eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Adrenal Insufficiency

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
Coauthor(s): Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Contributor Information and Disclosures

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 hemorrhage⁷
    • Infections (eg, TB, HIV infection)
    • Neoplastic destruction
    • Metabolic disorders (eg, various forms of adrenal leukodystrophy,^15,16 Wolman disease [OMIM 278000], Smith-Lemli-Opitz syndrome¹⁷ )
    • Administration of the anesthetic agent etomidate¹⁸
  • 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 118485²⁴ ). 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

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