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Clinical manifestations and diagnosis of adrenal insufficiency in children

Clinical manifestations and diagnosis of adrenal insufficiency in children
Author:
Mimi S Kim, MD, MSc
Section Editor:
Mitchell E Geffner, MD
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Oct 2022. | This topic last updated: Aug 30, 2021.

INTRODUCTION — Adrenal insufficiency is a potentially life-threatening condition defined by impaired synthesis and release of adrenocortical hormones. It can be caused by a variety of disorders that interfere with the production of adrenocortical hormones, including abrupt withdrawal of glucocorticoid medications or congenital adrenal hyperplasia (CAH).

The diagnosis of adrenal insufficiency will be discussed in this topic review. Other aspects of adrenal insufficiency are discussed in separate topic reviews:

(See "Causes of primary adrenal insufficiency in children".)

(See "Causes of central adrenal insufficiency in children".)

(See "Treatment of adrenal insufficiency in children".)

CLASSIFICATION — Adrenal insufficiency can be classified based upon the underlying mechanism:

Primary adrenal insufficiency results from disease that is intrinsic to the adrenal cortex (table 1). The most common cause of primary adrenal insufficiency in children is classic congenital adrenal hyperplasia (CAH). (See "Causes of primary adrenal insufficiency in children".)

Central adrenal insufficiency is characterized by lack of adrenocorticotropic hormone (ACTH) stimulation of cortisol production. Central adrenal insufficiency can be caused by either pituitary disease that impairs production of ACTH (secondary adrenal insufficiency) or by interference with corticotropin-releasing hormone (CRH) release from the hypothalamus (tertiary adrenal insufficiency) (table 2). The most common cause is chronic, high-dose glucocorticoid therapy, which suppresses the hypothalamic-pituitary-adrenal axis. Other patients have congenital or acquired hypothalamic or pituitary disease that causes multiple pituitary hormone deficiencies including ACTH deficiency. (See "Causes of central adrenal insufficiency in children".)

CLINICAL MANIFESTATIONS — The signs and symptoms of adrenal insufficiency vary depending on what class(es) of hormone are deficient and the severity of the defect(s). The adrenocortical hormones are divided into glucocorticoids (eg, cortisol), mineralocorticoids (eg, aldosterone), and adrenal androgens (eg, androstenedione, dehydroepiandrosterone). In primary adrenal insufficiency, any or all of these hormones may be deficient. Patients with secondary, or central, adrenal insufficiency do not have mineralocorticoid deficiency or adrenocorticotropic hormone (ACTH)-related hyperpigmentation.

Primary adrenal insufficiency — In general, clinical findings of children with untreated primary adrenal insufficiency are often nonspecific and include fatigue, nausea, and vomiting. Additional symptoms depend upon the specific hormones affected (table 3). Signs of mineralocorticoid deficiency (eg, hypotension, dehydration, and/or electrolyte abnormalities) are often observed. The underlying cause of adrenal insufficiency determines the type and extent of the deficiency.

Glucocorticoid deficiency — Clinical and laboratory findings associated with untreated or undertreated glucocorticoid (eg, cortisol) deficiency include [1]:

Weakness and fatigue

Nausea and vomiting

Fasting hypoglycemia (particularly in infants and young children) due to diminished counterregulation, which leads to increased insulin sensitivity [2]

Headache, particularly in the morning

Abdominal pain

Hyponatremia (with or without hyperkalemia, in the setting of primary adrenal insufficiency)

Skin hyperpigmentation

Weight loss, anorexia (particularly in chronic glucocorticoid deficiency)

The skin hyperpigmentation is most conspicuous in areas exposed to pressure (eg, elbows and knees, palmar creases, axillae) and in mucosal membranes (tongue, palate, gingival borders), and scars. In individuals with darker skin phototypes, the hyperpigmentation may be most apparent in the gingival borders and mucus membranes. The hyperpigmentation is due to increased production of proopiomelanocortin (POMC), which is triggered by the cortisol deficiency. POMC is a prohormone that is cleaved into equimolar amounts of the biologically active hormones ACTH, melanocyte-stimulating hormone (MSH), and beta-endorphin. The elevated MSH results in increased melanin synthesis, causing hyperpigmentation.

Mineralocorticoid deficiency — Clinical findings seen with untreated or undertreated mineralocorticoid (eg, aldosterone) deficiency include [1]:

Dizziness

Headache

Salt craving

Nausea and vomiting

Lethargy

Dehydration

Hypotension

Hyponatremia and hyperkalemia

These signs and symptoms primarily result from urinary sodium loss and/or potassium retention and metabolic acidosis.

Adrenal androgens — The adrenal cortex is a major source of androgen precursor production in prepubertal children and females of all ages. Patients with congenital adrenal hyperplasia (CAH; eg, 21-hydroxylase deficiency, 11-beta-hydroxylase deficiency), which is the most common cause of primary adrenal insufficiency, have excessive adrenal androgen production. The excessive androgen production is due to disrupted steroid biosynthesis, which increases ACTH signaling.

Other forms of adrenal insufficiency may include adrenal androgen deficiency. Clinical findings of adrenal androgen deficiency in postpubertal individuals can be subtle and include decreased or absent axillary and pubic hair and decreased libido in females. Clinical findings are unusual in pubertal and adult males because most of their androgen production occurs in the testes. Prepubertal children with adrenal androgen deficiency are asymptomatic.

Adrenal crisis — Adrenal crisis results from acute adrenal insufficiency. To minimize morbidity and mortality, prompt recognition and treatment of adrenal crisis are critical. A rapid overview of this issue can be found in the accompanying table (table 4).

Clinical presentation and features – Many patients with adrenal crisis due to primary adrenal insufficiency have features of both glucocorticoid deficiency and mineralocorticoid deficiency. The features of glucocorticoid deficiency may include vomiting, fever, diarrhea, and hypoglycemia. The features of mineralocorticoid deficiency may include headache, dizziness, electrolyte abnormalities (hyponatremia and hyperkalemia), and hypotension [3]. Patients with central adrenal insufficiency can also have adrenal crisis due to glucocorticoid deficiency alone.

Adrenal crisis should be specifically considered in the following clinical settings:

Young infants with CAH (typically due to 21-hydroxylase deficiency) may be identified by newborn screen and/or atypical genital appearance (46,XX females) or may first present with adrenal crisis, which typically develops within the first two weeks of life. An adrenal crisis in this setting is rare in areas where newborn screening for CAH is routinely performed. Uncommon causes of adrenal crisis in neonates include adrenal hypoplasia congenita and bilateral adrenal hemorrhage. Early diagnosis of adrenal insufficiency before the onset of circulatory collapse is imperative. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Approach by clinical presentation'.)

In individuals previously diagnosed with adrenal insufficiency, adrenal crisis may be triggered by a precipitating stress (eg, surgery, infection, or trauma) or by interruption in replacement therapy.

Patients with septic shock or those receiving anticoagulant therapy may develop acute adrenal insufficiency and crisis due to bilateral adrenal hemorrhage or infarction. Signs and symptoms include hypotension and shock that fail to respond to vigorous fluid resuscitation and inotropic medications, accompanied by hyponatremia and hyperkalemia.

Differential diagnosis – Other conditions that can cause signs or symptoms similar to adrenal crisis include:

Infants with obstructive uropathy, pyelonephritis, or tubulointerstitial nephritis may develop a salt-losing crisis that resembles a salt-losing adrenal crisis, presenting with vomiting, hyponatremia, and hyperkalemia [4]. This is caused by a reversible secondary aldosterone resistance due to the renal disease and is more likely to occur in infants than in older children. In any infant presenting with a salt-losing crisis, the possibility of pyelonephritis should be excluded (eg, by urinalysis). These types of salt-losing crises may present at any age.

Patients with chronic kidney disease may develop hyponatremia and hyperkalemia due to inadequate production of renin and consequent aldosterone deficiency [5].

Central adrenal insufficiency — Central adrenal insufficiency is characterized by:

Glucocorticoid deficiency – Signs and symptoms could include weakness, fatigue, and hypoglycemia. Acute episodes of hypoglycemia may be severe, leading to seizure and coma. These clinical findings are similar to those seen in primary adrenal insufficiency. (See 'Glucocorticoid deficiency' above.)

Related clinical manifestations – In addition, many patients with central adrenal insufficiency have signs and symptoms that reflect the underlying cause of the disorder:

Those with hypothalamic or pituitary disease may have multiple anterior pituitary hormone deficiencies, especially of growth hormone (symptoms of hypoglycemia in infants and toddlers and growth failure), thyroid-stimulating hormone (symptoms of hypothyroidism), and gonadotropins (signs/symptoms of hypogonadism, the presence of which depends on age).

Those with an underlying pituitary or hypothalamic tumor may have clinical manifestations due to the mass effect, such as headache and visual field defect or seizure.

Features of central adrenal insufficiency that differ from primary adrenal insufficiency:

Patients with central adrenal insufficiency do not have mineralocorticoid deficiency. As a result:

-Serum electrolytes usually are normal because the renin-angiotensin-aldosterone axis remains intact. However, patients with central forms of adrenal insufficiency may have isolated and sometimes severe hyponatremia (without hyperkalemia). The hyponatremia is dilutional because of loss of the facilitatory role of cortisol on free water excretion.

-Patients are not dehydrated (ie, not hypovolemic).

-Adrenal crisis is less common than in primary adrenal insufficiency but can occur due to cortisol deficiency alone.

Hyperpigmentation is not present, because POMC and MSH secretion is not increased.

DIAGNOSTIC APPROACH — Laboratory confirmation of the clinical diagnosis of adrenal insufficiency is a three-stage process (algorithm 1) [6]:

Confirm adrenal insufficiency by demonstrating inappropriately low cortisol secretion. (See 'Initial evaluation' below.)

Determine whether the adrenal insufficiency is primary or central (see 'Determine primary versus central adrenal insufficiency' below):

Primary adrenal insufficiency is indicated by low early AM cortisol, high adrenocorticotropic hormone (ACTH) concentrations, and possible hypoglycemia. In addition to glucocorticoid deficiency, these patients are at risk for mineralocorticoid deficiency, which is indicated by hyponatremia, hyperkalemia, elevated plasma renin activity (PRA), and low levels of aldosterone (if measured).

Central adrenal insufficiency is indicated by low ACTH levels and low early AM cortisol. These patients have glucocorticoid deficiency but not mineralocorticoid deficiency, so patients have normal results for serum potassium, PRA, and aldosterone. Many of these patients have deficiencies of one or more of the other pituitary hormones (ie, growth hormone, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone).

Evaluate for the cause of the underlying disorder (eg, autoimmune disease involving the adrenal glands or a pituitary lesion compromising normal brain function). (See 'Evaluate for cause' below.)

INITIAL EVALUATION

Basal (unstimulated) cortisol — The initial screening step in the laboratory diagnosis of adrenal insufficiency is measurement of serum cortisol in the early morning (between 6 and 8 AM) (algorithm 1 and table 5). Early morning testing is essential because of the diurnal variation in serum cortisol [7]. For patients <6 months of age, the early morning timing for testing is less important because young infants do not have significant diurnal variation of serum cortisol. Other tests (eg, electrolytes) are generally performed at the same time to support the diagnosis and evaluate for specific causes, depending on the patient's characteristics. (See 'Supportive tests' below.)

Interpretation — If the serum cortisol is low, then adrenal insufficiency is likely. Next steps may include an adrenocorticotropic hormone (ACTH) stimulation test to confirm the diagnosis, but the need for this depends upon the patient's clinical characteristics:

If basal morning serum cortisol is low (eg, <3 mcg/dL [8]) and the patient has strong clinical evidence of adrenal insufficiency (eg, hyperpigmentation, electrolyte abnormalities, or other pituitary hormone deficiencies), the clinician may decide that this combination of findings is sufficient to confirm the diagnosis of adrenal insufficiency and initiate treatment.

If basal serum cortisol is low and the patient is stable and does not have strong clinical signs of symptoms of adrenal insufficiency, then an ACTH stimulation test is advisable to make a definitive diagnosis.

If basal serum cortisol is indeterminate, options include repeating the basal test under optimal conditions (early morning, when the child is not ill) or performing an ACTH stimulation test.

If basal serum cortisol is normal (eg, ≥8 mcg/dL), then adrenal insufficiency is unlikely, assuming that the test was performed under optimal conditions. If there is ongoing clinical concern for adrenal insufficiency, further testing may include repeating the basal cortisol and/or performing an ACTH stimulation test.

The results should be interpreted using age- and laboratory-specific reference ranges.

Special circumstances

Infancy – Early morning cortisol levels in infancy be confounded by multiple factors, including immature hypothalamic-pituitary-adrenal axis, immature circadian rhythm, varied sleep patterns, and variations in cortisol-binding globulin [9].

Stress or illness – Serum cortisol in a patient with adrenal insufficiency may falsely appear to be normal if the child is very ill or otherwise stressed at the time of testing. Stress can increase serum cortisol in these patients so that it falls within the normal range.

Critical illness – Critical illness such as sepsis is an established cause of primary adrenal insufficiency (known as critical illness-related corticosteroid insufficiency [CIRCI]). Thus, there should be a high index of suspicion for adrenal insufficiency in these patients and a normal basal serum cortisol result is not sufficient to exclude CIRCI. (See "Causes of primary adrenal insufficiency in children", section on 'Critical illness-related corticosteroid insufficiency'.)

Supportive tests — We include additional laboratory tests, depending on the patient's clinical features:

Tests for mineralocorticoid deficiency

Electrolytes and glucose – For all patients with suspected adrenal insufficiency to identify abnormalities caused by mineralocorticoid deficiency that may require urgent management. Hyponatremia with hyperkalemia in a patient with normal renal function suggests mineralocorticoid deficiency.

Plasma renin activity (PRA) or direct renin – Elevations in PRA or renin provide an early and sensitive indicator of mineralocorticoid deficiency and should be measured in patients at high risk for an acute adrenal crisis [9-11]. In our practice, we include these tests in the initial evaluation of newborn infants with suspected congenital adrenal hyperplasia (CAH), eg, in an infant with atypical genital appearance, positive newborn screen, or hyponatremia and hyperkalemia. These tests also may be helpful for monitoring the adequacy of mineralocorticoid replacement therapy. (See 'Adrenal crisis' above.)

Aldosterone – Serum aldosterone is another index of mineralocorticoid deficiency. Measurement of aldosterone and its precursors is most useful for testing for enzymatic defects specific to mineralocorticoid synthesis, which are rare disorders.

ACTH – Perform this test in selected patients to help distinguish between primary and central adrenal insufficiency. This test is not necessary if an ACTH stimulation test is planned or if the type of adrenal insufficiency can be determined by the clinical features. The specimen should be drawn at the same time as basal serum cortisol and centrifuged immediately following blood collection to separate the plasma, which should then be frozen right away. (See 'Determine primary versus central adrenal insufficiency' below.)

17-hydroxyprogesterone – Perform this test in all patients with likely primary adrenal insufficiency to evaluate for CAH. Patients with classic CAH due to 21-hydroxylase (the most common enzyme deficiency) have markedly elevated 17-hydroxyprogesterone. Other steroid metabolites are sometimes measured to distinguish between 21-hydroxylase deficiency and other rare forms of CAH. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

Adrenal androgens – Tests of adrenal androgens (eg, dehydroepiandrosterone sulphate and androstenedione) and their steroid precursors may be helpful in establishing the diagnosis and type of CAH. Adrenal androgens are elevated in some forms of CAH before treatment is initiated due to disrupted steroid biosynthesis, including classic CAH due to 21-hydroxylase deficiency or 11-beta-hydroxylase deficiency. Mildly elevated concentrations of dehydroepiandrosterone sulphate (40 to 115 mcg/dL [1.1 to 3.1 micromol/L]) are also found in premature adrenarche, a normal variant in prepubertal children. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias" and "Premature adrenarche".)

Adrenal androgens are usually low-normal or subnormal in patients with other forms of adrenal insufficiency, and their measurements are not required for the initial diagnosis. (See 'Adrenal androgens' above.)

Normal values depend on the reference laboratory and vary by age and sex. Unlike other static tests of adrenocortical function, they are minimally affected by physiologic conditions such as stress and state of hydration.

Adrenocorticotropic hormone stimulation test — If basal serum cortisol is low, then an ACTH stimulation test usually should be performed to confirm the diagnosis of adrenal insufficiency [12,13]. However, ACTH stimulation testing is not always necessary or practical and the decision to perform this test depends on the clinical scenario. (See 'Basal (unstimulated) cortisol' above.)

The technique for an ACTH stimulation test and possible alternatives are shown in the table (table 6). In most forms of adrenal insufficiency, basal cortisol is low and fails to rise after ACTH stimulation. In patients with central adrenal insufficiency of short duration, basal cortisol is low and may rise after ACTH stimulation; a low-dose test may be more sensitive in this situation. (See 'Determine primary versus central adrenal insufficiency' below.)

FURTHER EVALUATION — If adrenal insufficiency is diagnosed, the next steps are to determine the level of defect (primary versus central), then to identify a specific cause.

Determine primary versus central adrenal insufficiency — In patients with adrenal insufficiency (low early AM cortisol levels), the distinction between primary and central (secondary or tertiary) adrenal insufficiency is often clear from the clinical characteristics and/or initial testing. As examples:

Primary adrenal insufficiency is likely in patients with any of the following:

Signs or symptoms of congenital adrenal hyperplasia (CAH; eg, in an infant with a positive newborn screen for CAH or older patient with elevated 17-hydroxyprogesterone, atypical genital appearance in females, and/or hyponatremia and hyperkalemia, indicating a salt-losing crisis).

Signs of mineralocorticoid deficiency (hyponatremia, hyperkalemia, or elevated plasma renin activity [PRA], occasionally with hypotension).

Elevated basal plasma adrenocorticotropic hormone (ACTH) concentration (unstimulated, 8 AM), if measured (table 5). In primary adrenal insufficiency, ACTH is typically more than twice the upper limit of the reference range, often >100 pg/mL [9,12].

Low basal serum cortisol concentration that fails to rise significantly after ACTH stimulation (table 6). However, this result does not exclude early central adrenal insufficiency, as discussed below.

Central adrenal insufficiency is likely in patients with any of the following:

Exogenous glucocorticoid use, with recent withdrawal or taper (or an acute illness that increases glucocorticoid needs).

Multiple pituitary hormone deficiencies, midline craniofacial defects, optic nerve hypoplasia, or other known central nervous system pathology.

Low basal plasma ACTH concentration (unstimulated, 8 AM), if measured.

Low basal serum cortisol concentration that rises with ACTH stimulation (table 6). However, cortisol may not rise, because chronic lack of ACTH stimulation impairs the ability of the adrenal cortex to produce cortisol in response to acute ACTH administration. Patients with recent-onset central adrenal insufficiency (duration four to six weeks) may have sufficient adrenal sensitivity to respond to ACTH stimulation as the adrenal cortex is not atrophied. In these patients, a low-dose protocol is more likely to help distinguish between primary and central adrenal insufficiency [13].

In clinical practice, it is not usually necessary to determine whether ACTH deficiency is due to a secondary (pituitary defect) versus tertiary (hypothalamic defect) cause. The clinical presentation as well as the treatment would be the same. However, if the clinician wishes to distinguish patients with tertiary adrenal insufficiency (eg, due to a hypothalamic injury), a corticotropin-releasing hormone (CRH) stimulation test could be used. In patients with tertiary adrenal insufficiency, plasma ACTH levels will rise in response to CRH. In those with secondary adrenal insufficiency (or in the rare circumstance of a defective CRH receptor), there will be no CRH-stimulated rise in ACTH secretion.

Evaluate for cause

Primary adrenal insufficiency – If primary adrenal insufficiency is diagnosed, further testing should be performed to determine the cause. The causes of primary adrenal insufficiency are summarized in the table (table 1) and discussed in more detail in a separate topic review. (See "Causes of primary adrenal insufficiency in children".)

Key considerations include:

In a newborn infant or individual presenting with atypical genital appearance or salt-losing adrenal crisis, the most likely cause of adrenal insufficiency is CAH. Measurement of 17-hydroxyprogesterone is the screening test for the most common cause of this disorder (21-hydroxylase deficiency). Diagnosis and immediate management of CAH are discussed separately. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Uncommon congenital adrenal hyperplasias".)

In older children, an important consideration is autoimmune adrenal insufficiency, which is diagnosed by measuring antiadrenal antibody titers.

-If adrenal antibodies are positive, screen for autoimmune polyglandular syndromes by measuring antibodies to other endocrine glands, including thyroid, parathyroids, and islet cells [12]. (See "Causes of primary adrenal insufficiency in children", section on 'Autoimmune disease'.)

-If the adrenal antibodies are negative, other important considerations include infection (eg, tuberculosis), adrenal hypoplasia congenita, or adrenoleukodystrophy or adrenomyeloneuropathy (in boys). (See "Causes of primary adrenal insufficiency in children".)

In males, adrenoleukodystrophy is an important cause of adrenal insufficiency. For some patients, adrenal insufficiency (including adrenal crisis) is the presenting event, with or without cerebral symptoms or myeloneuropathy (table 7) [14]. (See "Causes of primary adrenal insufficiency in children", section on 'Adrenoleukodystrophy'.)

In patients with septic shock or those receiving anticoagulant therapy who develop acute adrenal insufficiency, consider adrenal hemorrhage. (See "Causes of primary adrenal insufficiency in children", section on 'Adrenal hemorrhagic infarction'.)

Central adrenal insufficiency – In patients with central adrenal insufficiency (impaired ACTH secretion), the cause is often obvious from the clinical context (table 2):

Chronic glucocorticoid therapy is a common cause of central adrenal insufficiency. High-dose glucocorticoids suppress the hypothalamic-pituitary-adrenal axis, and abrupt withdrawal causes insufficiency.

Patients with central nervous system disease (eg, congenital anomalies including midline craniofacial defects, optic nerve hypoplasia, brain trauma, or brain tumor) may have adrenal insufficiency due to impaired pituitary ACTH secretion. These patients often have multiple pituitary hormone deficiencies, so they should be evaluated for central hypothyroidism by measuring serum thyroxine. They should also be monitored closely for growth (especially height velocity) and tested for growth hormone deficiency if there is any clinical evidence of growth failure. (See "Diagnosis of growth hormone deficiency in children".)

Chronic opioid use can cause central adrenal insufficiency by suppressing the hypothalamic-pituitary-adrenal axis [15]. (See "Causes of secondary and tertiary adrenal insufficiency in adults", section on 'Opiates'.)

Rarely, central adrenal insufficiency is caused by a genetic disorder of generalized pituitary dysfunction (POU1F1 or PROP1 gene mutations) or isolated ACTH deficiency (TBX19/TPIT, POMC, and possibly CRH gene mutations). (See "Causes of central adrenal insufficiency in children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Society guideline links: Adrenal insufficiency".)

SUMMARY AND RECOMMENDATIONS

Clinical manifestations – Adrenal insufficiency is suspected on the basis of clinical symptoms, which may include fatigue and gastrointestinal complaints of abdominal pain, nausea, and vomiting. Additional symptoms can be categorized based upon the specific hormones affected (table 3). Patients with primary adrenal insufficiency often have signs of mineralocorticoid deficiency, including hypotension, dehydration, and electrolyte abnormalities, and may present in adrenal crisis (table 4). (See 'Clinical manifestations' above and 'Adrenal crisis' above.)

Classification – Primary adrenal insufficiency is caused by disease of the adrenal cortex. Central adrenal insufficiency is caused by impaired production of adrenocorticotropic hormone (ACTH) from the pituitary gland or of corticotropin-releasing hormone (CRH) from the hypothalamus. (See 'Classification' above.)

Initial laboratory testing – A provisional diagnosis of adrenal insufficiency can be made if laboratory testing reveals inappropriately low cortisol secretion when tested in the morning (ie, 6 to 8 AM) (table 5). (See 'Basal (unstimulated) cortisol' above.)

Other static tests (unstimulated levels) may be included in the initial evaluation depending on the patient's clinical features (algorithm 1) (see 'Supportive tests' above):

Electrolytes, glucose, and renin – For all patients with suspected adrenal insufficiency to identify electrolyte abnormalities (hyponatremia and hyperkalemia) caused by mineralocorticoid deficiency or cortisol deficiency (isolated hyponatremia), which may require urgent management. Plasma renin activity (PRA) or direct renin may be included for selected patients with high risk for mineralocorticoid deficiency.

17-hydroxyprogesterone – If congenital adrenal hyperplasia (CAH) is suspected, eg, in an infant presenting with atypical genital appearance, electrolyte abnormalities, or a positive newborn screen for CAH.

Stimulation testing – The diagnosis of adrenal insufficiency is usually confirmed by serum cortisol responses to a rapid intravenous ACTH stimulation test (table 6). Cortisol results during this test are abnormal for either primary adrenal insufficiency or chronic central adrenal insufficiency (wherein sustained lack of endogenous ACTH stimulation leads to adrenal atrophy). Results of this test may be normal in recent-onset central adrenal insufficiency. (See 'Adrenocorticotropic hormone stimulation test' above.)

The ACTH stimulation test is not always necessary. If basal serum cortisol is low and the patient has strong clinical evidence of adrenal insufficiency (eg, hyperpigmentation, electrolyte abnormalities, or other pituitary hormone deficiencies), the clinician may decide that this combination of findings is sufficient to confirm the diagnosis of adrenal insufficiency and initiate treatment. (See 'Basal (unstimulated) cortisol' above.)

Further evaluation – Additional testing is performed as needed to establish the underlying cause of the adrenal insufficiency. (See 'Evaluate for cause' above and "Causes of primary adrenal insufficiency in children" and "Causes of central adrenal insufficiency in children".)

Children with primary adrenal insufficiency should have a full evaluation for CAH. This is the most common cause of primary adrenal insufficiency in children, with the severe forms usually presenting during infancy. If CAH is excluded, patients should be evaluated for other forms of primary adrenal insufficiency (table 1). (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Children with central adrenal insufficiency have deficient ACTH secretion from the pituitary due to pituitary dysfunction or deficient release of CRH from the hypothalamus (table 2). The most common cause is chronic, high-dose glucocorticoid therapy. In clinical situations unrelated to prior use of glucocorticoids, other pituitary hormones also should be measured.

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Patricia A Donohoue, MD, who contributed to an earlier version of this topic review.

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