| Patient Education |
|
Click here for patient education.
|
|
You are in: eMedicine Specialties >
Pediatrics: General Medicine > Endocrinology
Adrenal Insufficiency
Article Last Updated: Oct 23, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Coauthor(s):
Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Editors: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Author and Editor Disclosure
Synonyms and related keywords:
Addison disease, Addison's disease, adrenal crisis, adrenal insufficiency and adrenal crisis, glucocorticoid deficiency, familial glucocorticoid deficiency, hypoadrenalism, adrenal hypoplasia, hypocortisolism, adrenals, adrenal glands, adrenal failure, hormonal insufficiency, glucocorticoids, mineralocorticoids, androgens, primary adrenal insufficiency, secondary adrenal insufficiency, central adrenal insufficiency, dysfunctional adrenal gland CRH, corticotropin-releasing hormone, adrenocorticotropic hormone, corticotropic hormone, ACTH, hypofunction of the adrenal cortex, congenital adrenal insufficiency, acquired adrenal insufficiency, tuberculosis, TB, autoimmune adrenal insufficiency, adrenal hypoplasia congenita, AHC, congenital adrenal hypoplasia, congenital adrenal hyperplasia, CAH
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 corticotropic 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 becomes involuted 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. 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.
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
In Great Britain, the prevalence of adrenal insufficiency is 110 cases per million persons of all ages. More than 90% of cases are attributed to autoimmune disease. Willis and Vince (1997) reported data from Coventry County, Great Britain.1 An Italian study provided statistics similar to those observed in Great Britain. The incidence in Italy is estimated to be 117 cases per million persons.2 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. 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. 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. As a form of congenital adrenal hypoplasia, this condition is called adrenal hypoplasia congenita. Both conditions are relatively rare.
- Secondary adrenal insufficiency due to a deficiency of ACTH or CRH, or a lack of ACTH receptors, is 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, are most commonly recognized in childhood.
History
- In infants, acute adrenal insufficiency may occur in the context of serious illness (eg, sepsis), prolonged and difficult labor, or traumatic delivery. Children and adults may also have a history of infectious illness, particularly TB or meningococcemia, though any type of severe sepsis may trigger adrenal insufficiency.
- Adrenal insufficiency may occur without concomitant illnesses when it is due to congenital adrenal hyperplasia or congenital adrenal hypoplasia.
- Antiphospholipid syndrome occasionally results in acute adrenal insufficiency secondary to bilateral adrenal hemorrhage.
- In general, patients present with chronic symptoms (eg, fatigue, anorexia, abdominal pain) if they have 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. Acute adrenal crisis may exacerbate their symptoms. (See also Adrenal Crisis and Adrenal Insufficiency and Adrenal Crisis.)
- 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.
- Symptoms of hypoglycemia are common in small children.
- Altered mental status, even without hypoglycemia, is common in patients with acute adrenal insufficiency.
- Increased skin pigmentation and salt craving are common among individuals with chronic primary adrenal insufficiency.
- These symptoms are not noted in patients with secondary or central adrenal insufficiency due to ACTH or CRH deficiency because these conditions do not elevate serum ACTH concentrations.
- Excess MSH activity causes hyperpigmentation.
- 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 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.
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. The patient also may 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. However, they may not become totally alopecic because adrenal androgens support growth of body hair in these areas.
- Wolman disease (OMIM 278000) is an autosomal recessive disorder caused by a deficiency of lysosomal acid lipase. In general, Wolman disease is accompanied by hepatosplenomegaly and adrenal calcifications, which may be seen on plain radiographs or CT scans 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. 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), or it may be associated with achalasia and alacrima (as in achalasia-addisonism-alacrima syndrome, or triple A syndrome [AAAS], OMIM 231550). Acquired primary adrenal insufficiency In developed countries, the most common cause is autoimmune destruction of the adrenal cortex. This disorder may exist in isolation or may be part of a polyglandular autoimmune disorder. Patients with type 1 autoimmune polyglandular disease (OMIM 240300) present in the first decade of life. Type 1 autoimmune polyglandular disease is transmitted as an autosomal recessive disorder with all or some of the following features: - Adrenal failure
- Hypoparathyroidism
- Hypothyroidism
- Gonadal failure
- Diabetes mellitus type 1
- Vitiligo
- Alopecia
- Pernicious anemia
- Chronic mucocutaneous candidiasis
Type 2 autoimmune polyglandular disease consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. Individuals with this condition present in the second or third decades of life. Type 2 autoimmune polyglandular disease is transmitted as an autosomal disorder with variable penetrance. Relatively uncommon causes of adrenal failure are the following: - Adrenal hemorrhage
- Infections (eg, TB, HIV infection)
- Neoplastic destruction
- Metabolic disorders (eg, various forms of adrenal leukodystrophy, Wolman disease [OMIM 278000], Smith-Lemli-Opitz syndrome)
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 or hyperplasia. Inherited as an X-linked disorder, adrenal hypoplasia congenita (OMIM 300200) is caused by deletion of the DAX1 gene on chromosome X. This change is often part of a contiguous gene deletion that involves glycerol kinase deficiency, Duchenne muscular dystrophy, and hypogonadotropic hypogonadism. 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 1 of several enzymes required for adrenal synthesis of cortisol. 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) or a mutation in the cholesterol side-chain cleavage gene (at the cytochrome P450 [CYP] 11A locus; OMIM 118485). 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 primary hypogonadism.
3-Beta-Hydroxysteroid Dehydrogenase Deficiency
Adrenal Hypoplasia
Birth Trauma
Chronic Fatigue Syndrome
Congenital Adrenal Hyperplasia
Familial Glucocorticoid Deficiency
Hypopituitarism
Pseudohypoaldosteronism
Other Problems to be Considered
ACTH receptor defect
Adrenoleukodystrophy and adrenomyeloneuropathy
Autoimmune polyglandular endocrinopathy syndromes
Infectious adrenalitis (eg, in association with HIV infection or TB)
Lipoid adrenal hyperplasia
Wolman disease
Lab Studies
General considerations and tests
Clinical suspicion is important because the presentation of patients with adrenal insufficiency may be insidious and subtle. When adrenal insufficiency is suspected, laboratory studies of the following measures help to establish the diagnosis: - Electrolyte levels
- Fasting blood sugar concentration
- Serum ACTH concentration
- Plasma renin activity
- Serum cortisol concentration
- Serum aldosterone concentration
When hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine levels. Also order a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring. Serum cortisol testing and the administration of cosyntropin Interpret random serum cortisol concentrations in the context in which they were obtained. For example, adrenal insufficiency is unlikely in an otherwise healthy individual whose 8:00 am serum cortisol concentration is more than 10 mcg/dL. By contrast, a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient is highly suggestive of adrenal insufficiency. Results diagnostic of adrenal insufficiency A diagnosis of adrenal insufficiency is confirmed if the serum cortisol level is more than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity or a concentration lower than a level obtained 60 minutes after an administration of cosyntropin. The diagnosis is also confirmed when serum cortisol concentrations fail to increase to more than 18-20 mcg/dL by 60 minutes after cosyntropin administration. Note that the guidelines just discussed do not apply to premature or low-birth-weight infants, who have low cortisol secretion. If the serum cortisol level is low but the ACTH value is elevated, measure antiadrenal antibodies concentrations. Antibodies to 1 or more steroidogenic enzymes, particularly 21-hydroxylase, are often found in patients with autoimmune adrenal disease. The administration of cosyntropin is controversial because whether the best dose is 250 mcg (standard dose), 1 mcg, or 0.5 mcg/m2 (low dose) is unresolved, particularly in the pediatric age group. Therefore, the standard dose is suggested. The common preparation of cosyntropin makes it cumbersome to deliver 1 mcg or less, and both doses seem supraphysiologic. When a patient's serum cortisol response to cosyntropin is subnormal but his or her serum ACTH level is not elevated, investigate the possibility of central adrenal insufficiency. In this context, 6-hour or 3-day treatment with ACTH can produce a normal cortisol response. If it does, this result confirms that the initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. The dose of ACTH for the 6-hour test is 25 IU administered intravenously over 6 hours. If the 3-day test is chosen, intramuscularly administer 25 mg/m2 of ACTH gel every 12 hours for 3 days. Plasma cortisol levels should increase to more than 40 mcg/dL in response to either of these challenges, or 24-hour urinary concentrations of 17-hydroxysteroid should increase 5-10 fold in response to 3-day ACTH stimulation. Insulin-tolerance testing and metyrapone stimulation If the patient has recent-onset (ie, <10 d) central adrenal insufficiency (eg, a patient who recently underwent surgery of the hypothalamus or pituitary regions), the relatively cumbersome and risky insulin-tolerance test or metyrapone stimulation test may be preferable to a cosyntropin challenge. These conditions are the only real indications for performing these tests in a patient with adrenal insufficiency. 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 a person's blood sugar concentration. Measure cortisol and glucose concentrations every 15 minutes for 60 minutes. The test is considered adequate if the patient's blood sugar level decreases by at least 50%. In response to the hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 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 overly symptomatic. Standard metyrapone stimulation tests involve administering metyrapone 300 mg/m2 in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, which is involved 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- to 3-fold increase in 24-hour urinary concentrations of 17-hydroxycorticosteroid (which include tetrahydro compound S, a urinary metabolite of 11-deoxycortisol) on the day of or the day after the administration of metyrapone. This test is cumbersome and carries some risk of inducing an adrenal crisis. Test for antiadrenal antibodies When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If results for antiadrenal antibodies are negative, search for another etiology, such as TB, adrenal hemorrhage, or adrenoleukodystrophy. CRH stimulation test The standard ovine or human CRH stimulation test is reliable for the diagnosis and differential diagnosis of adrenal insufficiency. Results in patients with glucocorticoid deficiency Patients with glucocorticoid deficiency of any etiology have subnormal cortisol responses. Patients with primary glucocorticoid deficiency have elevated ACTH concentrations at baseline and after the administration of CRH. Patients with secondary glucocorticoid deficiency have low ACTH levels throughout the test if they have primary pituitary deficiency, or they have exaggerated responses if their condition is tertiary.
Imaging Studies
- CT is the imaging study of choice and helps in identifying adrenal hemorrhage, calcifications, or infiltrative disease.
- MRI is not as useful as CT.
- Abdominal radiographs may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease.
- Ultrasonography is a poor imaging modality for investigating the adrenal glands.
- Iodocholesterol scanning is not particularly useful.
Procedures
CT-guided fine-needle aspiration sometimes helps in diagnosing the etiology of infiltrative adrenal disease.
Histologic Findings
Histologic findings depend on the underlying cause. - In cases of autoimmune adrenal failure, lymphocytic infiltration destroys the adrenal gland.
- Granulomatous changes in the adrenal glands indicate TB-related adrenal insufficiency.
- Neoplastic infiltrations are caused by metastatic tumors.
- Hemorrhagic adrenal insufficiency results in hemorrhagic destruction of the adrenal glands.
- Fungal disease produces the typical picture.
Medical Care
Patients are generally hypovolemic, and they may be hypoglycemic, hyponatremic, or hyperkalemic. Initial therapy consists of intravenously administered saline and dextrose. If patients are hypotensive, a 20-mL/kg bolus of isotonic sodium chloride solution given over the first hour may be necessary to restore their blood pressure. The bolus may be repeated if the patient's blood pressure remains low. After results for the patient's electrolyte, blood sugar, cortisol, and ACTH concentrations are obtained, administer glucocorticoids if adrenal insufficiency is suspected. If a cosyntropin stimulation test is chosen, dexamethasone may be administered before cosyntropin without interfering with results. A short-term dexamethasone administration does not interfere with the cortisol response or with cortisol assays.
Surgical Care
No surgical management is needed in most cases. If a patient with adrenal insufficiency requires surgery, treat him or her with stress doses of glucocorticoids (eg, hydrocortisone 50-75 mg/m2 given intramuscularly or intravenously when the patient is being transported from the floor to the operating room or in advance of the planned surgery). During surgery, administer additional doses by giving either a hydrocortisone infusion at a dosage of 2-4 mg/m2/h or additional intravenous boluses of 10-25 mg/m2 every 6 hours throughout the procedure. After surgery, continue the administration of hydrocortisone in the immediate postoperative period. On the second and third postoperative days, the dosage of hydrocortisone can be decreased by 50% each day to a minimum of the patient's usual daily requirement if the patient is recovering well and has no complications. By the fourth postoperative day, the usual daily dosage of steroids may be resumed if the patient is recovering satisfactorily. If complications occur, stress doses of glucocorticoids must be continued. Fludrocortisone may be withheld on the day of surgery and while the patient is receiving stress doses of hydrocortisone. If the patient is unable to take oral fludrocortisone in the postoperative period, stress doses of hydrocortisone may be continued for a prolonged period to provide adequate mineralocorticoid activity.
Consultations
Consult an endocrinologist if adrenal insufficiency is suspected.
Diet
- Patients should eat an unrestricted diet.
- Patients with primary adrenal insufficiency should have ample access to salt because they excrete too much salt if their condition is untreated.
- Infants with primary adrenal insufficiency often need 2-5 g of sodium chloride per day.
- The patient's caloric intake may need to be monitored. Restrict the patient's caloric intake if excess weight gain occurs, because glucocorticoids stimulate appetite.
Activity
- No restrictions are necessary after adequate replacement therapy is started.
- If patients exercise in warm climates, provide them with sufficient sodium chloride to prevent hyponatremia.
Glucocorticoid replacement is required in all forms of adrenal insufficiency. Mineralocorticoid replacement is required only in primary adrenal insufficiency because aldosterone secretion is reduced in primary adrenal insufficiency but not in secondary (central) adrenal insufficiency. Treat an acute adrenal crisis (eg, hypotension, hypoglycemia) with pharmacologic doses of glucocorticoids, which can be in the form of hydrocortisone, methylprednisolone, or dexamethasone. Acute adrenal insufficiency In a hypotensive patient, rapidly administer isotonic sodium chloride solution (eg, 450 mL/m2 or 20 mL/kg) over the first hour. Follow this with the typical continuous infusion of 3200 mL/m2/d or 200 mL/kg per 100 calories of estimated energy expenditure at rest to restore intravascular volume. Dextrose must be provided. If the patient is hypoglycemic, 2-4 mL/kg of 25% dextrose in water (D25W) corrects hypoglycemia. Provide 5% dextrose in water (D5W) to prevent initial or further hypoglycemia. Potassium is generally not needed in acute situations, especially in patients with primary adrenal insufficiency, who are often hyperkalemic. After intravenous fluids are provided, administer stress doses of glucocorticoid. The recommended stress dosage of hydrocortisone is an initial dose of 50-75 mg/m2 given intravenously, followed by 50-75 mg/m2/d divided in 4 intravenous doses. Hydrocortisone may be given intramuscularly if intravenous access is unavailable. However, intramuscular administration works slowly. Comparable stress doses of methylprednisolone are 10-15 mg/m2 and dexamethasone 1-1.5 mg/m2. Dexamethasone is preferable for patients with suspected but unproved adrenal insufficiency because the physician can simultaneously treat the patient while performing a diagnostic cosyntropin stimulation test. Methylprednisolone and dexamethasone have negligible mineralocorticoid effects. Large doses of hydrocortisone (ie, even double or triple the stress doses previously mentioned) are preferred if the patient is hypovolemic, hyponatremic, or hyperkalemic. No parenteral form of a mineralocorticoid is currently available in the United States. However, if the patient has good GI function, fludrocortisone 0.1-0.2 mg may be administered. Long-term medical therapy In a child with adrenal insufficiency, long-term glucocorticoid replacement must be balanced between the need to prevent symptoms of the adrenal insufficiency and the need to allow the child to grow at a normal rate while preventing symptoms of glucocorticoid excess. Individualize the dosage for each patient. The range for hydrocortisone is 7-20 mg/m2/d given orally in 2 or 3 divided doses. Hydrocortisone is available in 5-, 10-, and 20-mg tablets. Hydrocortisone is recommended for long-term therapy because of its relatively low potency, which eases the titration of appropriate doses. In a large patient, prednisone or dexamethasone may be substituted. Estimated equivalencies are as follows: - 1 mg of prednisone = 4-10 mg of hydrocortisone
- 1 mg of dexamethasone = 50-100 mg of hydrocortisone
Patients with primary adrenal insufficiency who also have mineralocorticoid deficiency require fludrocortisone at 0.1-0.2 mg/d. Young patients must be given adequate access to sodium chloride (2-5 g/d) to counteract salt wasting. Adjust the dose of glucocorticoid for each patient on the basis of clinical criteria (eg, absence of symptoms of glucocorticoid deficiency, excessive or normal growth). In the author's experience, plasma 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. Stress and illness An important physiologic response to stress is an increase in ACTH-mediated cortisol production. Patients with adrenal insufficiency are unable to mount this response, regardless of the reason, and they must be given stress doses of glucocorticoid. When a febrile illness occurs or when a patient requires a surgical or stressful procedure, triple the dosage. If a patient is vomiting or listless, administer parenteral glucocorticoid (hydrocortisone 50-75 mg/m2 given intramuscularly or intravenously or equivalent methylprednisolone 10-15 mg/m2 or dexamethasone 1-1.5 mg/m2). Repeat the dose every 6-8 hours until patient recovers because hydrocortisone succinate has a short duration of action. Injectable glucocorticoid must be provided to all patients with adrenal insufficiency. Include instructions to the patient and caretaker about its use and importance. Mineralocorticoid therapy does not need to be tripled during periods of illness or physical stress. Glucocorticoid or mineralocorticoid replacement is not contraindicated when needed. This therapy is involved in few drug-drug interactions. Preferred glucocorticoids during pregnancy are hydrocortisone or prednisone because the placenta inactivates them. In contrast, dexamethasone readily crosses the placenta and suppresses fetal adrenal function.
Drug Category: Mineralocorticoids
Mineralocorticoids are used as replacement therapy in aldosterone deficiency and as prophylaxis against hyponatremia and hyperkalemia in patients with primary adrenal insufficiency.
| Drug Name | Fludrocortisone (Florinef) |
|---|
| Description | Drug of choice (DOC) for mineralocorticoid replacement therapy if zona glomerulosa of adrenal cortex does not produce aldosterone. Allows patient to achieve normal sodium homeostasis. Available only PO. If patient cannot tolerate PO, parenteral hydrocortisone can provide mineralocorticoid effect. Infant may require sodium chloride supplements because their diets often provide insufficient sodium. |
|---|
| Adult Dose | 0.1-0.2 mg/d PO qd or divided bid |
|---|
| Pediatric Dose | 0.05-0.2 mg/d PO |
|---|
| Contraindications | Documented hypersensitivity; systemic fungal infections |
|---|
| Interactions | Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | May cause sodium retention, hypokalemia, and hypertension; use cautiously in patients with hypertension and in patients taking potassium-depleting diuretics and digoxin; gradually taper dose when discontinuing |
|---|
Drug Category: Glucocorticoids
Glucocorticoids give patients with adrenal insufficiency the equivalent of the body's missing cortisol produced by the adrenal cortex under normal conditions and under stress. Dexamethasone and betamethasone cross the placenta to an appreciable degree; therefore, they should not be used in pregnant women unless they are specifically indicated (ie, to aid maturation of the fetal lung or to suppress fetal adrenal function).
| Drug Name | Hydrocortisone (Hydrocortone, A-Hydrocort) |
|---|
| Description | DOC because of mineralocorticoid activity and glucocorticoid effects. Equivalent to adrenal product (ie, cortisol). Has short half-life; therefore, does not inhibit growth to same degree as more potent, longer-acting synthetic glucocorticoids (eg, prednisone, methylprednisolone, dexamethasone). Because of short action, must be administered PO bid/tid; usually given q6h when administered IV.
In healthy person, mean cortisol secretion is about 7-10 mg/m2/d. Aim of replacement therapy is to supply only as much as needed. Target is best judged subjectively on basis of patient's own sense of well-being.
Dose requirements are greater PO than parenterally because some hydrocortisone is inactivated as it passes through liver. Equivalent low doses can be derived for prednisone, methylprednisolone, and dexamethasone (which have about 4, 5, and 40-50 times the potency of hydrocortisone, respectively). |
|---|
| Adult Dose | 10-20 mg/m2/d PO q6h |
|---|
| Pediatric Dose | Dosing guidelines similar to those in adults, except in patients with congenital adrenal hyperplasia.
Congenital adrenal hyperplasia: Typical mean dosage is 15 mg/m2/d; ACTH often refractory to suppression with low doses of glucocorticoid; dosages >20 mg/m2/d may lead to growth suppression; very low doses allow for unchecked secretion of adrenal androgens and adverse growth consequences |
|---|
| Contraindications | Documented hypersensitivity; pharmacologic doses generally contraindicated in viral, fungal, or TB infections |
|---|
| Interactions | Live-virus immunization may be undertaken in patients receiving corticosteroids as replacement therapy for Addison disease; phenytoin, phenobarbital, ephedrine, and rifampin may increase hepatic clearance of steroids (increased doses required); frequently check prothrombin time (PT) in patients receiving glucocorticoids and coumarin anticoagulants because steroids may inhibit (or, in rare cases, enhance) response to these anticoagulants; when administered with potassium-depleting diuretics, closely observe patients for possible hypokalemia |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | Regularly observe patients taking steroids for potential development of iatrogenic Cushing syndrome; closely monitor children for growth; caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis |
|---|
| Drug Name | Dexamethasone (Decadron) |
|---|
| Description | Provides glucocorticoid activity. At pharmacologic doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reducing capillary permeability. May be used for allergic and inflammatory conditions. |
|---|
| Adult Dose | Equivalent to 1/40th the dose of hydrocortisone; adjust dosage to clinical response |
|---|
| Pediatric Dose | Older children: Equivalent to 1/40th the dose of hydrocortisone; physiologic replacement dosage is 0.6-0.75 mg/m2/d PO divided q6-12h; titrate up or down on basis of clinical response |
|---|
| Contraindications | Documented hypersensitivity; active bacterial or fungal infection |
|---|
| Interactions | Effects decrease with coadministration of barbiturates, phenytoin and rifampin; decreases effect of salicylates and vaccines used for immunization |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | Increases risk of several complications, including severe infections; monitor for signs of adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use |
|---|
| Drug Name | Methylprednisolone (Medrol, Solu-Medrol) |
|---|
| Description | Provides glucocorticoid activity. At pharmacologic doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability. Available in liquid form, unlike hydrocortisone. |
|---|
| Adult Dose | Physiologic replacement: 2-3 mg/m2/d initially; titrate up or down on basis of clinical response |
|---|
| Pediatric Dose | Not established but may be used if hydrocortisone use problematic.
Physiologic replacement: 2-3 mg/m2/d initially; titrate up or down depending on clinical response |
|---|
| Contraindications | Documented hypersensitivity; viral, fungal, or TB infections |
|---|
| Interactions | Coadministration with digoxin may increase digitalis toxicity due to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia if concurrently taking diuretics |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | Possible complications of glucocorticoids include hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections |
|---|
| Drug Name | Prednisone (Liquid Pred, Prednisone Intensol Concentrate, Deltasone) |
|---|
| Description | Provides glucocorticoid activity. At pharmacologic doses, decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability. Available in liquid form. |
|---|
| Adult Dose | Physiologic replacement: 2-4 mg/m2/d initially; titrate up or down depending on clinical response |
|---|
| Pediatric Dose | Not established but may be used if hydrocortisone problematic.
Physiologic replacement: 2-4 mg/m2/d initially; titrate up or down depending on clinical response |
|---|
| Contraindications | Documented hypersensitivity; viral, fungal, or TB infections |
|---|
| Interactions | Coadministration with digoxin may increase digitalis toxicity due to hypokalemia; phenobarbital, phenytoin and rifampin may decrease levels (adjust dosage); monitor patients for hypokalemia if concurrently taking diuretics |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | Possible complications of glucocorticoids include hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections |
|---|
Further Outpatient Care
- Monitor the adequacy of dosing in patients receiving long-term glucocorticoid therapy.
- Too little glucocorticoid causes symptoms of adrenal insufficiency, such as anorexia, nausea, vomiting, abdominal pain, asthenia, poor weight gain, and weight loss.
- Too much glucocorticoid causes excessive weight gain, cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure.
- In children, growth failure is a sensitive indicator of exposure to excessive glucocorticoids.
- If adrenal insufficiency has an autoimmune etiology, monitor patients for the development of associated autoimmune phenomena, such as hypoparathyroidism, hypogonadism, vitiligo, pernicious anemia, thyroid dysfunction, and diabetes mellitus.
In/Out Patient Meds
In addition to the standard maintenance drugs described above for use in patients with adrenal insufficiency (see Medication), provide injectable hydrocortisone. Patients and their family members should use this medication when an impending adrenal crisis becomes apparent or when the patient cannot tolerate oral drugs. An intramuscular injection of hydrocortisone (eg, 25 mg for infants, 50 mg for children, 100 mg for adults) can be lifesaving in the interval before the patient receives professional medical care. If this injection is not possible, rectal hydrocortisone can be used until systemic glucocorticoids can be administered.
Deterrence/Prevention
Iatrogenic adrenal insufficiency due to glucocorticoid therapy can be prevented by giving the patient dosages below his or her physiologic requirements. Treatment with alternate-day oral prednisone, or with topical or inhaled glucocorticoids, can reduce the risk of iatrogenic adrenal insufficiency.
Complications
Hypotension, shock, hypoglycemia, and death are the primary complications of adrenal insufficiency. Complications of excessive glucocorticoids include the following: - Growth failure
- Obesity
- Striae
- Osteoporosis
- Muscle weakness
- Hypertension
- Hyperglycemia
- Cataracts
Daily oral glucocorticoid therapy may provide iatrogenic suppression of the hypothalamic-pituitary-adrenal axis within 2 weeks. Effects can last for weeks to months depending on the duration of exposure to pharmacologic doses of glucocorticoids. Complications of excessive administration of mineralocorticoids include hypertension and hypokalemia.
Prognosis
- The prognosis for an untreated patient is poor. Death is a common outcome unless replacement steroid therapy is begun.
- With proper treatment and compliance, patients can live a normal life span without limitations.
Patient Education
- Teach patients and their caretakers about the consequences and potential for death if adequate replacement therapy is not provided.
- Teach patients and their caretakers how to administer supplemental glucocorticoid in times of illness or traumatic stress. Include education about how to administer an injectable glucocorticoid when the patient is vomiting or unable to take oral stress doses. Periodically reinforce this information because caretakers are often reluctant to inject medications.
- Advise patients and their caretakers to immediately seek medical help if the patient becomes ill.
Medical/Legal Pitfalls
- Physicians must consider adrenal insufficiency in the differential diagnosis of patients with suggestive symptoms, such as chronic fatigue, anorexia, nausea, vomiting, diarrhea, unexplained weight loss, dehydration, hypoglycemia, and hypotension.
- Do not forget that chronic infections, such as TB and HIV infection, can impair adrenal function.
- The possibility of central adrenal insufficiency must be investigated, identified, and treated in all patients who have undergone pituitary surgery, irradiation, or prolonged treatment with glucocorticoids.
- Advise patients to wear or carry a medical alert tag or card at all times to help them receive appropriate emergency care if they are found unconscious.
Special Concerns
Dosage requirements may increase during pregnancy.
| Media file 1:
Left, Photograph shows hyperpigmentation on the dorsum of the hand before the treatment of primary adrenal insufficiency. Right, Photograph shows normal pigmentation after treatment. |
 |  View Full Size Image | |
Media type: Photo
|
| Media file 2:
Left, Photograph in a patient with Addison disease shows prominent pigmentation in areas not exposed to the sun, such as the palmar creases. Right, Photograph shows normal pigmentation after treatment. |
 | View Full Size Image | |
Media type: Photo
|
| Media file 3:
Left, Vitiligo in a patient with autoimmune adrenalitis. Right, Note the area of hyperpigmentation surrounding the vitiligo. |
 | View Full Size Image | |
Media type: Photo
|
| Media file 4:
Illustration shows the hypothalamic-pituitary-adrenal axis under normal circumstances and in primary adrenal insufficiency. ACTH = corticotropic hormone; CRH = corticotropin-releasing hormone. |
 | View Full Size Image | |
Media type: Illustration
|
| Media file 5:
Left, Photomicrograph shows autoimmune adrenalitis. Right, Photomicrograph shows tuberculous adrenalitis. Note the caseous granuloma. |
 | View Full Size Image | |
Media type: Histology
|
| Media file 6:
CT scan shows enlarged adrenal glands in a patient with early active autoimmune adrenalitis. Patients with chronic disease present with the opposite picture of hypotrophic adrenals. |
 | View Full Size Image | |
Media type: CT
|
- Willis AC, Vince FP. The prevalence of Addison's disease in Coventry, UK. Postgrad Med J. May 1997;73(859):286-8. [Medline].
- Laureti S, Vecchi L, Santeusanio F, Falorni A. Is the prevalence of Addison's disease underestimated? [letter]. J Clin Endocrinol Metab. May 1999;84(5):1762. [Medline]. [Full Text].
- Andersson HC, Frentz J, Martínez JE, Tuck-Muller CM, Bellizaire J. Adrenal insufficiency in Smith-Lemli-Opitz syndrome. Am J Med Genet. Feb 19 1999;82(5):382-4. [Medline].
- Arlt W, Allolio B. Adrenal insufficiency. Lancet. May 31 2003;361(9372):1881-93. [Medline].
- Besser GM, Thorner MO. Adrenal insufficiency. In: Clinical Endocrinology. [CD-ROM]. St Louis, Mo: Mosby-Year Book; 1996.
- Clark A, Weber A. Molecular insights into inherited ACTH resistance syndromes. Trends Endocrinol Metab. 1994;5:209-14. [Full Text].
- Dickstein G. Commentary to the article: Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease [letter]. J Clin Endocrinol Metab. Dec 1998;83(12):4531-3. [Medline]. [Full Text].
- Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. Mar 2004;36(3):228-30. [Medline].
- Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, von Petrykowski W. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child. Jun 1993;68(6):779-82. [Medline].
- Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. Feb 1 2001;10(3):283-90. [Medline].
- Heckmann M, Hartmann MF, Kampschulte B, Gack H, Bödeker RH, Gortner L. Cortisol production rates in preterm infants in relation to growth and illness: a noninvasive prospective study using gas chromatography-mass spectrometry. J Clin Endocrinol Metab. Oct 2005;90(10):5737-42. [Medline]. [Full Text].
- Kamoi K, Tamura T, Tanaka K, Ishibashi M, Yamaji T. Hyponatremia and osmoregulation of thirst and vasopressin secretion in patients with adrenal insufficiency. J Clin Endocrinol Metab. Dec 1993;77(6):1584-8. [Medline]. [Full Text].
- Korenke GC, Roth C, Krasemann E, Hüfner M, Hunneman DH, Hanefeld F. Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy: clinical, laboratory and genetic findings. Eur J Endocrinol. Jul 1997;137(1):40-7. [Medline]. [Full Text].
- Lalli E, Sassone-Corsi P. DAX-1 and the adrenal cortex. Curr Opin Endocrinol Diabetes. 1999;6:185-90. [Full Text].
- Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med. Oct 30 1997;337(18):1285-92. [Medline].
- Laureti S, Casucci G, Santeusanio F, Angeletti G, Aubourg P, Brunetti P. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients. J Clin Endocrinol Metab. Feb 1996;81(2):470-4. [Medline]. [Full Text].
- Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab. May 1998;83(5):1558-62. [Medline]. [Full Text].
- McKusick VA, et al. OMIM Online Mendelian Inheritance in Man. Baltimore, Md: Johns Hopkins University. Available at http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM.
- Orme LM, Bond JD, Humphrey MS, Zacharin MR, Downie PA, Jamsen KM. Megestrol acetate in pediatric oncology patients may lead to severe, symptomatic adrenal suppression. Cancer. Jul 15 2003;98(2):397-405. [Medline].
- Orth DN, Kovacs WJ. The adrenal cortex. In: Williams RH, Foster DW, Kronenberg HM, eds. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders; 1998:547-65.
- Pandey AV, Flück CE, Huang N, Tajima T, Fujieda K, Miller WL. P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes. Endocr Res. Nov 2004;30(4):881-8. [Medline].
- Perry R, Kecha O, Paquette J, Huot C, Van Vliet G, Deal C. Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. Jun 2005;90(6):3243-50. [Medline]. [Full Text].
- Peter M, Viemann M, Partsch CJ, Sippell WG. Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene. J Clin Endocrinol Metab. Aug 1998;83(8):2666-74. [Medline]. [Full Text].
- Purandare A, Godil MA, Prakash D, Parker R, Zerah M, Wilson TA. Spontaneous adrenal hemorrhage associated with transient antiphospholipid antibody in a child. Clin Pediatr (Phila). Jun 2001;40(6):347-50. [Medline].
- Thaler LM. Comment on the low-dose corticotropin stimulation test is more sensitive than the high-dose test. [letter]. J Clin Endocrinol Metab. Dec 1998;83(12):4530-1; author reply 4532-3. [Medline].
- Barone MA, ed. The Harriet Land Handbook. 1996:681.
- Tordjman K, Jaffe A, Greenman Y, Stern N. Comments on the comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab. Dec 1998;83(12):4530; author reply 4532-3. [Medline].
- Tsigos C, Arai K, Hung W, Chrousos GP. Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. J Clin Invest. Nov 1993;92(5):2458-61. [Medline]. [Full Text].
Adrenal Insufficiency excerpt Article Last Updated: Oct 23, 2007
|
