adrenal hyperplasia, congenital adrenal hypoplasia, and defects in the ACTH receptor, most commonly become apparent in childhood.

With proper treatment and compliance, patients with adrenal insufficiency (Addison disease) can live a normal life span without limitations. However, the prognosis for an untreated patient with adrenal insufficiency (Addison disease) is poor. 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.

Death is a common outcome, usually from hypotension or cardiac arrhythmia secondary to hyperkalemia, unless replacement steroid therapy is begun.

A nationwide Swedish study, by Chantzichristos et al, indicated that the mortality risk is higher in patients with both diabetes mellitus and adrenal insufficiency (Addison disease) than in those with diabetes alone. Among the diabetes/adrenal insufficiency patients, the mortality rate was 28%, compared with 10% in patients with just diabetes, with the estimated relative risk increase in overall mortality being 3.89 for the diabetes/adrenal insufficiency group compared with the diabetes patients. Although mortality in both groups most commonly resulted from cardiovascular problems, the death rate from diabetes complications, infectious diseases, and unknown causes was higher in the diabetes/adrenal insufficiency group than in the controls with diabetes.[40]

Complications

Hypotension, shock, hypoglycemia, and death are the primary complications of adrenal insufficiency.[41] In addition, daily oral glucocorticoid therapy may provide iatrogenic suppression of the hypothalamic-pituitary-adrenal (HPA) 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 glucocorticoids include the following:

• Growth failure

• Obesity

• Striae

• Osteoporosis

• Muscle weakness

• Hypertension

• Hyperglycemia

• Cataracts

Complications of excessive administration of mineralocorticoids include hypertension and hypokalemia.

Educate patients with adrenal insufficiency (Addison disease) and their caretakers about the consequences and potential for death if adequate replacement therapy is not provided.

Advise patients and their caretakers to immediately seek medical help if the patient becomes ill. Patients should wear or carry a medical alert tag or card at all times to help them receive appropriate emergency care if they are found unconscious.

Supplemental and injectable glucocorticoid

Patients and their caretakers should know 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.

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.

Patients with adrenal insufficiency (Addison disease) may have hypoglycemia, and most have hypotension. Orthostatic changes in blood pressure and pulse are cardinal signs of adrenal insufficiency. Symptoms of hypoglycemia are common in small children. Altered mental status, even without hypoglycemia, is common in affected patients with acute adrenal insufficiency.

In infants, acute adrenal insufficiency may occur in the context of serious illness (eg, sepsis), prolonged and difficult labor, or traumatic delivery. Tuberculosis (TB), meningococcemia, or any severe septicemia may also result in adrenal insufficiency. However, adrenal insufficiency may occur without concomitant illness when it is due to congenital adrenal hyperplasia or congenital adrenal hypoplasia.

Chronic adrenal insufficiency

Patients with chronic adrenal insufficiency (Addison disease) usually have chronic fatigue, anorexia, asthenia, nausea, vomiting, loss of appetite, weight loss, recurring abdominal pain, and weakness and a lack of energy. Increased skin pigmentation and salt craving are common among individuals with chronic primary adrenal insufficiency. Salt craving is a symptom typical of patients with dysfunction of the zona glomerulosa; this craving may be the first sign of autoimmune adrenal destruction.

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 (Addison disease) 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.

Autoimmune adrenal insufficiency, adrenal insufficiency from adrenoleukodystrophy

In general, autoimmune adrenal insufficiency or adrenal insufficiency due to adrenoleukodystrophy (Online Mendelian Inheritance in Man [OMIM 300100]), chronic infections (eg, human immunodeficiency virus [HIV] infection, TB, fungal infection), or infiltrative lesions usually present with chronic symptoms (eg, fatigue, anorexia, abdominal pain). However, an acute adrenal crisis may exacerbate the symptoms.

See also Adrenal Crisis and Adrenal Insufficiency and Adrenal Crisis.

Patients with acute adrenal insufficiency (Addison disease) generally present with acute dehydration, hypotension (especially orthostatic hypotension and tachycardia), symptomatic hypoglycemia, or altered mental status. These signs may occur in conjunction with acute sepsis or disseminated intravascular coagulation or in a patient after a traumatic delivery.

As previously discussed, hyperpigmentation may be seen in primary adrenal insufficiency due to adrenocorticotropic hormone (ACTH) overproduction by the pituitary. The ACTH molecule contains the sequence for alpha-melanocyte-stimulating hormone (MSH), which stimulates melanocytes.

Note increased skin pigmentation, particularly in the areolae and genitalia, as well as any scars or moles. Recent scars are typically affected more than old scars. In addition, 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. See the images below.

Left photograph shows hyperpigmentation on the dorsum of a patient's hand before the treatment of primary adrenal insufficiency. Right photograph shows normal pigmentation after treatment.

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.

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

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.

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

Provision of stress steroids in critically ill patients should 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 for those who have hypotension that is unresponsive to adequate fluid administration and catecholamines.[44, 45]

Wolman disease (OMIM 278000), an autosomal recessive disorder caused by a deficiency of lysosomal acid lipase, may present with adrenal calcifications that may be seen on plain radiography or computed tomography (CT) scanning of the adrenal glands.

Hyponatremia with or without hyperkalemia is common in patients with primary adrenal insufficiency (Addison disease), 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.[46]

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 (see Medscape Reference Laboratory Medicine articles Serum Sodium, Urine Sodium, Potassium, and Creatinine). A plasma renin activity (PRA)–to–aldosterone ratio of more than 30 is suggestive of inadequate mineralocorticoid production.

Interpret random serum cortisol concentrations in the context in which they were obtained. For example, adrenal insufficiency (Addison disease) 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 under Etiology).

Criteria for diagnosis

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 adrenocorticotropic hormone (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 intravenous (IV) administration of 250 mcg of cosyntropin (synthetic ACTH 1-24) in children over age 2 years. The cosyntropin test dose may be decreased to 15 mcg/kg for infants and 125 mcg for children under age 2 years.[2, 3, 47]

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.[4] Therefore, the diagnosis of adrenal insufficiency in premature infants remains problematic.

If the serum cortisol level is low and 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.

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 previous glucocorticoid exposure (suggesting a suppressed hypothalamic-pituitary-adrenal axis) or evidence of other pituitary dysfunction (suggesting hypopituitarism) are helpful. Because the adrenal gland may not yet be hypoplastic, a normal cortisol response to cosyntropin may be seen in patients who recently began suffering from ACTH or CRH deficiency. A smaller dose of cosyntropin (1 µg) may be more sensitive in this setting.[48, 49]

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 since plasma ACTH concentrations can be measured.

Salivary cortisol testing

A study by Chao et al indicated that salivary cortisol may be used to confirm or replace serum cortisol testing in the diagnosis of adrenal insufficiency in children. The investigators measured salivary cortisol via liquid chromatography–tandem mass spectrometry, employing a cutoff value of 500 ng/dL for salivary cortisol and 18 μg/dL for serum cortisol. They found that during high-dose adrenocorticotropic hormone (ACTH) stimulation testing, salivary and serum cortisol each had 100% specificity and sensitivity in the detection of adrenal insufficiency in pediatric patients. Recognize that there may be limitations to the approach in a pediatric setting, as compliance with the collection procedure in patients below age 8 years may be suboptimal.[50]

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 adrenocorticotropic hormone (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.[51] Ovine CRH is difficult to obtain, and this test is mainly performed for research purposes.

A study by Iwanaga et al indicated that CRH stimulation tests can be effectively used in the diagnosis of relative adrenal insufficiency in preterm infants. Administering CRH stimulation tests to preterm infants with relative adrenal insufficiency and to those without it, the investigators found that neither base nor peak serum cortisol levels differed between the two groups. However, in the group with relative adrenal insufficiency, significant reductions were seen in delta cortisol levels and in the responsive ratio (peak-to-base ratio).[52]

The best dose of cosyntropin to administer for a cosyntropin stimulation test remains controversial,[53, 54, 55, 56] and this issue remains unresolved in the pediatric age group.

The standard dose is 250 mcg intravenously; some pediatric endocrinologists reduce the cosyntropin dose to 50-125 mcg for infants. Very low cosyntropin 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 insufficiency.[48] Meta-analysis suggested that the low-dose cosyntropin stimulation test may be superior, but the difference was small.[53] There actually may be a higher rate of false-positive test results with the low-dose ACTH stimulation test.[57]

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

Insulin-tolerance test

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.

Metyrapone stimulation

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.

When primary adrenal insufficiency (Addison disease) is confirmed, antiadrenal antibodies, specifically anti-21-hydroxylase 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.

Computed tomography (CT) scanning is the imaging study of choice in the evaluation of adrenal insufficiency (Addison disease) and helps to identify adrenal hemorrhage, calcifications (see the following image), or infiltrative disease. Magnetic resonance imaging (MRI) is not as useful as CT scanning, and iodocholesterol scanning is also not particularly useful for adrenal insufficiency.

Computed tomography 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.

Abdominal radiography may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, tuberculosis (TB), or Wolman disease. Ultrasonography is a poor imaging modality for investigating the adrenal glands.

Histologic findings in adrenal insufficiency (Addison disease) depend on the underlying cause. CT scan–guided fine-needle aspiration sometimes helps in diagnosing the etiology of infiltrative adrenal disease.

In cases of autoimmune adrenal failure, lymphocytic infiltration destroys the adrenal gland. Granulomatous changes in the adrenal glands indicate tuberculosis (TB)-related adrenal insufficiency (see the image below). 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 adrenocorticotropic hormone (ACTH) deficiency or resistance. Hyperplasia of the adrenals is characteristic of defects in steroidogenesis.

Left photomicrograph shows autoimmune adrenalitis. Right photomicrograph shows tuberculous adrenalitis. Note the caseous granuloma.

Glucocorticoid replacement is required in all forms of adrenal insufficiency (Addison disease). 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. Consult an endocrinologist if adrenal insufficiency is suspected.

Patients with suspected adrenal crisis should undergo immediate treatment with a parenteral injection of 100 mg (50 mg/m2 for young children) hydrocortisone, after which, appropriate fluid resuscitation should be administered, as well as 200 mg (50-100 mg/m2 for children) of hydrocortisone/24 hours (by way of continuous IV therapy or 6-hourly injection). If hydrocortisone is unavailable, prednisolone may be used. Dexamethasone is least-preferred, as its onset of action is slow.[47]

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 measurement of the cortisol response to cosyntropin.

No surgical management is needed in most cases.

Supplementation of patients with primary adrenal insufficiency with dehydroepiandrosterone has not proven to be beneficial.[58, 59]

Do not forget that chronic infections, such as tuberculosis (TB) and human immunodeficiency virus (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.

Patients with adrenal insufficiency (Addison disease) are generally hypovolemic and may be hypoglycemic, hyponatremic, or hyperkalemic. Initial therapy consists of intravenously administered saline and dextrose. Potassium is generally not needed in acute situations, especially in patients with primary adrenal insufficiency, who are often hyperkalemic.

Fluid resuscitation

In a hypotensive patient, rapidly administer isotonic sodium chloride solution (eg, 450 mL/m2 or 20 mL/kg bolus) over the first hour. If the patient remains hypotensive, a second 20-mL/kg bolus of isotonic sodium chloride solution may be given. 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.

Correction of hypoglycemia

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.

Glucocorticoid administration

After intravenous fluids are provided, administer stress doses of glucocorticoid. The recommended stress dosage of hydrocortisone is an initial dose of 50-100 mg/m2 given intravenously, followed by 50-100 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 (Addison disease), 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, due to the mineralocorticoid effects of hydrocortisone (lacking in prednisone or dexamethasone).

A study by Quinkler et al found that patients with adrenal insufficiency (Addison disease) who received prednisolone have significantly higher mean low-density lipoprotein cholesterol levels than do those being treated with hydrocortisone (3.9 vs 3.2 mmol/L, respectively). In addition, research suggests that prednisolone is associated with decreased bone mineral density in adrenal insufficiency.[60, 61]

No parenteral form of a mineralocorticoid is currently available in the United States. However, if the patient has good gastrointestinal function, fludrocortisone 0.1-0.2 mg may be orally administered.

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.

If a patient with adrenal insufficiency (Addison disease) requires surgery, treat him or her with stress doses of glucocorticoids (eg, hydrocortisone 50-100 mg/m2 given intramuscularly or intravenously when the patient is being transported to the operating room or in advance of the planned surgery). Fludrocortisone may be withheld on the day of surgery and while the patient is receiving stress doses of hydrocortisone.

Intraoperative period

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. Note that these dosage recommendations are empiric, not evidence based.

Postoperative period

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.

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.

An important physiologic response to stress is an increase in adrenocorticotropic hormone (ACTH)-mediated cortisol production. Patients with adrenal insufficiency (AI) (Addison disease) 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 glucocorticoid dosage. If a patient is vomiting or listless, administer parenteral glucocorticoid (hydrocortisone 50-100 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 lifesaving 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.

Pregnant women

Preferred glucocorticoids during pregnancy are hydrocortisone or prednisone, because the placenta inactivates them and thereby prevents exposing the fetus to excess glucocorticoids. Therefore, dosage requirements may increase during pregnancy.

In contrast, dexamethasone and betamethasone readily cross 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 cortisol deficiency have deficient epinephrine responses to stress, a condition not amenable to replacement therapy.[62, 63]

In a child with adrenal insufficiency (Addison disease), 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, because excess replacement with glucocorticoid diminishes growth velocity.

Hydrocortisone is available in 5-mg, 10-mg, and 20-mg tablets. This agent 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; however, individual sensitivity to these drugs widely varies. Estimated equivalencies are as follows:[64]

• 1 mg of prednisone = typically given as 4-6 mg of hydrocortisone, but may be up to 15 mg

• 1 mg of dexamethasone = 20-25 mg of hydrocortisone but was previously thought to be up to 100 mg

Patients with primary adrenal insufficiency who also have mineralocorticoid deficiency require fludrocortisone at 0.1-0.2 mg/d. Infants with primary adrenal insufficiency usually require sodium chloride supplementation, the usual dosage being 2-4 g/d (4 g = 1 teaspoon). Older children generally do not need sodium chloride supplements, since they can access salt to meet their requirements.[10]

If the patient's 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.

Glucocorticoid dosing

Individualize the maintenance dosage for each patient. The range for hydrocortisone is 7-20 mg/m2/d given orally in 2 or 3 divided doses.

Monitor the adequacy of dosing in patients with adrenal insufficiency who receive long-term glucocorticoid therapy, and 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). Too little glucocorticoid causes symptoms of adrenal insufficiency. 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.

In the authors' 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.

Caloric and activity monitoring

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.

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

It is advisable for patients with adrenal insufficiency to wear a medical alert bracelet or necklace.[10]

Patients should eat an unrestricted diet. Those with primary adrenal insufficiency (Addison disease) 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 2-4 g of sodium chloride per day.

Glucocorticoid replacement is required in all forms of adrenal insufficiency (Addison disease). 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. In acute adrenal crisis (eg, hypotension, hypoglycemia) use pharmacologic doses of glucocorticoids, which can be in the form of hydrocortisone, methylprednisolone, or dexamethasone.

Class Summary

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

Fludrocortisone

Fludrocortisone is the drug of choice (DOC) for mineralocorticoid replacement therapy if the zona glomerulosa of the adrenal cortex does not produce aldosterone. This agent allows patients to achieve normal sodium homeostasis.

Fludrocortisone is available only in an oral (PO) formulation. If patient cannot tolerate PO, parenteral hydrocortisone can provide a mineralocorticoid effect. Infants may require sodium chloride supplements, because their diets often provide insufficient sodium.

Class Summary

Glucocorticoid agents give patients with adrenal insufficiency (Addison disease) 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, both agents 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 (Alkindi Sprinkle, Cortef, SoluCortef)

Hydrocortisone is the glucocorticoid drug of choice (DOC) because of its mineralocorticoid activity and glucocorticoid effects and its equivalency to the adrenal product (ie, cortisol). This agent has a short half-life; therefore, hydrocortisone does not inhibit growth in children to same degree as more potent, longer-acting synthetic glucocorticoid agents (eg, prednisone, methylprednisolone, dexamethasone). Because of short action, hydrocortisone must be administered orally (PO) twice or thrice daily (bid/tid). When administered intravenously, hydrocortisone is usually given every 6 hours.

In a healthy person, mean cortisol secretion is about 5-10 mg/m2/d. The aim of replacement therapy is to supply only as much as needed. The target level 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 a minimum of about 4, 5, and 40-50 times the potency of hydrocortisone, respectively). An immediate-release oral granule product (Alkindi Sprinkle) is available in 0.5-mg, 1-mg, 2-mg, and 5-mg dosage sizes to assist with dosing in young children.

Dexamethasone (Baycadron)

Dexamethasone provides glucocorticoid activity. At pharmacologic doses, this agent decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reducing capillary permeability. Dexamethasone and prednisone may be used for allergic and inflammatory conditions.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Methylprednisolone also provides glucocorticoid activity. At pharmacologic doses, this agent decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability.

Methylprednisolone is available in a liquid formulation, unlike hydrocortisone.

Prednisone

Prednisone provides glucocorticoid activity. At pharmacologic doses, this agent decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability. Like methylprednisolone, prednisone is available in a liquid formulation.