Pediatric Adrenal Insufficiency (Addison Disease)

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Adrenal insufficiency (Addison disease) can be classified as primary, which occurs when the adrenal gland itself is dysfunctional, or secondary, also called central adrenal insufficiency, which 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. [1] See the image below.

Adrenal insufficiency can further be classified as congenital or acquired (see Etiology).

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

A diagnosis of adrenal insufficiency is confirmed if the serum cortisol level is less than 18 mcg/dL in the presence of a markedly elevated serum ACTH concentration and plasma renin activity. Based on normative data of children of various ages, adrenal insufficiency is likely if the serum cortisol concentration is less than 18 mcg/dL 30-60 minutes after administration of 250 mcg of cosyntropin (synthetic ACTH 1-24). [2, 3] 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.

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.

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 (eg, a patient who recently underwent surgery of the hypothalamus or pituitary regions). The insulin-tolerance test is still considered the criterion standard.

Computed tomography (CT) scanning is the imaging study of choice in the evaluation of adrenal insufficiency and helps to identify adrenal hemorrhage, calcifications, and infiltrative disease.

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

Patients with adrenal insufficiency 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.

Glucocorticoid replacement is required in all forms of adrenal insufficiency. Mineralocorticoid replacement is required only in primary adrenal insufficiency, because aldosterone secretion is reduced in primary adrenal insufficiency but not in central adrenal insufficiency.

No surgical management is needed in most cases of adrenal insufficiency.

See also Addison Disease (Adrenal Insufficiency).

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.

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. This unresponsiveness may be isolated (as in Familial Glucocorticoid Deficiency) (Online Mendelian Inheritance in Man database [OMIM] 202200), [9, 10] or it may be associated with achalasia and alacrima (as in achalasia-addisonism-alacrima syndrome, or triple A syndrome [AAAS]) (OMIM 231550). [11, 12]

In developed countries, the most common cause of adrenal insufficiency (Addison disease) is autoimmune destruction of the adrenal cortex. [13] 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 [14]

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

Neoplastic destruction

Metabolic disorders (eg, various forms of adrenal leukodystrophy [OMIM 300100], [15, 16] Wolman disease [OMIM 278000], Smith-Lemli-Opitz syndrome [OMIM 270400] [17]

Ketoconazole and related antifungals, as well as the anesthetic etomidate, can inhibit steroid synthesis, causing adrenal insufficiency [18, 19, 20]

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 Addison disease may occur as a result of adrenal hypoplasia [21, 22, 23] 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. [24] 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. [19] 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) [25] or a mutation in the cholesterol side-chain cleavage gene (at the cytochrome P450 [CYP] 11A locus) (OMIM 118485). [26] 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). [27, 28, 29]

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. [30] 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. [31] 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. [32] 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. [33]

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. [34] 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. [35] More than 90% of cases have been attributed to autoimmune disease. An Italian study provided statistics comparable to those observed in Great Britain: [36]  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. [37]

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. [38]

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

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.

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Kimberly Tafuri, DO Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Stony Brook Children’s Hospital

Kimberly Tafuri, DO is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children’s Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Sasigarn A Bowden, MD Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD is a member of the following medical societies: American Society for Bone and Mineral Research, Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children’s Medical Center of New York; Professor of Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

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