The adult adrenal cortex consists of three zones responsible for synthesis of different steroids:
Outermost zona glomerulosa—aldosterone.
Middle zona fasciculata—cortisol and small amounts of mineralocorticoids.
Innermost zona reticularis—androgens and estrogens.
A fetal zone, or provisional cortex, predominates during fetal development and produces glucocorticoids, mineralocorticoids, androgens, and estrogens. The fetal zone is relatively deficient in 3β-hydroxysteroid dehydrogenase (see Figure 34–8); hence, placental progesterone is the major precursor for fetal adrenal production of cortisol and aldosterone.
The adrenal cortical production of cortisol is under the control of pituitary adrenocorticotropic hormone (ACTH; see Figure 34–1 and Table 34–1), which is in turn regulated by hypothalamic corticotropin-releasing hormone (CRH). ACTH concentration is greatest during the early morning hours with a smaller peak in the late afternoon and a nadir at night. The pattern of serum cortisol concentration follows this pattern with a lag of a few hours. In the absence of cortisol feedback, there is dramatic CRH and ACTH hypersecretion.
Glucocorticoids are critical for gene expression in a many cell types. Glucocorticoids also help maintain blood pressure by promoting peripheral vascular tone and sodium and water retention. In excess, glucocorticoids are both catabolic and antianabolic; they promote the release of amino acids from muscle and increase gluconeogenesis while decreasing incorporation of amino acids into muscle protein. They also antagonize insulin activity and facilitate lipolysis.
Mineralocorticoids (primarily aldosterone in humans) promote sodium retention and stimulate potassium excretion in the distal renal tubule. The predominant regulator of aldosterone secretion is the volume- and sodium-sensitive renin-angiotensin-aldosterone system. Hyperkalemia also directly stimulates aldosterone release from the adrenal.
Androgen (dehydroepiandrosterone and androstenedione) production by the zona reticularis is insignificant before puberty. At the onset of puberty, androgen production increases and is an important contributor to pubertal development in both sexes; the adrenal gland is the major source of androgen in females.
ADRENOCORTICAL INSUFFICIENCY (ADRENAL CRISIS, ADDISON DISEASE)
Adrenal insufficiency may be primary—due to disorders of the adrenal gland itself, or central—due to disorders of CRH and/or ACTH secretion.
The causes of primary adrenal insufficiency include the following:
Hereditary enzyme defects (congenital adrenal hyperplasia).
Autoimmune destruction of the glands (Addison disease)—Addison disease may be familial and can be isolated or associated with hypoparathyroidism, mucocutaneous candidiasis, hypothyroidism, pernicious anemia, hypogonadism, and diabetes mellitus in one of the polyglandular autoimmune syndromes.
Destruction of the gland by tumor, calcification, or hemorrhage (Waterhouse-Friderichsen syndrome).
Adrenal disease secondary to opportunistic infections (fungal or tuberculous) such as in immunocompromised patients.
Rare forms of genetic adrenal insufficiency occur in association with cerebral sclerosis and spastic paraplegia (adrenoleukodystrophy); muscular dystrophy, hypogonadotropic hypogonadism, and glycerol kinase deficiency (congenital adrenal hypoplasia); or with achalasia and alacrima (Allgrove) syndromes.
Salt-losing disorders can occur due to homozygous mutations of aldosterone synthase (CYP11B2) or from partial or complete unresponsiveness of the mineralocorticoid receptor to aldosterone (pseudohypoaldosteronism). A transient autosomal dominant form of pseudohypoaldosteronism has been reported in infancy.
The causes of central adrenal insufficiency include the following:
Intracranial neoplasm or its treatment.
Congenital midline defects associated with optic nerve hypoplasia (septo-optic dysplasia).
Chronic iatrogenic exposure to exogenous glucocorticoids.
Anterior pituitary tumor is a rare cause of central glucocorticoid deficiency.
Acute illness, surgery, trauma, or hyperthermia may precipitate an adrenal crisis in patients with adrenal insufficiency. Patients with primary adrenal insufficiency are at greater risk for life-threatening crisis than patients with central ACTH deficiency because mineralocorticoid secretion and some autonomous cortisol secretion remain intact in central ACTH deficiency.
1. Acute form (adrenal crisis)
Nausea, vomiting, diarrhea, abdominal pain; dehydration; fever (sometimes followed by hypothermia); weakness; hypotension and circulatory collapse; confusion and coma.
Fatigue; hypotension; weakness; weight loss or failure to gain weight; salt craving (primary insufficiency); vomiting and dehydration; recurrent hypoglycemia; a small heart on chest radiograph. Diffuse tanning occurs with increased pigmentation over pressure points, scars, and mucous membranes in primary adrenal insufficiency due to melanocyte stimulating activity of alternate products of hypersecreted pro-opiomelanocortin, the parent molecule of ACTH.
1. Suggestive of adrenocortical insufficiency
Primary adrenal insufficiency
Decreased—serum sodium, serum bicarbonate, arterial CO2, blood pH, and blood volume.
Increased—serum potassium, urea nitrogen levels.
Urinary sodium and the ratio of urinary sodium to potassium inappropriate for the degree of hyponatremia.
Central adrenal insufficiency—serum sodium levels may be mildly decreased as a result of impaired water excretion but true salt-wasting is not present.
Eosinophilia and moderate lymphopenia occur in both forms of insufficiency.
a. Acth (cosyntropin) stimulation test
Primary adrenal insufficiency—plasma cortisol less than 18 mcg/dL 30 and 60 minutes after 250 mcg of cosyntropin given intravenously and failure of aldosterone to rise above baseline
Central adrenal insufficiency—plasma cortisol less than 18 mcg/dL 30 and 60 minutes after 1 mcg of cosyntropin given intravenously
b. Baseline serum acth concentration—Elevated in primary adrenal failure and low/low-normal in central adrenal insufficiency
c. Urinary free cortisol—Decreased
d. CRH test—After administration of ovine CRH, serum concentrations of ACTH and cortisol are measured. Localization of the site of impairment is possible based on careful interpretation of results. The CRH test has not been widely used in pediatrics.
Acute adrenal insufficiency must be differentiated from sepsis, diabetic coma, CNS disturbances, and acute poisoning. In the neonatal period, adrenal insufficiency may be clinically indistinguishable from respiratory distress, intracranial hemorrhage, or sepsis. Chronic adrenocortical insufficiency must be differentiated from anorexia nervosa, certain muscular disorders (myasthenia gravis), salt-losing nephropathy, and chronic debilitating infections.
A. Acute Insufficiency (Adrenal Crisis)
Hydrocortisone sodium succinate (50 mg/m2 intravenously over 2–5 minutes or intramuscularly) is given initially followed by 12.5 mg/m2, every 4–6 hours until stabilization is achieved and oral therapy can be tolerated. Cortisol replacement is critical because pressor agents may be ineffective with cortisol insufficiency.
2. Fluids and electrolytes
In primary adrenal insufficiency, 5%–10% glucose in normal saline, 10–20 mL/kg intravenously, is given over the first hour and repeated if necessary to reestablish vascular volume. Normal saline is continued thereafter at 1.5–2 times maintenance fluid requirements until volume and electrolytes have normalized. In central adrenal insufficiency, routine fluid management is generally adequate after initial restoration of vascular volume and institution of cortisol replacement.
Treatment with fludrocortisone, a mineralocorticoid agonist, is not required acutely, as hydrocortisone in stress doses has adequate mineralocorticoid action. When oral intake is tolerated, fludrocortisone, is started, 0.05–0.15 mg daily, and continued every 12–24 hours for primary adrenal insufficiency.
4. Waterhouse-Friderichsen syndrome with fulminant infections
Corticosteroids should be considered if there is possible adrenal insufficiency, particularly if there is hypotension and circulatory collapse.
A maintenance dosage of 6–10 mg/m2/day of hydrocortisone (or equivalent) is given orally in two or three divided doses. The dosage of all glucocorticoids is increased to 30–50 mg/m2/day during intercurrent illnesses or other times of stress (fever > 101.5°F, trauma, surgery, or systemic illness) and should also be increased during significant diarrhea due to reduced absorption. Families should be encouraged to give stress doses of hydrocortisone if they have concerns, as brief exposure to stress doses of hydrocortisone will not have adverse effects. Rarely, families become overly anxious and give stress doses frequently. This should be avoided as it can contribute to obesity, growth retardation, and other cushingoid features.
In primary adrenal insufficiency, fludrocortisone is given, 0.05–0.15 mg orally daily as a single dose or in two divided doses. Periodic monitoring of blood pressure is recommended to avoid overdosing.
Children should be given ready access to table salt. In the infant, supplementation of breast milk or formula with 3–5 mEq Na+/kg/day is generally required until table foods are introduced.
C. Corticosteroids in Patients with Adrenocortical Insufficiency Who Undergo Surgery
Hydrocortisone sodium succinate, 30–50 mg/m2 IM or intravenously 1 hour before surgery.
Hydrocortisone sodium succinate, 12.5 mg/m2 intravenously or intramuscularly every 4 hours.
Hydrocortisone sodium succinate, 12.5 mg/m2 intravenously or intramuscularly every 4–6 hours until oral doses are tolerated. The oral stress hydrocortisone dose (30–50 mg/m2/day) is continued until the acute stress is over, at which time the patient can be returned to the maintenance dose.
The course of acute adrenal insufficiency is rapid and death may occur within a few hours, particularly in infants, unless adequate treatment is given. Spontaneous recovery is unlikely. Patients who have received long-term treatment with glucocorticoids may exhibit adrenal collapse if they undergo surgery or other acute stress, though central adrenal insufficiency is usually less severe. Pharmacologic doses of glucocorticoids during these episodes may be needed throughout life. In all forms of acute adrenal insufficiency, the patient should be observed carefully once the crisis has passed and evaluated with laboratory tests to assess the degree of permanent adrenal insufficiency.
J: The diagnosis and treatment of adrenal insufficiency during childhood and adolescence. Arch Dis Child 2016 Sep;101(9):860–865
T: The clinical manifestations, diagnosis, and treatment of adrenal emergencies. Emerg Med Clin North Am 2014 May;32(2):367–378
CONGENITAL ADRENAL HYPERPLASIAS
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES–CONGENITAL
Genital virilization in females, with labial fusion, urogenital sinus, enlargement of the clitoris, or other evidence of androgen action.
Salt-losing crises in infant males or isosexual precocity in older males with infantile testes.
Increased linear growth and advanced skeletal maturation.
Elevation of plasma 17-hydroxyprogesterone concentrations in the most common form; may be associated with hyponatremia, hyperkalemia, and metabolic acidosis, particularly in newborns.
Autosomal recessive mutations in the enzymes of adrenal steroidogenesis cause impaired cortisol biosynthesis with increased ACTH secretion. ACTH excess subsequently results in adrenal hyperplasia with increased production of adrenal hormone precursors that are metabolized through the unblocked androgen pathway. Increased pigmentation, especially of the scrotum, labia majora, and nipples, is common due to excessive ACTH secretion. CAH is most commonly (> 90% of patients) the result of homozygous or compound heterozygous mutations in the cytochrome P-450 C21 (CYP21A2) gene causing 21-hydroxylase deficiency (see Figure 34–8). The defective gene is present in 1:250–1:100 people and the worldwide incidence of the disorder is 1:15,000, with increased incidence in certain ethnic groups. In its severe form, excess adrenal androgen production starting in the first trimester of fetal development causes virilization of the female fetus and life-threatening hypovolemic, hyponatremic shock (adrenal crisis) in the newborn, if untreated. There are also other enzyme defects that less commonly result in CAH. The clinical syndromes associated with these defects are shown in Figure 34–8 and Table 34–10.
Table 34–10.Clinical and laboratory findings in adrenal enzyme defects resulting in congenital adrenal hyperplasia. ||Download (.pdf) Table 34–10. Clinical and laboratory findings in adrenal enzyme defects resulting in congenital adrenal hyperplasia.
|Enzyme Deficiencya ||Elevated Plasma Metabolite ||Plasma Androgens ||Aldosterone ||Hypertension/Salt Loss ||External Genitalia |
|StAR protein ||– ||↓↓↓ ||↓↓↓ ||–/+ || |
|3β-Hydroxysteroid-dehydrogenase ||17-OH pregnenolone (DHEA) ||↑ (DHEA) ||↓↓↓ ||–/+ || |
Females: possibly virilized
|17α-Hydroxylase/17-20 lyase ||Progesterone ||↓↓ ||(↑ DOC) ||+/– || |
Females: normal, absent puberty
|21-Hydroxylasea ||17-OHP ||↑↑ ||↓↓ ||–/+ || |
|11β-Hydroxylase ||11-Deoxycortisol, DOC ||↑↑ ||(↑ DOC) ||+/– || |
|P450 oxidoreductase ||17-OHP (mild elevation) ||↓↓ ||Normal or mildly elevated ||+/– || |
Prenatal diagnosis is now possible and newborn screening by measurement of serum 17-hydroxyprogesterone has been established in all 50 US states and many other countries worldwide.
In nonclassic presentations of 21-hydroxylase deficiency, affected individuals have a normal phenotype at birth but develop virilization during later childhood, adolescence, or early adulthood. Hormonal studies are characteristic of 21-hydroxylase deficiency, with cosyntropin stimulated 17-OHP levels intermediate between those of nonaffected individuals and those with the classic form of the disease. Individuals with the nonclassic form of the disease may be asymptomatic or only mildly symptomatic, but they can carry a severe CYP21A2 mutation resulting in offspring with the classic form.
Abnormality of the external genitalia varies from mild enlargement of the clitoris to complete fusion of the labioscrotal folds, forming an empty scrotum, a penile urethra, a penile shaft, and clitoral enlargement sufficient to form a normal-sized glans (see Figure 34–7). Signs of adrenal insufficiency (salt loss) typically appear 5–14 days after birth. With milder enzyme defects, clinically apparent salt loss may not occur and virilization predominates with accelerated growth and skeletal maturation. Pubic hair appears early, acne may be excessive, and the voice may deepen. Excessive pigmentation may develop. Isosexual central precocious puberty may occur if treatment is not initiated before the bone age is significantly advanced. Final adult height is often compromised.
The male infant usually appears normal at birth but may present with salt-losing crisis in the first weeks of life. In milder forms, salt-losing crises may not occur and virilization predominates, with enlargement of the penis and increased pigmentation, as well as other symptoms and signs similar to those of affected females. The testes are not enlarged unless there are rare adrenal rests in the testes producing asymmetrical enlargement. In some rare enzyme defects, ambiguous genitalia may be present due to impaired androgen production (see Figure 34–8).
Hormonal studies are essential for accurate diagnosis. Findings characteristic of the enzyme deficiencies are shown in Table 34–10.
Rapid assessment of genetic sex should be obtained in any newborn with ambiguous genitalia since 21-hydroxylase deficiency is the most common cause of ambiguity in females.
Assessment of urinary steroid metabolites is no longer routine, but is reserved for rare forms of CAH.
Imaging is generally not required to make the diagnosis of CAH. Ultrasonography, CT scanning, and MRI may be useful in defining pelvic anatomy or to exclude an adrenal tumor.
Treatment goals in CAH are to provide the smallest dose of glucocorticoid that will adequately suppress excess androgen precursors and produce normalization of growth velocity and skeletal maturation; excessive glucocorticoids cause the undesirable side effects of Cushing syndrome. Mineralocorticoid replacement sustains normal electrolyte homeostasis, but excessive mineralocorticoids cause hypertension and hypokalemia.
Supraphysiologic doses of hydrocortisone are often needed to suppress androgen excess in CAH. Initially, parenteral or oral hydrocortisone (30–50 mg/m2/day) is provided until suppression of abnormal adrenal steroidogenesis has been accomplished, as evidenced by normalization of serum 17-hydroxyprogesterone. Subsequently, patients are placed on maintenance doses of 10–15 mg/m2/day in three divided doses. Dosage is adjusted to maintain normal growth rate and skeletal maturation. Serum 17-hydroxyprogesterone and androstenedione are usually used to monitor therapy; however, no one test is universally accepted. In pregnant females with CAH, suppression of adrenal androgen secretion is critical to avoid virilization of the fetus, particularly a female fetus. Hydrocortisone is the preferred choice for glucocorticoid replacement therapy in pregnant women with CAH because it does not cross the placenta.
Fludrocortisone, 0.05–0.15 mg, is given orally once a day or in two divided doses. Periodic monitoring of blood pressure and plasma renin activity are recommended to avoid overdosing.
For affected females, consultation with a urologist or gynecologist experienced in female genital reconstruction should be arranged as soon as possible during infancy.
When initiated in early infancy, treatment with glucocorticoids permits normal growth, development, and sexual maturation. If not adequately controlled, CAH results in sexual precocity and masculinization throughout childhood. Affected individuals will be tall as children but short as adults because of rapid skeletal maturation and premature closure of the epiphyses. If treatment is delayed or inadequate, true central precocious puberty may occur in males and females.
Patient education stressing lifelong therapy is important to ensure compliance in adolescence and later life. Virilization and multiple surgical genital reconstructions may be associated with risk of psychosexual disturbances in female patients and ongoing psychological evaluation and support is a critical component of care.
DP: Management of adolescents with congenital adrenal hyperplasia. Lancet Diabetes Endocrinol 2013 Dec;1(4):341–352
et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133–4160
ADRENOCORTICAL HYPERFUNCTION (CUSHING DISEASE, CUSHING SYNDROME)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Truncal adiposity, thin extremities, moon facies, muscle wasting, weakness, plethora, easy bruising, purple striae, decreased growth rate, and delayed skeletal maturation.
Hypertension, osteoporosis, and glycosuria.
Elevated urinary free cortisol, elevated midnight salivary cortisol.
Cushing syndrome may result from excessive autonomous secretion of adrenal steroids (adrenal adenoma or carcinoma), excess pituitary ACTH secretion (Cushing disease), ectopic ACTH or CRH secretion, or chronic exposure to exogenous glucocorticoids. In children younger than 12 years, Cushing syndrome is usually iatrogenic. It is less commonly due to adrenal tumor, adrenal hyperplasia, pituitary adenoma, or extrapituitary ACTH-producing tumor.
Adiposity, most marked on the face, neck, and trunk—a fat pad (buffalo hump) in the interscapular area is characteristic but not diagnostic; fatigue; plethoric facies; purplish striae; easy bruising; osteoporosis and back pain; hypertension and glucose intolerance; muscle wasting and weakness; retardation of growth and skeletal maturation.
2. Excess mineralocorticoid
Hypokalemia and mild hypernatremia; increased blood volume; edema; hypertension.
Hirsutism; acne; virilization; and menstrual irregularities.
a. Plasma cortisol—Values are generally elevated, with loss of normal diurnal variation. Determination of cortisol level at the expected nadir between midnight and 2 am is a sensitive indicator of the loss of diurnal variation.
b. Serum electrolytes—Serum sodium and bicarbonate are mildly elevated, with metabolic alkalosis, while potassium may be low.
c. Serum ACTH—Morning ACTH concentration is decreased in adrenal tumors and increased with ACTH- or CRH-producing pituitary or extrapituitary tumors.
Salivary cortisol obtained at midnight is a noninvasive and highly specific and sensitive test for hypercortisolism.
3. 24-Hour urinary free cortisol excretion
Measurement of urinary free cortisol/creatinine ratio is a useful way to document hypercortisolism, though midnight salivary cortisol is now considered a more practical and specific alternative.
4. Response to dexamethasone suppression testing
Suppression of adrenal function by a small dose (0.5–1.0 mg) of dexamethasone is seen in children who may have elevated urinary free cortisol excretion due to obesity, but not in children with an ACTH-secreting tumor or adrenal tumor. Larger doses (4–16 mg/day in four divided doses) of dexamethasone cause suppression of adrenal activity when the disease is due to ACTH hypersecretion by a pituitary tumor, whereas hypercortisolism due to adrenal adenomas or adrenal carcinomas is rarely suppressed.
The CRH stimulation test, in conjunction with petrosal sinus sampling, is used to distinguishing pituitary and ectopic sources of ACTH excess and to assess lateralization prior to surgery.
Pituitary imaging may demonstrate a pituitary adenoma. Adrenal imaging by CT scan may demonstrate adenoma or bilateral hyperplasia. MRI and nuclear medicine studies of the adrenals may be useful in complex cases. Skeletal maturation is usually delayed.
Children with exogenous obesity accompanied by striae and hypertension are often suspected of having Cushing syndrome. However, children with Cushing syndrome have a poor growth rate, relatively short stature, and delayed skeletal maturation, while those with exogenous obesity usually have a normal or slightly increased growth rate, normal to tall stature, and advanced skeletal maturation. The color of the striae (purplish in Cushing syndrome, pink in obesity) and the distribution of the obesity may assist in differentiation. The urinary-free cortisol excretion (in milligrams per gram of creatinine) may be mildly elevated in obesity, but midnight salivary cortisol is normal and cortisol secretion is suppressed by a relatively small dose of dexamethasone.
In all cases of primary adrenal hyperfunction due to tumor, surgical removal is indicated if possible. Glucocorticoids should be administered parenterally in pharmacologic doses during and after surgery until the patient is stable. Supplemental oral glucocorticoids, potassium, salt, and mineralocorticoids may be necessary until the suppressed contralateral adrenal gland recovers, sometimes over a period of several months. Mitotane, a DDT derivative toxic to the adrenal cortex, is often used as adjuvant therapy, but increases glucocorticoid requirements. Similarly, pituitary adenomas and ectopic sources of ACTH or CRH are generally treated surgically. Recurrent adenomas may respond to irradiation.
If the adrenal tumor is malignant, the prognosis is poor if it cannot be completely removed. If it is benign, cure is to be expected following proper preparation and surgery. The prognosis in pituitary adenoma is generally good, though the occurrence of pituitary hormone deficiencies is variable, depending on the extent of the surgery and additional therapies. Prognosis in Cushing syndrome caused by ectopic ACTH or CRH secretion depends on the nature of the tumor of origin.
CA: Diagnosis and clinical genetics of Cushing syndrome in pediatrics. Endocrinol Metab Clin North Am 2016 Jun;45(2):311–328
Primary hyperaldosteronism may be caused by an adrenal adenoma or adrenal hyperplasia. It is characterized by paresthesias, tetany, weakness, periodic paralysis; nocturnal enuresis; hypokalemia, hypernatremia, metabolic alkalosis, alkaline urine; hypertension; glucose intolerance; elevated plasma and urinary aldosterone; and suppressed plasma renin activity.
Primary hyperaldosteronism is rare in pediatrics. However, there are three recognized genetic causes (types I–III). Type I (glucocorticoid remediable hyperaldosteronism) is due to a hybrid of the genes encoding 11β-hydroxylase and aldosterone synthase. Type III results from mutations in the KCNJ5 gene encoding a K+ channel. Somatic mutations of this gene are also seen in later onset hyperaldosteronism. The cause for type II is unknown.
Treatment is with glucocorticoids (type I), spironolactone (type II), or subtotal or total adrenalectomy for hyperplasia or tumor.
et al: The management of primary aldosteronism: Case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016 May;101(5):1889–1916
USES OF GLUCOCORTICOIDS & ADRENOCORTICOTROPIC HORMONE IN TREATMENT OF NONENDOCRINE DISEASES
Glucocorticoids are used for their anti-inflammatory and immunosuppressive properties in a variety of conditions in childhood. Pharmacologic doses are necessary to achieve these effects, and side effects are common. Numerous synthetic preparations possessing variable ratios of glucocorticoid to mineralocorticoid activity are available (Table 34–11).
Table 34–11.Potency equivalents for adrenocorticosteroids. ||Download (.pdf) Table 34–11. Potency equivalents for adrenocorticosteroids.
When prolonged use of pharmacologic doses of glucocorticoids is necessary, clinical manifestations of Cushing syndrome are common. Side effects may occur with the use of synthetic exogenous agents by any route, including inhalation and topical administration, or with the use of ACTH. Alternate-day therapy lessens the incidence and severity of some of the side effects (Table 34–12).
Table 34–12.Side effects of glucocorticoid use. ||Download (.pdf) Table 34–12. Side effects of glucocorticoid use.
Endocrine and metabolic effects
Hyperglycemia and glycosuria (chemical diabetes)
Persistent suppression of pituitary-adrenal responsiveness to stress with resultant hypoadrenocorticism
Effects on electrolytes and minerals
Marked retention of sodium and water, producing edema, increased blood volume, and hypertension (more common in endogenous hyperadrenal states)
Potassium loss with symptoms of hypokalemia
Effects on protein metabolism and skeletal maturation
Negative nitrogen balance, with loss of body protein and bone-protein, resulting in osteoporosis, pathologic fractures, and aseptic bone necrosis
Suppression of growth, retarded skeletal maturation
Muscular weakness and wasting
Effects on the gastrointestinal tract
Excessive appetite and intake of food
Activation or production of peptic ulcer
Gastrointestinal bleeding from ulceration or from unknown cause (particularly in children with hepatic disease)
Fatty liver with embolism, pancreatitis, nodular panniculitis
Lowering of resistance to infectious agents; silent infection; decreased inflammatory reaction
Susceptibility to bacterial, fungal, and parasitic infections
Activation of tuberculosis; false-negative tuberculin reaction
Reactivation and poor containment of herpesviruses
Euphoria, excitability, psychotic behavior, and status epilepticus with electroencephalographic changes
Increased intracranial pressure with pseudotumor cerebri syndrome
Hematologic and vascular effects
Bleeding into the skin as a result of increased capillary fragility
Thrombosis, thrombophlebitis, cerebral hemorrhage
Myocarditis, pleuritis, and arteritis following abrupt cessation of therapy
Acne (in older children), hirsutism, amenorrhea, irregular menses
Posterior subcapsular cataracts; glaucoma
Tapering of Pharmacologic Doses of Steroids
Prolonged use of pharmacologic doses of glucocorticoids causes suppression of ACTH secretion and consequent adrenal atrophy; the abrupt discontinuation of glucocorticoids may result in adrenal insufficiency. ACTH secretion generally does not restart until the administered steroid has been given in subphysiologic doses (< 6 mg/m2/day orally) for several weeks.
If pharmacologic glucocorticoid therapy has been given for less than 10–14 days, the drug can be discontinued abruptly because adrenal suppression will be short-lived. However, it is advisable to educate the patient and family about the signs and symptoms of adrenal insufficiency in case problems arise.
If tapering is necessary in treating the condition for which the glucocorticoid is prescribed, a reduction of 25%–50% every 2–7 days is sufficiently rapid to permit observation of clinical symptomatology. An alternate-day schedule (single dose given every 48 hours) will allow for a 50% decrease in the total 2-day dosage while providing the desired pharmacologic effect. If tapering is not required for the underlying disease, the dosage can be safely decreased to the physiologic range. Although a rapid decrease in dose to the physiologic range will not lead to frank adrenal insufficiency (because adequate exogenous cortisol is being provided), some patients may experience a steroid withdrawal syndrome, characterized by malaise, insomnia, fatigue, and loss of appetite. These symptoms may necessitate a two- or three-step decrease in dose to the physiologic range.
Once a physiologic equivalent dose (8–10 mg/m2/day hydrocortisone or equivalent) is achieved and the patient’s underlying disease is stable, the dose can be decreased to 4–5 mg/m2/day given only in the morning. This will allow the adrenal axis to recover. After this dose has been given for 4–6 weeks, endogenous adrenal activity is assessed by obtaining fasting plasma cortisol concentrations between 7 and 8 am prior to the morning steroid dose. When an alternate-day schedule is followed, plasma cortisol is measured the morning before treatment. Plasma cortisol concentration in the physiologic range (> 10 mg/dL) indicates return of basal physiologic adrenal rhythm. Exogenous steroids may then be discontinued safely, although it is advisable to continue giving stress doses of glucocorticoids when appropriate until recovery of the response to stress has been documented.
After basal physiologic adrenal function returns, the adrenal reserve or capacity to respond to stress and infection can be estimated by the low-dose ACTH stimulation test, in which 1 mcg of synthetic ACTH (cosyntropin) is administered intravenously. Plasma cortisol is measured 45–60 minutes after the infusion. A plasma cortisol concentration greater than 18 mg/dL indicates a satisfactory adrenal reserve. Even if the results of testing are normal, careful monitoring and the use of stress doses of glucocorticoids should be considered during severe illnesses and surgery.
et al: A search for variables predicting cortisol response to low-dose corticotropin
stimulation following supraphysiological doses of glucocorticoids. J Pediatr 2013 Aug;163(2):484–488
ADRENAL MEDULLA PHEOCHROMOCYTOMA
Pheochromocytoma is an uncommon tumor, but up to 10% of reported cases occur in pediatric patients. The tumor can be located wherever chromaffin tissue (adrenal medulla, sympathetic ganglia, or carotid body) is present. It may be multiple, recurrent, and sometimes malignant. Familial forms include pheochromocytomas associated with the dominantly inherited neurofibromatosis type 1, MEN type 2, and von Hippel-Lindau syndromes, as well as mutations of the succinate dehydrogenase genes. Neuroblastomas, ganglioneuromas, and other neural crest tumors, as well as carcinoid tumors, may secrete pressor amines and mimic pheochromocytoma.
The symptoms of pheochromocytoma are caused by excessive secretion of epinephrine or norepinephrine: headache; sweating; tachycardia, hypertension, vasomotor instability (flushing and postural hypotension); anxiety; dizziness, weakness; nausea, vomiting, diarrhea; dilated pupils, blurred vision; abdominal and precordial pain.
Laboratory diagnosis is possible in more than 90% of cases. Serum and urine catecholamines are elevated, but abnormalities may be limited to periods of symptomatology or paroxysm. Plasma-free metanephrine is the most sensitive and specific test, though phenoxybenzamine, tricyclic antidepressants, and β-adrenoreceptor blockers can cause false-positive results. A level three times the normal range is diagnostic. Intermediate values may require additional testing with serum and urine catecholamines. After demonstrating a tumor biochemically, imaging methods including CT or MRI are used to localize the tumor and nuclear medicine using functional ligands such as (123)I-MIBG, [18F]DA positron emission tomography scanning, and somatostatin receptor scintigraphy (with either [123I]Tyr3-octreotide or [111In] DTPA-octreotide) are useful in further diagnostic evaluation.
Laparoscopic tumor removal is the treatment of choice; however, the procedure must be undertaken with great caution and with the patient properly stabilized. Oral phenoxybenzamine or intravenous phentolamine is used preoperatively. Profound hypotension may occur as the tumor is removed but may be controlled with an infusion of norepinephrine, which may have to be continued for 1–2 days.
Unless irreversible secondary vascular changes have occurred, complete relief of symptoms is to be expected after recovery from removal of a benign tumor. However, prognosis is poor in patients with metastases, which occur more commonly with large, extra-adrenal pheochromocytomas.
et al: A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2010;95(5):2023–2037