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Adrenal Disorders The adrenal gland is composed of two embryologically distinct tissues, the cortex and medulla, arising from the mesoderm and neuroectoderm, respectively. Adrenal cortex consists of three anatomically distinct zones 1. The outer zona glomerulosa: site of mineralocorticoid production (aldosterone), regulated mainly by renin-angiotensin system, and partially by ACTH. 2. The central zona fasciculata: responsible for glucocorticoid synthesis, regulated by ACTH. 3. The inner zona reticularis: site of adrenal androgen (predominantly dehydroepiandrostenedione (DHEA, DHEA sulfate and androstenedione) secretion. With regard to function, there is no strict separation between the steroid-producing adrenal cortex and the catecholamine-producing medulla. Recent studies have provided evidence that chromaffin cells once thought to be located exclusively in the medulla, are found in all zones of the adult adrenal cortex, and that cortical cells are found in the medulla. Congenital Adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a family of inherited enzyme deficiencies that impair normal corticosteroid synthesis by the adrenal cortex. The most common enzyme deficiency is 21-hydroxylase deficiency, which accounts for over 90% of cases. CAH due to 21-hydroxylase deficiency can be classified as either classical (simple virilizing or salt-wasting types) or nonclassical. Other rare enzyme deficiencies resulting in CAH include 17-alpha-hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 11-beta-hydroxylase deficiency. Compensatory increase in adrenocorticotrophic hormone secretion leads to overproduction of steroid precursors in the adrenal cortex, resulting in adrenal hyperplasia. Excess precursors may be converted to androgens that may result in virilization of female fetuses. The phenotype is determined by the severity of the cortisol deficiency and the nature of the steroid precursors that accumulate proximal to the enzymatic block. The most common abnormality, which is responsible for greater than 90% of patients with CAH, is caused by a deficiency of the 21-hydroxylase enzyme. Less common causes for CAH include deficiencies in 11β-hydroxylase and 17αhydroxylase. Reduced 21-hydroxylase activity results in accumulation of 17-hydroxyprogesterone as a result of impaired conversion to 11-deoxycorticosterone. Excess 17-hydroxyprogesterone is then converted through androstenedione to androgens, levels of which can increase by as much as several hundred fold. Excess androgens virilizing the undifferentiated female external genitalia, ranging from mild clitoral hypertrophy to complete formation of a phallus and scrotum. In contrast, genital development in male fetuses is normal, although excess androgens cause postnatal virilization in both genders and may manifest in precocious puberty. A severe enzyme deficiency or even a complete block of enzymatic activity produces the classic form of CAH. Two thirds to three fourths of cases have salt loss, which may be life threatening. It has been known that the fetal adrenal gland can be pharmacologically suppressed by maternal replacement doses of dexamethasone. Suppression can prevent masculinization of affected female fetuses in couples who are carriers of classic CAH. Differentiation of the external genitalia begins at about 7 weeks of gestation. Chorionic villus sampling has traditionally been the earliest approach for determining gender, although earlier detection should now be possible by molecular testing for Y-sequences in maternal blood. Pharmacologic therapy can be initiated before diagnosis, but therapy is continued only if the fetus is an affected female. Hundreds of fetuses have been treated successfully with prevention or amelioration of masculinization. 1 Screening studies indicate a worldwide incidence of classical 21-hydroxylase deficient CAH as 1 in 14,000 live births. Incidences vary among different populations, ranging from 1 in 600 live births in Alaska, to 1 in 5,000 live births in Saudi Arabia, to 1 in 23,000 live births in New Zealand. The prevalence frequency of non-classical 21-hydroxylase deficient CAH is considerably higher at 1 in 1,000 in white populations, with an even higher frequency among selected ethnic groups most notably, Ashkenazi Jews. Prevalence of non-classical CAH is 1 in 27 Ashkenazi Jews, 1 in 40 Hispanics, 1 in 50 Yugoslavs, 1 in 300 Italians, and 1 in 100 in a heterogeneous New York population. The fertility rate among untreated females with non-classical CAH is reported to be 50%. CAH is an autosomal recessive disorder and the gene encoding 21-hydroxylase enzyme, CYP21A2, is mapped to the short arm of chromosome 6 (6p21.3). To date, more than 100 mutations have been described. Approximately 95% to 98% of the mutations causing 21hydroxylase deficiency have been identified through molecular genetic studies of gene rearrangement and point mutations arrays. Deficiency of 21-hydroxylase enzyme causes insufficient cortisol production, stimulating increased production of corticotropin-releasing hormone and ACTH. High ACTH levels lead to adrenal hyperplasia and production of excess androgens (e.g., delta-4-androstenedione), which do not require 21-hydroxylation for synthesis. Symptoms of excessive androgens are found in varied degrees in classical and non-classical forms of 21-hydroxylase deficiency and are attributable to the severity of the enzyme defect. The internal female reproductive tract remains normal, as the ovaries do not produce antiMullerian hormone. Postnatal virilization includes rapid growth, premature development of pubic hair, and advanced body maturation leading to secondary precocious puberty, early epiphysis fusion, and short final adult height. Short stature may be the combined result of elevated adrenal 2 androgens causing advanced epiphyseal maturation and premature epiphyseal fusion, with glucocorticoid overproduction inducing growth suppression, leading to short stature. Gonadal dysfunction usually occurs, as the excess adrenal androgens suppress pituitary gonadotropins and thus impair testicular growth and function. When the loss of 21-hydroxylase function is severe, adrenal aldosterone secretion is insufficient to stimulate sodium reabsorption by the distal renal tubules, resulting in salt-wasting as well as cortisol deficiency, in addition to androgen excess. Clinical characteristics of different enzyme deficiency forms of CAH 21-hydroxylase deficiency Non-classical CAH o Mild-to-moderate enzyme deficiency o Females do not have virilized genitalia at birth o May present in a child as precocious development of axillary hair or odor, pubic hair, acne, or tall stature as a child with an advanced bone age that may eventually result in short stature as an adult. o Adolescent females may also present with oligomenorrhoea, amenorrhea, polycystic ovaries, acne, hirsutism, or alopecia. Classical CAH: salt-loser o Most severe form of the disease o Approximately 75% of classical cases o commonly present with ambiguous genitalia in the female o Characterized by insufficient aldosterone, with vomiting and dehydration occurring early (1-4 weeks) in infant life and risk of life-threatening adrenal crises. Classical CAH: simple virilized (non salt-loser) o Enzyme defect is moderate o Approximately 25% of classical cases o Retain ability to conserve salt. 17-alpha-hydroxylase deficiency Hypertension (HTN) and Hypokalemia Delayed puberty in females and virilization in males No salt-wasting occurs. 3-beta-hydroxysteroid dehydrogenase deficiency Ambiguous genitalia in both males and females Salt-wasting (rare). 11-beta-hydroxylase deficiency Hypertension (HTN) Hyperandrogenism, causing ambiguous genitalia in female infants and childhood virilization in both sexes. Antenatal diagnosis can be performed in the first trimester by molecular genetic analysis of fetal DNA from chorionic villus sampling or amniocentesis. 3 Dexamethasone treatment of the affected female fetus does not prevent the development of CAH, but helps in prevention of antenatal virilization in affected girls. Newborn screening is performed by measuring 17-hydroxyprogesterone on a filter paper blood spot sample obtained by the heel-prick technique. Screening serves several important purposes: Identifying the classical form of 21-hydroxylase CAH Determining patients at risk for life-threatening salt-wasting crises Expediting the diagnosis of females with ambiguous genitalia Detecting some (though not all) people with the non-classical form. Diagnosis at birth of a female usually is made immediately due to the apparent genital ambiguity. As differentiation of the external genitalia is unaffected in newborn males, only hyperpigmentation may suggest increased ACTH secretion. Diagnosis at birth in males usually depends on antenatal or newborn screening. A positive family history is common. Infertility, both male and female, is commonly identified when a couple attempts to have a child. Signs of hyperandrogenism in affected children include precocious puberty or early onset of facial, axillary, and pubic hair, adult body odor, and rapid somatic growth. This early growth spurt is accompanied by premature epiphyseal maturation and closure, resulting in a final height that is below that expected from parental heights. Patients tend to be tall children, but short adults. In adolescence and adult age, signs of hyperandrogenism may include temporal balding, severe acne, irregular menses, hirsutism, and infertility. Menstrual irregularity and secondary amenorrhea with or without hirsutism occur in a subset of post-menarche females, especially those in poor hormonal control. Primary amenorrhea or delayed menarche can occur if females with classical CAH if untreated, inadequately treated, or over treated with glucocorticoid. Infants with salt-wasting have poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatraemia, and hyperkalaemic metabolic acidosis progressing to adrenal crisis (azotaemia, vascular collapse, shock, and death). Adrenal crisis can occur as early as 1 to 4 weeks of age. Non-classical CAH A positive family history is common. Symptoms include acne, premature development of pubic hair, accelerated growth, advanced bone age, and reduced adult stature as a result of premature epiphyseal fusion. Acne tends to be severe with pustules and red papules on the face, back, and other regions of the body. Females are born with normal genitalia; postnatal symptoms may include hirsutism, temporal baldness, delayed menarche, menstrual irregularities, and infertility. Among adult females, most present with hirsutism only, with rare presentations of only hirsutism and menstrual disorder or menstrual disorder only. Males may have early beard growth and an enlarged phallus with relatively small testes. Symptoms in adult males may be limited to short stature or oligozoospermia and diminished fertility. Diagnosis Classic 21-hydroxylase deficiency The characteristic biochemical abnormality is an elevated serum concentration of 17hydroxyprogesterone. False positive results from neonatal screening are common with premature infants, and many screening programs have established reference ranges that are based upon 4 weight and gestational age. High serum androstenedione, testosterone, 08:00 am serum cortisol level will be low and serum ACTH will be high, and increased urinary excretion of metabolites of cortisol precursors, particularly pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids. (Pregnanetriol and its glucuronide are the major metabolites of 17-hydroxyprogesterone, and 17ketosteroids are metabolites of androgens). Patients with the salt-losing form of 21-hydroxylase deficiency have low serum concentrations of aldosterone and 11-deoxycorticosterone and increased plasma renin activity. The mineralocorticoid deficiency can lead to volume depletion, hyponatremia, and hyperkalemia. Patients are also at risk for hypoglycemia during an adrenal crisis. To assess borderline cases, the standard high-dose (250 mcg cosyntropin) test, not the low-dose (1 mcg) test, should be used. Genetic testing also can be used to evaluate borderline cases. Genetic testing detects approximately 95 percent of mutant alleles. Newborns or infants with ambiguous genitalia are recommended for karotyping or FISH (fluorescence in situ hybridization) for X and Y chromosome detection, and an ultrasound of the pelvis to identify internal female genitalia and adrenal glands to look for the large size. Prader score for genital ambiguity Genital ambiguity can be evaluated by the Prader score in newborn females. The scores range on a scale of 1 to 5 (I to V). The genitalia can be scored from slightly virilized (score of 1) to indistinguishable from a male (score of 5). Most females with classical 21-hydroxylase deficiency are born with Prader IV genitalia. Ferriman-Gallwey score for hirsutism The scoring system quantifies the extent of hair growth in nine key anatomical sites. Hair growth is graded using a scale from zero (no terminal hair) to 4 (maximal growth), for a maximum score of 36. A score of 8 or more indicates the presence of androgen excess. The degree of facial and body hair excess can be objectively scored by this method. 5 Treatment Adrenal crisis The initial goals are treatment of hypotension and dehydration, reversal of electrolyte abnormalities, and correction of cortisol deficiency. Normal (0.9 percent) saline solution or 5 percent dextrose in normal saline should be infused intravenously as quickly as possible. An intravenous bolus of 10 to 20 mL/kg of normal saline should be administered. An intravenous bolus of 2 to 4 mg/kg of 10 percent dextrose should be considered if there is significant hypoglycemia. Hypotonic saline should not be used because it can worsen the hyponatremia; the same is true of 5 percent dextrose without the addition of normal saline. Hyperkalemia should be corrected with the administration of glucose and insulin if necessary. Glucocorticoid is usually administered as hydrocortisone (cortisol) in a dose of 12 to 15 mg/m2 body surface area per day. In the early phase of treatment, infants may require up to 25 mg/m2/day of hydrocortisone to reduce markedly elevated adrenal hormones. This dose range exceeds the daily cortisol secretory rate of normal infants and children, which is estimated to be 7 to 9 mg/m2 body surface area in neonates and 6 to 7 mg/m2 body surface area in children and adolescents. For older adolescents and adults, long-acting glucocorticoids such as dexamethasone or prednisolone are the preferred treatment. When given at bedtime, these drugs effectively suppress ACTH secretion for much of the next day. However, the longer duration of action and greater potency of dexamethasone may increase the risk of over treatment, restricting linear growth if given prior to epiphyseal closure. Dexamethasone is given as a bedtime dose of 0.25 to 0.50 mg. The usual pediatric dose of fludrocortisone is 0.05 to 0.20 mg per day. Infants with the salt-losing form may require higher doses of fludrocortisone (occasionally up to 0.30 mg per day) and also require sodium chloride supplementation of 1 to 3 g per day (about 17 to 51 mEq per day) distributed in several feedings. Fludrocortisone doses may be decreased after 6 to 12 months of age because sensitivity to mineralocorticoid increases as the kidneys mature in the first year of life. Salt tablets can be discontinued as the child begins to eat table food and the taste for salty food increases. Additional salt intake may be needed with exposure to hot weather or with intense exercise. CAH is associated with short stature in adults even when optimal adrenal hormonal control is maintained throughout childhood and puberty. It has been shown that growth hormone therapy, alone or in combination with a gonadotropin-releasing hormone analogue, is effective in improving growth rate, height deficit, and final height in children. Dosing is determined and delivered by an endocrinologist familiar with the use of these hormones. Important notes 6 The goal of therapy in CAH is to both correct cortisol deficiency and to suppress ACTH overproduction. The usual requirement of hydrocortisone (or its equivalent) for the treatment of classical CAH is about 10-15 mg/m2/day divided into 2 or 3 doses per day. Dosage requirements for patients with non classical CAH may be less. Adults may be treated with the longer-acting dexamethasone or prednisone. A small dose of dexamethasone at bedtime (0.25 to 0.5 mg) is usually adequate for androgen suppression in non-classical patients. Anti-androgen treatment may be useful as adjunctive therapy in adolescent females who continue to have hyperandrogenic signs despite good adrenal suppression. Females with concomitant PCOS may benefit from an oral contraceptive, though this treatment would not be appropriate for patients trying to get pregnant. Over-treatment should be avoided because it can lead to Cushing syndrome. Depending on the degree of stress, stress dose coverage may require doses of up to 50100 mg/m2/day. Stress dosing of glucocorticoid During periods of stress (surgery, febrile illness, shock), all patients with classical CAH require increased amounts of glucocorticoid. Typically, 2 to 3 times the normal dose is administered orally, or by IM injection when oral intake is not tolerated. Up to 5 to 10 times the daily dosage may be required during surgical procedures. Affected patients should always carry information regarding corticosteroid dosing to alert and inform healthcare personnel in case of emergency. The mineralocorticoid dose does not need to be increased during stress. Feminizing genitoplasty In females with classical CAH who are virilized at birth, feminizing genitoplasty may be performed to remove the redundant erectile tissue while preserving the sexually sensitive glans clitoris. This procedure also intends to provide a normal vaginal orifice that functions adequately for menstruation, intercourse and delivery. Clitoroplasty is typically performed in early childhood (preferably at age 6 to 18 months). When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina. Adrenalectomy Bilateral adrenalectomy has been reported as an experimental treatment of patients with severe disease who are homozygous for 2 null mutations and who have a history of poor control with hormonal replacement therapy. This procedure is done only rarely. It is important to note that recurrence of increased serum concentration of adrenal corticosteroid hormones has been observed in some females undergoing adrenalectomy. The elevated serum concentration of adrenal corticosteroids is thought to result from the presence of ectopic adrenal rests (tumors) in the ovaries. More long-term data are needed to determine the significance and frequency of the rests in these women. Monitoring Successful treatment of affected children hinges on the delicate balance of suppressing adrenal androgen secretion with glucocorticoid administration while maintaining normal growth. In growing children, follow-up is every 3 months. In adulthood, the appointment frequency can be spaced to every 6 to 12 months. Growth data, pubertal assessment, and blood pressure measurements are necessary for each visit. Serum concentrations of 17-hydroxyprogesterone, delta-4-androstenedione, dehydroepiandrosterone, testosterone and renin) are monitored every 6 7 months. Bone maturation is assessed by bone age of the left hand, usually annually. In adult patients, bone mineral density to assess bone strength and imaging of the gonads to assess adrenal rest tumors are performed periodically. Complications 1. Adrenal crisis is characterized by azotaemia, vascular collapse, shock, and death. This can occur as early as 1 to 4 weeks of age. An intravascular injection of hydrocortisone with intravenous fluids containing dextrose and saline should be given immediately. 2. Hydrocortisone dose adjustment depends on patient's symptoms and signs of androgen excess, steroid measurements, and growth and development all need to be considered. 3. Central precocious puberty is most likely to develop when the diagnosis of CAH is delayed or when adrenal androgen secretion is poorly controlled; such patients may benefit from treatment with gonadotropin-releasing hormone analog 4. Testicular adrenal rests (benign tumors) are most often seen in male patients with classical salt-wasting CAH who are inadequately treated. Deficient spermatogenesis is also found. Imaging with MRI or ultrasound plus biopsies can confirm the benign nature of the tumor. Treatment with glucocorticoid replacement therapy will usually cause reduction in the masses, but testis-sparing surgery or orchiectomy may be required. 5. Short stature due to excess androgens cause precocious puberty and advanced bone age. optimum glucocorticoid replacement therapy and in some cases a combination treatment of growth hormone and GnRH analogues results in improved final height and reduction of the early onset of puberty. Prognosis Patients who are compliant will maintain healthy, normal lives. Patients who are non-compliant will suffer many of the signs and symptoms of hyperandrogenaemia. Poor compliance with medication can also lead to a potentially fatal addisonian crisis. Key points CAH is suspected in females who are virilized at birth, who become virilized postnatal, or who have precocious puberty or Adrenarche. Males with virilization in childhood and infants of either sex with a salt-wasting crisis in the first 1- 4 weeks of life are likely to be affected with CAH. The diagnosis is confirmed by biochemical findings of elevated serum concentration of 17hydroxyprogesterone. Serum concentrations of delta-androstenedione and progesterone are increased in males and females with 21-hydroxylase deficient CAH. Serum concentrations of testosterone and adrenal androgen precursors are increased in affected females and prepubertal males. Adrenal insufficiency Adrenal insufficiency is defined by the impaired synthesis and release of adrenocortical hormones. It is classified based upon whether the etiology is primary, secondary, or tertiary. Primary adrenal insufficiency results from disease intrinsic to the adrenal cortex. Secondary adrenal insufficiency is caused by either impaired release or effect of adrenocorticotropic hormone (ACTH) from the pituitary gland. 8 Tertiary adrenal insufficiency results from the impaired release or effect of corticotropin releasing factor (CRH) from the hypothalamus. In addition, disorders of end-organ unresponsiveness to ACTH hormone that present in a similar manner as diseases caused by adrenocortical hormone deficiencies. Causes of primary adrenal insufficiency Addison's disease Adrenal insufficiency is the result of an autoimmune process that destroys the adrenal cortex. Approximately 90% of the adrenal cortex needs to be destroyed to produce adrenal insufficiency.Both humoral and cell-mediated immune mechanisms directed at the adrenal cortex are involved. Antibodies that react with several steroidogenic enzymes as well as all three zones of the adrenal cortex are detected in 60-75% of patients with autoimmune primary adrenal insufficiency. Approximately 50% of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders, whereas patients with the more common autoimmune endocrine disorders, such as type 1 diabetes mellitus, chronic autoimmune thyroiditis, or Graves' disease, rarely develop adrenal insufficiency. The combination of autoimmune adrenal insufficiency with other autoimmune endocrine disorders is referred to as the autoimmune polyglandular syndrome APS1 and APS2. APS1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), includes hypoparathyroidism, chronic mucocutaneous candidiasis, and adrenal insufficiency. Other findings include primary hypogonadism and malabsorption. APS2 has primary adrenal insufficiency, with additional features being thyroiditis and type 1 diabetes mellitus. APS2 is more prevalent than type 1. The age of onset ranges from childhood to late adulthood with most cases presenting between 20 to 40 years of age. Infectious adrenalitis: Tuberculosis is the second most common cause of primary adrenal insufficiency. Less common causes include meningococcal infection, systemic fungal infections (histoplasmosis and paracoccidioidomycosis), and opportunistic infections secondary to HIV infection. Hemorrhagic infarction: Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis may also lead to adrenal insufficiency. Adrenal hemorrhage has been mostly associated with meningococcemia (Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa infection. Drugs: may cause adrenal insufficiency by inhibiting cortisol biosynthesis include antiepileptic, ketoconazole and metyrapone. Drugs that accelerate the metabolism of cortisol such as phenytoin, barbiturates, and rifampicin can cause adrenal insufficiency in patients with limited pituitary or adrenal reserve and those on glucocorticoid replacement therapy. Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism. They may either result from a defect in a single peroxisomal enzyme or from abnormal peroxisomal biogenesis affecting multiple peroxisomal functions.Neurologic impairment in most of peroxisomal disorders. The adrenal gland is involved in adrenoleukodystrophy (ALD), as well as the peroxisomal disorders resulting from abnormal biogenesis (such as neonatal ALD, Refsum disease, and Zellweger syndrome). Adrenoleukodystrophy ( ALD) is X-linked disorder caused by mutations of the ATP-Binding Cassette, Subfamily D, Member 1 gene (ABCD1 gene). These mutations prevent normal transport of very long chain fatty acids (VLCFA) into peroxisomes, thereby preventing betaoxidation and breakdown of VLCFA. Accumulation of abnormal VLCFA in affected organs (central 9 nervous system, Leydig cells of the testes, and the adrenal cortex), is presumed to be the underlying pathologic process of these disorders. In almost all cases, adrenocortical failure occurs along with irreversible degenerative neurologic defects. Adrenal failure may predate, occur simultaneously with, or follow the onset of the neurologic deterioration. Adrenal hypoplasia congenita (AHC) results from mutations in the DAX-1 gene (dose-sensitive sex-reversal) on the short arm of X chromosome (Xp21). In AHC, both cortisol and aldosterone secretion are reduced because of impaired development of the definitive zone in the first trimester of gestation. DAX-1 is expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Children with AHC present as neonates (1 to 4 weeks of age), the age and severity of the disease can vary. Some individuals present later in childhood. Clinical manifestations include the following: Neonatal presentation: Affected neonates most often present with signs and symptoms of salt-losing crisis similar to that of CYP21A2 (21-hydroxylase) deficiency including hyponatraemia, hyperkalemia, hypovolemia, and hypotension. Patients have low serum cortisol and aldosterone levels, and elevated plasma ACTH levels as well as hyperpigmentation. Hypogonadotropic hypogonadism occurs in surviving affected males treated with replacement steroids, prepubertal gonadal development is normal, but pubertal development is impaired, resulting in hypogonadism. The site of the defect appears to be within the hypothalamic-pituitary-gonadal axis. Xp21 contiguous gene complex — DAX-1 gene is contiguous with the dystrophin (Duchenne muscular dystrophy) and glycerol kinase (juvenile glycerol kinase deficiency) genes on the short arm of the X chromosome. There are case reports of patients with deletions of this complex who present with adrenal insufficiency, muscular dystrophy, and intellectual disability (mental retardation). Other features include short stature, testicular abnormalities (cryptorchidism and/or hypogonadism), and peculiar facies (drooping mouth and wide-set eyes) Steroidogenic factor-1 (SF-1) gene maps to chromosome 9q33. SF-1 regulates tissue-specific expression of cytochrome P450 steroid hydroxylases and is expressed in the gonads, adrenal glands, anterior pituitary gland, and hypothalamus. SF-1 interacts with DAX-1, and is important in both male sexual differentiation and adrenal gland development. Case reports of mutations of SF1 describe male to female sex reversal with ambiguous genitalia noted at birth in affected males. Patients also present as neonates with signs and symptoms of salt-loss similar to those with DAX-1 mutations. Other patients with SF-1 mutations have disorders of sex development but no adrenal abnormalities IMAGe syndrome is characterized by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. The cause is unknown and reported cases do not have either DAX-1 or SF-1 mutations. X-linked inheritance (inheritance from maternal line) is suspected in some pedigrees, and both affected males and females have been described. Familial glucocorticoid resistance is a rare hereditary disorder resulting from mutations in the glucocorticoid receptor gene. It is characterized by unresponsiveness of targeted end-organs to the actions of cortisol. Although there are high circulating levels of cortisol, the glucocorticoid receptor defect results in clinical manifestations similar to those with glucocorticoid deficiency Triple A syndrome composed of ACTH-resistant cortisol deficiency, achalasia, and absent lacrimation have the triple A syndrome (AAAS) or Allgrove syndrome. This is an autosomal recessive disorder resulting from a defect in the AAAS gene located on chromosome 12q13. Many of these patients have neurologic disorders including peripheral, autonomic, and central nervous system impairments. Some also have a mild defect in mineralocorticoid (aldosterone) secretion, particularly when salt restricted. 10 Key points Primary adrenal insufficiency is defined as the impaired synthesis and/or release of adrenocortical hormones on account of disease intrinsic to the adrenal cortex. Clinical manifestations are dependent on the type of hormonal class affected and the severity of the defect(s). The hormones are divided into glucocorticoid (cortisol), mineralocorticoid (aldosterone), and adrenal androgens (dehydroepiandrosterone). Adrenal crisis or acute adrenal insufficiency can be observed as the initial presentation of adrenal insufficiency or as the result of inadequate replacement therapy in patients with known adrenal insufficiency. To minimize morbidity and mortality, prompt recognition and treatment of adrenal crisis is critical. Causes of secondary and tertiary adrenal insufficiency Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. The ACTH deficiency may be isolated or occur in association with other pituitary hormone deficits. On the other hand, tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with CRH secretion. The most common causes of tertiary adrenal insufficiency are abrupt cessation of high-dose glucocorticoid therapy and treatment of Cushing's syndrome. Clinical manifestations of adrenal insufficiency The clinical manifestations of adrenal insufficiency depend upon the extent of loss of adrenal function and whether mineralocorticoid production is preserved. The onset of adrenal insufficiency is often gradual and may go undetected until an illness or other stress precipitates an adrenal crisis. Glucocorticoid deficiency Clinical findings associated with glucocorticoid deficiency (cortisol) include fasting hypoglycemia, increased insulin sensitivity, muscle weakness, and morning headache. As a secondary consequence of cortisol deficiency, there also is increased production of pro-opiomelanocortin (ACTH precursor); this results in increased melanin synthesis, causing hyperpigmentation. This is most conspicuous in areas exposed to sunlight or pressure (elbows and knees) and also is prominent in the areas not typically exposed to sun, such as palmar creases, axillae, and gingival borders. Mineralocorticoid deficiency Clinical findings with mineralocorticoid deficiency (aldosterone) primarily result from sodium loss. These include hypotension, dizziness, salt-craving, weight loss, anorexia, and electrolyte abnormalities (hyponatraemia, hyperkalemia, and metabolic acidosis). Adrenal androgen deficiency Clinical findings of adrenal androgen deficiency include decreased axillary and pubic hair as well as a loss in libido. By comparison, changes are unusual in males as most of their androgen production occurs in the testes. Prepubescent children with adrenal androgen deficiency are most commonly asymptomatic. Adrenal crisis or acute adrenal insufficiency may complicate the course of chronic primary adrenal insufficiency, and may be precipitated by a serious infection, acute stress, bilateral 11 adrenal infarction or hemorrhage. It is rare in patients with secondary or tertiary adrenal insufficiency. The main clinical manifestation of adrenal crisis is shock, but patients may also have nonspecific symptoms such as anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, confusion or coma. Hypoglycemia is rare in acute adrenal insufficiency, but more common in secondary adrenal insufficiency. Hypoglycemia is a common manifestation in children and thin women with the disorder. Hyperpigmentation due to chronic ACTH hypersecretion and weight loss are indicative of long-standing adrenal insufficiency, while additional symptoms and signs relating to the primary cause of adrenal insufficiency may also be present. Patients with secondary or tertiary adrenal insufficiency usually have normal mineralocorticoid function Diagnosis The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (04:00h - 08:00h) and increase further with stress. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency, while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. Basal urinary cortisol and 17hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may be low-normal in patients with partial adrenal insufficiency. Generally, baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency. Primary adrenal insufficiency is diagnosed if ACTH levels are high in the setting of low cortisol, with hyponatraemia/hyperkalemia, or with an abnormal rapid ACTH stimulation test. Other common features are laboratory evidence of mineralocorticoid deficiency (low fasting glucose, hyponatraemia, and hyperkalemia) and elevated plasma renin activity or renin concentration. Confirmation of the diagnosis requires stimulation of the adrenal glands with exogenous ACTH. Secondary or tertiary adrenal insufficiencies are diagnosed if ACTH levels are low in the setting of low cortisol. Dynamic tests If static tests suggest adrenal insufficiency, then dynamic tests often are used to determine the level of the defect (whether it is a defect intrinsic to the adrenal gland or if the cortisol deficiency is the result of ACTH deficiency) Short synacthen test Used for assessing cortisol production (ACTH responsiveness) in a patient with adrenal insufficiency. In this test, serum cortisol levels are measured before and 60 minutes after the rapid intravenous infusion of synthetic ACTH. A subnormal response in a patient who has not received glucocorticoid therapy may indicate primary adrenal failure. The result of the short ACTH stimulation test is also abnormal in most patients with secondary ACTH deficiency because chronic lack of ACTH impairs the ability of the adrenal cortex to respond to acute ACTH administration, and is thus unable to produce cortisol. Such patients do not have a significantly elevated ACTH level, and have normal mineralocorticoid status. In this case, ACTH secretory ability can be accessed directly with a glucagon stimulation test or insulin-induced hypoglycemia. Prolonged synacthen test On rare occasions, the results of insulin-induced hypoglycemia or glucagon stimulation tests are equivocal. In these cases, a prolonged ACTH test (three days of prolonged ACTH infusions, or IM ACTH) may be indicated. The prolonged ACTH test also may be useful in differentiating between 12 primary adrenal unresponsiveness to ACTH and low cortisol due to secondary or tertiary adrenal insufficiency, in cases when the baseline ACTH level is not below normal (a rare situation). Tests of ACTH secretory ability If static tests and ACTH stimulation test suggest hypopituitarism (low 8 a.m. cortisol and low ACTH) and if further confirmation is needed, then the next step is to assess ACTH secretion with one or more dynamic tests. Several dynamic tests can be used for this purpose. Insulin-induced hypoglycemia is the most sensitive standard test of ACTH release. Serial measurements of blood glucose and cortisol are made before and at 15, 30, 45, and 60 minutes after an infusion of insulin (0.05 units/kg). The peak cortisol level should be at least double the baseline level or greater than 20 mcg/dL . If desired, samples for growth hormone can be obtained at the same time. A normal GH response is usually defined as a peak of ≥10 mcg/L. Symptomatic hypoglycemia is desirable during the test, but marked changes in levels of consciousness or blood glucose <30 mg/dL must be treated with prompt administration of intravenous dextrose. The test is not recommended for children younger than three years old because of the risk of damage to the central nervous system resulting from hypoglycemia. Glucagon stimulation test is more appropriate in children younger than three years. After an intramuscular injection of glucagon, the blood glucose level initially raises then drops rapidly because of the release of endogenous insulin. Serum cortisol and growth hormone levels should increase in response to this fall in blood glucose Metayrapone test is used in the assessment of ACTH secretory ability, but is rarely used clinically. Metayrapone blocks the activity of the enzyme 11-beta-hydroxylase, which is needed to convert 11-deoxycortisol to cortisol, causing a decrease in serum cortisol levels. In a normal patient, the decrease in cortisol levels will stimulate ACTH secretion and increase the production of cortisol precursors. This can be measured by a rise in serum levels of ACTH and 11deoxycortisol and/or in urinary 17-hydroxycorticosteroids and free cortisol. The ACTH-stimulated gland eventually overrides the enzymatic block, allowing cortisol production to occur. However, patients must be observed closely during this test, because acute adrenal insufficiency may be precipitated if the patient has marked ACTH deficiency CRH Stimulation Test: This test is used to differentiate between secondary and tertiary adrenal insufficiency. In both conditions cortisol levels are low at baseline and remain low after CRH. In patients with secondary adrenal insufficiency, there is little or no ACTH response, whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response. Key points Adrenal insufficiency is suspected on the basis of clinical symptoms, which may include fatigue, nausea and vomiting. Patients with primary adrenal insufficiency often have signs of mineralocorticoid deficiency, including hypotension, dehydration, and electrolyte abnormalities, and may present in adrenal crisis. Primary adrenal insufficiency is caused by disease of the adrenal cortex. Secondary or tertiary adrenal insufficiency are caused by impaired release or effect of ACTH from the pituitary gland or of CRH from the hypothalamus, respectively Primary adrenal insufficiency is diagnosed if ACTH levels are high in the setting of low cortisol, with hyponatraemia/hyperkalemia, or with an abnormal short ACTH stimulation test. 13 Other common features are laboratory evidence of mineralocorticoid deficiency (low fasting glucose, hyponatraemia, and hyperkalemia) and elevated plasma renin activity or renin concentration. Secondary or tertiary adrenal insufficiency are diagnosed if ACTH levels are low in the setting of low cortisol A variety of dynamic tests are used to further evaluate findings of the static tests. If initial cortisol results are indeterminate, one of the tests for ACTH secretory ability (using insulin-induced hypoglycemia, glucagon, or metyrapone) will establish whether pituitary insufficiency is present. If initial static ACTH tests are low, then these tests will determine if the adrenal insufficiency is secondary or tertiary In the case of primary adrenal insufficiency, adrenal androgens should be measured to evaluate for congenital adrenal hyperplasia. This is the most common cause of primary adrenal insufficiency but usually presents during infancy.Antibodies to the adrenals and other endocrine glands may establish an autoimmune mechanism. Children with secondary adrenal insufficiency have deficient ACTH secretion from the pituitary. Therefore, other pituitary hormones also should be measured. Treatment Adrenal crisis is a life-threatening emergency that requires immediate treatment. The aim of initial management in adrenal crises is to treat hypotension, and to reverse the electrolyte abnormalities and cortisol deficiency. Dextrose with normal saline solution should be given intravenously. The glucocorticoid deficiency should be treated by immediate intravenous administration of hydrocortisone. Once the initial treatment is offered, the cause of the adrenal crisis should be sought and treated. Once the patient's condition is stable, and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose. Patients with primary adrenal insufficiency require lifelong glucocorticoid and mineralocorticoid replacement therapy. Important notes An important aspect of the management of chronic primary adrenal insufficiency is patient and family education. Patients should understand the reason for life-long replacement therapy. Need to increase the dose of glucocorticoid during minor or major stress and to inject hydrocortisone in emergencies. Patients with adrenal insufficiency should be treated with hydrocortisone, the natural glucocorticoid. The hydrocortisone daily dose is (10-15 mg per meter square body surface area) and can be given in two to three divided doses. A longer-acting synthetic glucocorticoid such as prednisolone, prednisone or dexamethasone, may be employed after the child growth is completed. During minor illnesses or surgical procedures, the dosage of glucocorticoid can be increased up to three times the usual maintenance dosage for three days. Depending on the nature and severity of the illness, additional treatment may be required. During major illness or surgery, high doses of glucocorticoid up to 5-10 times the daily production are required to avoid an adrenal crisis. A continuous infusion of 10 mg of hydrocortisone per hour eliminates the possibility of glucocorticoid deficiency. This dose can be halved the second postoperative day, and the maintenance dosage can be resumed the third postoperative day. 14 Mineralocorticoid replacement therapy is required to prevent sodium loss, intravascular volume depletion, and hyperkalemia. It is given in the form of fludrocortisone in a dose of 0.1 mg daily. The dose of fludrocortisone is titrated individually on the basis of the clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma rennin activity. The mineralocorticoid dose may have to be increased in the summer, and advised to increase water and salt to avoid electrolyte disturbances and dehydration. Androgen replacement: In female adolescents, the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Their replacement is being increasingly considered in the treatment of adrenal insufficiency. In chronic secondary or tertiary adrenal insufficiency, glucocorticoid replacement is similar to that in primary adrenal insufficiency, however, measurement of plasma ACTH concentration cannot be used to titrate the optimal glucocorticoid dose. Mineralocorticoid replacement is rarely required, while replacement of other anterior pituitary deficits might be necessary. Key points Presentation may be acute or insidious, with substantial fatigue and weakness associated with mucocutaneous hyperpigmentation, hypotension and/or postural hypotension, and salt craving. ACTH stimulation test is performed to confirm or exclude the diagnosis of Addison's disease. All patients receive mineralocorticoid and glucocorticoid replacement for life and are instructed to increase the dose of glucocorticoid during surgery, and during any stressful or infectious conditions. Treatment complications arise from over-replacement of mineralocorticoid and/or glucocorticoid. Cushing’s syndrome Cushing’s syndrome results from chronic exposure to excessive levels of glucocorticoid. It is considered rare condition; the clinical spectrum of the disease is broad. Classic signs and symptoms as described by Harvey Cushing early in the last century. In its severe form and when untreated, the metabolic upset of Cushing's syndrome is associated with a high mortality, approximately 50% at five years. Excesses of cortisol may have significant effects on glycaemic control and blood pressure, and pathological obesity. Causes of Cushing's syndrome Cushing's syndrome may be either corticotropin (ACTH)-dependent or -independent. ACTH-dependent The causes of ACTH-dependent Cushing's syndrome are associated with bilateral adrenocortical hyperplasia: 1. Cushing's disease (pituitary hypersecretion of ACTH) — 65 to 70 percent 2. Ectopic secretion of ACTH by non pituitary tumors — 10 to 15 percent 3. Ectopic secretion of corticotropin-releasing hormone (CRH) by non hypothalamic tumors causing pituitary hypersecretion of ACTH — less than 1 percent 4. Iatrogenic or factitious Cushing's syndrome due to administration of exogenous ACTH — less than 1 percent ACTH-independent The causes of ACTH-independent Cushing's syndrome are: 15 1. Iatrogenic or factitious Cushing's syndrome, which is by far the most common cause; it is usually ACTH-independent and caused by the exogenous administration of glucocorticoid, usually for their anti-inflammatory effects. 2. Adrenocortical adenomas and carcinomas — 18 to 20 percent. 3. Primary pigmented nodular adrenocortical disease, also called bilateral adrenal micronodular hyperplasia — less than 1 percent. 4. Bilateral ACTH-independent macronodular hyperplasia, — less than 1 percent; this disorder must be distinguished from macronodular hyperplasia in Cushing's disease in which plasma ACTH concentrations are not suppressed Exclusion of exogenous hypercortilism (most common cause) It is essential that a careful history has excluded exogenous glucocorticoid intake. The most common cause of hypercortisolism is ingestion of prescribed prednisolone, usually for non-endocrine disease. Cushing's syndrome also can be caused by other oral, injected, topical, and inhaled glucocorticoid and by progestin with some intrinsic glucocorticoid activity. Cushing's syndrome may also be caused by the use of glucocorticoid-containing creams or herbal preparations. Factitious Cushing's syndrome is a rare disorder that refers to surreptitious intake of a glucocorticoid, often by patients who are close to the health professions Pseudo Cushing's syndrome Hypercortisolism can occur in several disorders other than Cushing's syndrome for example, those who are physically stressed, severe obesity, especially visceral obesity or polycystic ovary syndrome and psychological conditions, especially severe major depressive disorders. The clinical manifestations of the disease as the association of gross obesity of the trunk with wasting of the limbs, facial rounding and plethora, hirsutism with frontal balding, muscle weakness, fractures, hypertension and diabetes mellitus, lethargy, depression, acne and easy bruising. In children, weight gain associated with growth retardation should highlight the possibility of the diagnosis. Some cases of ACTH-dependent Cushing's syndrome occur in a periodic or cyclical form, with intermittent and variable cortisol secretion, the symptoms and signs waxing and waning according to the active periods of the disease. These patients can cause particular diagnostic difficulty, as these patients may 'cycle in' or 'cycle out' over periods of months or years; if at presentation they are eucortisolaemic, they will need regular re-evaluation to allow full investigation at the appropriate time . Cyclicity can occur with all causes of Cushing’s syndrome. Screening of Cushing's syndrome includes the following: Circadian rhythm assessment Measurement of serum cortisol at three time-points 09.00 h, 18.00 h and midnight (sleeping) to assess circadian rhythm. Midnight cortisol should be less than 50 nmol/l, although young children may reach their cortisol nadir earlier than midnight. Elevation of midnight sleeping serum cortisol 16 has the greatest sensitivity of all tests for Cushing's syndrome in children. Precannulation is essential, so as not to wake the child. Urinary free cortisol Measurement of three consecutive 24 h urine collections for urinary free cortisol (UFC) is a noninvasive test that is widely used in the screening of Cushing's syndrome. 24-hour UFC measurements have a high sensitivity if collected correctly, values greater than threefold of normal are rare except in Cushing's syndrome. For intermediate values the specificity is somewhat lower, and thus patients with marginally elevated levels require further investigation. The two most important factors in obtaining a valid result are collection of a complete 24-hour specimen and a reliable reference laboratory. Overnight dexamethasone suppression test Dexamethasone is a synthetic glucocorticoid that is 30 times more potent than cortisol, and with an extremely long duration of action. It does not cross-react with most cortisol assays. Measurement of a 08.00h plasma cortisol after a single dose of 1mg dexamethasone taken at midnight, and is thus considerably easier to perform. Using current specific immunoassays, most normal individuals have an 8 AM serum cortisol value of less than 2 mcg/dL (55 nmol/L) Late night salivary cortisol test Salivary cortisol measurement accurately reflects the plasma free cortisol concentration. Loss of the circadian rhythm of cortisol secretion by measuring night-time salivary cortisol has been studied at a number of centers as a screening test for Cushing’s syndrome. Late-night salivary cortisol appears to be a useful and convenient additional screening test for Cushing's syndrome, particularly in the outpatient setting. The sensitivity and specificity of this test appears to be relatively consistent at different centers, ranging from 92% to 100%, and 93% to 100% respectively. Low-dose dexamethasone suppression test is the standard screening tests to differentiate patients with Cushing's syndrome of any cause from patients who do not have Cushing's syndrome. High-dose dexamethasone suppression tests were used to distinguish Cushing's syndrome caused by pituitary hypersecretion of ACTH from most patients with the ectopic ACTH syndrome (Cushing's syndrome caused by non-pituitary ACTH-secreting tumors). Low-dose dexamethasone suppression test (LDDST) The two-day 2 mg test consists of administering 0.5 mg of dexamethasone every six hours for eight doses, and measurement of serum cortisol either two or six hours after the last dose. (If child weighs less than 40 kg, when to use the recommended dose of 30 µg/kg/day). Serum cortisol then measured at 0 and at 48 h, when it should be undetectable (< 1.8 mcg/dL , <50 nmol/L). These tests individually, and in combination, have a high sensitivity for Cushing's syndrome and an even higher specificity for the exclusion of this diagnosis. High dose dexamethasone suppression test (HDDST) To differentiate between cortisol-secreting adrenal tumors and Cushing's disease. The HDDST’s role in the differential diagnosis of ACTH-dependent Cushing’s syndrome is based on the same 17 premise: that most pituitary corticotroph tumor retain some albeit reduced responsiveness to negative glucocorticoid feedback, whereas ectopic ACTH-secreting tumors like adrenal tumors typically do not. The CRH test The use of the CRH (corticotrophin-releasing hormone) test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Pituitary corticotrophin adenoma retain responsivity to CRH, while ectopic ACTH tumors lack CRH receptors and therefore do not respond to the agent. CRH either 1 μg/kg or 100 μg synthetic ovine (oCRH) or human sequence CRH (hCRH) is given as a bolus injection and the change in ACTH and cortisol measured. CRH test is a useful discriminator between causes of ACTH-dependent Cushing's syndrome, but which cut-off to use should be evaluated at individual centers, and caution should be exercised as there will undoubtedly be patients with the ectopic ACTH syndrome who respond outside these cut-off. Bilateral inferior petrosal sampling This procedure involves placement of sampling catheters in the inferior petrosal sinuses that drain the pituitary. Blood for measurement of ACTH is obtained simultaneously from each sinus and a peripheral vein at two time points before and at 3-5 minutes and possibly also 10 minutes after the administration of ovine or human CRH (IV 1 μg/kg or 100μg respectively). A central (inferior petrosal) to peripheral plasma ACTH gradient of 2:1 or greater pre-CRH, or a gradient of 3:1 post-CRH is consistent with Cushing's disease. It is also useful to lateralize microadenoma within the pituitary using the inferior petrosal sinus ACTH gradient, with a basal or post-CRH inter-sinus ratio of at least 1.4 being the criteria for lateralization used in all large studies. The accuracy of lateralization appears to be higher in children (90%), a situation where imaging is often negative. There is some discrepancy between studies as to whether CRH improves the predictive value of the test. If a reversal of lateralization is seen pre- and post-CRH, the test cannot be relied upon. Ectopic tumors The most common site of the secretory lesion is the chest, and although small cell lung carcinomas are generally easily visualized, small bronchial carcinoid tumors that can be less than 1cm in diameter often prove more difficult. Fine-cut high-resolution CT scanning with both supine and prone images can help differentiate between tumors and vascular shadows. MRI can identify chest lesions that are not evident on CT scanning, and characteristically show a high signal on T2-weighted and short-inversion-time inversion-recovery images. The majorities of ectopic ACTH secreting tumors are of neuroendocrine origin and therefore may express somatostatin receptor subtypes. Recommendations : The Endocrine Society Guidelines: Recommend at least two first-line tests should be abnormal to establish the diagnosis of Cushing's syndrome. Late night salivary cortisol, urinary cortisol, and the low-dose dexamethasone suppression tests as first line tests. The Urinary and salivary cortisol measurements should be obtained at least twice. The urinary cortisol excretion should be unequivocally increased (threefold above the upper limit of normal for the assay), or the diagnosis of Cushing's syndrome is uncertain and other tests should be performed. The diagnosis of Cushing's syndrome is confirmed when two tests are unequivocally abnormal. 18 The patient should undergo additional evaluation if the test results are discordant or only slightly abnormal. If test results are normal, the patient does not have Cushing's syndrome unless it is extremely mild or cyclic. No additional evaluation unless symptoms progress or cyclic Cushing's syndrome Management Transphenoidal surgery Is widely regarded as the treatment of choice for Cushing’s disease. The overall remission rate in various large series is in the order of 70%-75%, although higher rates of approximately 90% can be achieved with microadenoma. Of the patients achieving remission, about 25% of these will have a recurrence by 10 years. Where remission is not achieved at the first operation, a reoperation may be attempted, but appears to offer prolonged remission in only around 50% of cases, and with a high risk of hypopituitarism. Adrenalectomy Adrenalectomy is the definitive treatment for all cases ACTH-independent Cushing’s syndrome. This is either unilateral in the case of an adrenal adenoma or carcinoma or bilateral in cases of bilateral hyperplasia. In adrenal adenomas cure following surgery in skilled hands approaches 100%. Bilateral adrenalectomy is also an important therapeutic option in patients with ACTHdependent Cushing’s syndrome not cured by other techniques. However, the development of Nelson’s syndrome in patients with ACTH-secreting pituitary adenomas occurs in between 8% and 38% of cases. The chance of developing Nelson’s syndrome appears to be greater if adrenalectomy is performed at a younger age, and if a pituitary adenoma is confirmed at previous pituitary surgery. Surgery for the ectopic ACTH syndrome If the ectopic ACTH-secreting tumor is benign and amenable to surgical excision, such as in a lobectomy for a bronchial carcinoid tumor, the chance of cure of Cushing’s syndrome is high. However, if significant metastatic disease is present, surgery is not curative although it may still be of benefit in selected cases. Radiotherapy Primary pituitary radiotherapy for the treatment of Cushing’s disease has been shown to produce poor long-term remission rates of only 37% in one series. In contrast, as a second line therapy to failed pituitary surgery better results are achieved with 83% showing long-term remission as defined by the normalization of the clinical state and biochemical parameters in a series of 30 patients, 88% of these achieving remission within two years, although it can take up to 5 years. The major side effect is hormone deficiency, occurring in 68%, with a lesser incidence of hypogonadism (40%) and hypothyroidism (16%), with only one patient developing hypocortisolaemia in the reported series. Gamma knife radio surgery is a relatively new development that has been utilized in patients with Cushing’s disease as a second-line treatment and also in Nelson’s syndrome. 19 Medical Management Medical treatment is desirable in patients with Cushing's disease whilst waiting for pituitary radiotherapy to take effect. In patients where surgery and/or radiotherapy has failed, medical management is often essential prior to (or long-term as an alternative) bilateral adrenalectomy. It may not always be possible to identify the source of ACTH in certain cases of ACTH-dependent Cushing's syndrome, and therefore medical management is desirable pending re-investigation. Finally, medical therapy is helpful as a palliative modality in patients with metastatic disease causing Cushing's syndrome. Adrenolytic therapy These agents are primarily used as inhibitors of steroid biosynthesis in the adrenal cortex, and thus can be utilized in all cases of hypercortisolaemia regardless of cause, often with rapid improvement in the clinical features of Cushing's syndrome. The most commonly used agents are metyrapone, ketoconazole, mitotane and in certain circumstances etomidate. Monitoring Treatment It is important to monitor all patients on medical therapy for Cushing’s syndrome, to assess the effectiveness of treatment, and in particular to avoid adrenal insufficiency. We use the mean of five serum cortisol measurements across the day, although others favour measurement of urinary free cortisol (UFC). A mean serum cortisol between 150 and 300 nmol/l corresponds to a normal cortisol production rate, and this range should be the aim of therapy. Conclusions Cushing’s syndrome is a complex endocrine disorder that often requires intensive investigation, best carried out at centers with a long-standing experience. Modern surgical techniques and medical therapies have resulted in an improved outcome for most patients, but it is still a condition that can cause considerable morbidity and increased mortality. Key Points The clinical manifestation of pathological hypercortisolism from any cause. Cushing's disease, which is hypercortisolism caused by an ACTH-secreting pituitary adenoma, is the most common cause of Cushing's syndrome, and is responsible for 60% to 70% of cases. Though uncommon, the prevalence of endogenous Cushing's syndrome is greater than previously thought. It may be difficult to distinguish patients with mild Cushing's syndrome from those with the metabolic syndrome (central obesity with insulin resistance, and hypertension). Features more specific to Cushing's syndrome include proximal muscle weakness, increased supraclavicular fat pads, facial plethora, violaceous striae, easy bruising, and premature osteoporosis. After exclusion of exogenous corticosteroid use, patients with suspected Cushing's syndrome should be tested for hypercortisolism with 1 of 4 high-sensitivity tests (latenight salivary cortisol; 1 mg overnight low-dose dexamethasone suppression testing, 24hour urinary free cortisol, or 48-hour 2 mg dexamethasone suppression testing). At least 1 additional test should be used to confirm hypercortisolism in patients with a positive initial screening test. 20 Once endogenous hypercortisolism is confirmed, plasma ACTH should be measured. If ACTH is suppressed, diagnostic testing should focus on the adrenal glands. If ACTH is not suppressed, pituitary or ectopic disease should be sought. In the vast majority of cases, surgical resection of the pituitary adenoma or adrenal adenoma that is causing hypercortisolism is the primary treatment of choice. Aldosterone deficiency and resistance Characterized by defective aldosterone action includes diseases of aldosterone resistance such as pseudohypoaldosteronism type 1 and sodium-wasting states resulting from excessive amounts of circulating mineralocorticoid antagonists, such as spironolactone and its analogues, and synthetic progestin or natural agonists, such as progesterone or 17-hydroxyprogesterone. These mineralocorticoid antagonists may antagonize aldosterone at the levels of mineralocorticoid receptor and frequently, these states are compensated for by elevated concentrations of plasma aldosterone. Primary hypoalosteronism (Aldosterone synthase) deficiency Congenital hypoalosteronism is a rare inherited disorder transmitted as either an autosomal recessive or autosomal dominant trait with mixed penetrance. Isolated aldosterone deficiency results from loss of activity of aldosterone synthase encoded by CYP11B2 gene. Therefore, the term aldosterone synthase deficiency type 1 (ASD1) and type 2 (ASD2) reflects more appropriately the molecular basis of this disease. In both ASD1 and 2, glomerulosa zone corticosterone is increased and aldosterone decreased, but 18-hydroxycorticosterone is increased in ASD2. The clinical presentation is typical of aldosterone deficiency, including electrolyte abnormalities such as a variable degree of hyponatraemia, hyperkalemia and metabolic acidosis, with poor growth in childhood. In infants, it is characterized by recurrent dehydration, salt wasting and failure to thrive. These symptoms are present generally within the first 3 months of life, and most often after the first 5 days of life. Mineralocorticoid resistance (pseudohypoaldosteronism type 1, PHA1 Clinical Presentation Results from inability of aldosterone to exert its effect on its target tissues and was first reported by Cheek and Perry as a sporadic occurrence in 1958. This disease, usually presents in infancy with severe salt-wasting and failure to thrive, accompanied by profound urinary sodium loss, severe hyponatraemia, hyperkalemia, acidosis, hyperreninemia and paradoxically markedly elevated plasma and urinary aldosterone concentrations. Usually, renal and adrenal functions are normal. Approximately one fifth of these cases were familial, and both an autosomal dominant and a recessive form of genetic transmission were observed. All patients had renal tubular unresponsiveness to aldosterone, while some had involvement of other mineralocorticoid targettissues, including the sweat and salivary glands, and the colonic epithelium. Autosomal recessive PHA1 presents in the neonatal period with hyponatraemia caused by multi-organ salt loss, including kidney, colon, and sweat and salivary glands. Autosomal recessive PHA1 persists into adulthood and shows no improvement over time. In contrast, autosomal dominant PHA1 is characterized by an isolated renal resistance to aldosterone, leading to renal salt loss. Particularly autosomal dominant form of PHA1 typically shows a gradual clinical improvement during childhood, allowing the cessation of sodium supplementation. Diagnosis Electrolyte profiles suggest mineralocorticoid deficiency or end-organ resistance, along with hyperkalemia, hyponatraemia and metabolic acidosis associated with profound urinary salt loss. 21 Renal and adrenal function is normal. The diagnosis is confirmed as markedly elevated plasma aldosterone concentrations and plasma renin activity. The differential diagnosis of PHA1 includes salt-wasting states due to hypoalosteronism, including several forms of congenital adrenal hyperplasia, isolated hypoaldosteronism due to corticosterone methyloxidase (CMO) I and II deficiencies and congenital adrenal hypoplasia. Normal cortisol and excessive aldosterone responses to adrenocorticotropin (ACTH) are expected in patients with congenital PHA. Therapy The standard treatment of PHA has been replacement with high doses of salt, with a variable response among patients. Recently, carbenoxolone, an 11β-hydroxysteroid dehydrogenase inhibitor, was employed as therapy in PHA1 and an ameliorating effect was observed which was attributed to mediation by mineralocorticoid receptor (MR). Both carbenoxolone and fludrocortisone normalized the serum electrolytes, suggesting the presence of a functional defective, renal MR. Interestingly, the same patient was unresponsive to intravenous infusion of aldosterone and fludrocortisone (up to 3 mg/day) when studied in infancy, suggesting that the clinical improvement that has been noted in the majority of PHA patients with age may be related to changes in their responsiveness to mineralocorticoid. Conn’s syndrome Characterized by increased aldosterone secretion from the adrenal glands, suppressed plasma renin activity (PRA), hypertension, and hypokalemia. It was first described in 1955 by JW Conn in a patient who had an aldosterone-producing adenoma. Later, many other cases of adrenal hyperplasia with increased aldosterone secretion were described, and now the term primary hyperaldosteronism is used to describe Conn syndrome and other etiologies of primary hypersecretion of aldosterone (adrenal hyperplasia). Currently, primary hyperaldosteronism seems to be the most common form of secondary hypertension. Clinical presentationsFew symptoms are specific, and mostly they result from hypokalemia and alkalosis by inducing renal distal tubular reabsorption of sodium, enhances secretion of potassium and hydrogen ions, causing hypernatremia, hypokalemia, and metabolic alkalosis. Patients with severe hypokalemia report fatigue, muscle weakness, cramping, headaches, and palpitations. They can also have polydipsia and polyuria from hypokalemia-induced nephrogenic diabetes insipidus. As mentioned previously, long-standing hypertension may lead to cardiac and neurologic problems, with all the associated symptoms. Causes Primary hyperaldosteronism can be divided into many subtypes. The most common subtype is Conn syndrome, an APA that is usually small (<3 cm), unilateral, and renin-unresponsive. This means that aldosterone secretion is not affected by changes in posture. Rarely, the adenoma is renin-responsive (ie, aldosterone levels increase with standing). Conn syndrome occurs in 50-60% of cases. The remaining 40-50% of cases due to bilateral adrenal hyperplasia, in which aldosterone increases in response to postural studies. Rarely, patients are hyperplastic (primary adrenal hyperplasia), and the response of aldosterone to standing is similar to renin-unresponsive APA. Rarely, adrenocortical carcinomas secrete aldosterone. Usually, the tumors are large (>4 cm). 22 Aldosterone can be ectopically secreted by adrenal embryologic rest neoplasm within the kidney and ovary. Primary hyperaldosteronism can be inherited in an autosomal dominant fashion in patients with GRA, in whom activation of aldosterone secretion is induced by corticotropin and is suppressible with glucocorticoid. The involved gene is on chromosome 8. Laboratory Studies Routine laboratory studies can show hypernatremia, hypokalemia, and metabolic alkalosis resulting from the action of aldosterone on the distal tubule of the kidney (enhancing sodium reabsorption and potassium and hydrogen ion excretion). Almost 20% of patients have impaired glucose tolerance resulting from the inhibitory affect of hypokalemia on insulin action and secretion; however, diabetes mellitus is rare. Typically, renin levels are suppressed to less than 1 ng/mL/h in patients with primary hyperaldosteronism, and levels do not stimulate above 2 ng/mL/h with diuretics and upright posture. Because of this finding, some experts suggest that suppressed renin levels should be used as a screen for detecting primary hyperaldosteronism. Plasma Aldosterone / plasma renin ratio "PA/PRA ratio" (obtained in the morning) of 20 or greater (with PA ≥15 ng/dL) provide a sensitivity of 100% and a specificity of 80%, indicating the need for further study. Others use a ratio greater than 30 and a PA level greater than 20 ng/dL, with a sensitivity of 90% and a specificity of 91%. Important note Plasma Aldosterone / plasma renin ratio should be calculated when the patient is not taking interfering medications. For examples, spironolactone should be stopped for 6 weeks prior to testing, eplerenone, another aldosterone receptor antagonist, can also interfere with testing and should be stopped for at least 2 weeks before, diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) can falsely elevate PRA, leading to a lower PA/PRA ratio; therefore, the presence of suppressed PRA in a patient treated with a diuretic or, especially, an ACE inhibitor or ARB, is a strong predictor for primary hyperaldosteronism. Because of limited specificity, a positive screening test result should be followed by a confirmatory test. The most commonly used confirmatory test is a 24-hour urine aldosterone level obtained after 3 days of salt loading. The patient can be instructed to maintain a sodium intake of at least 200 meq/d (1 teaspoon of salt 3 times daily) for 3 days. Care must be taken to ensure that potassium stores are replete and that the patient is normokalemic at the time of testing, because hypokalemia can inhibit aldosterone release and salt loading can exacerbate hypokalemia. A 24-hour aldosterone excretion rate of greater than 14 mcg (with a concomitant 24-h urine sodium >200 meq) is diagnostic of primary hyperaldosteronism. Imaging Studies Abdominal CT scanning is considered the procedure of choice. Some investigators suggest that when a solitary unilateral macroadenoma (>1 cm) is detected in the setting of unequivocal hyperaldosteronism in a young patient, unilateral adrenalectomy is indicated. 23 Lesions smaller than 1 cm, may be missed by CT scanning. Furthermore, bilateral lesions are not always diagnostic of adrenal hyperplasia because of the high incidence of adrenal incidentaloma. In these cases, adrenal vein sampling is the only way to make a firm diagnosis. Overall, CT scanning has a sensitivity of 67-85% in patients with primary hyperaldosteronism. Scanning with iodine I-131 iodocholesterol (precursor of aldosterone) has been used to detect unilateral functional adrenal lesions. In experienced hands, has a sensitivity of 88%. However, this procedure is not widely available, requires careful patient preparation, is very expensive, and rarely detects lesions larger than 1.5 cm. Medical Care In patients with primary hyperaldosteronism, the goal of treatment is to prevent the morbidity and mortality associated with hypertension and hypokalemia. The appropriate treatment depends on the cause. Although hypertension is frequently cured after unilateral adrenalectomy in patients with Conn syndrome, the mean cure rate is only 19% after unilateral or bilateral adrenalectomy in patients with IHA, in whom treatment mainly is medical. A sodium-restricted diet (<2 g of sodium per day), maintenance of ideal body weight, and regular aerobic exercise contribute substantially to the success of pharmacologic treatment. Frequently, hypertension and hypokalemia can be controlled with a potassium-sparing agent (first-step agent), such as spironolactone. Hypokalemia is promptly corrected, but hypertension may take as long as 4-8 weeks to correct. Potassium supplementation should not be routinely administered with spironolactone because of the potential for the development of hyperkalemia. If hypertension persists despite titration, a second-step agent is added to the treatment. Second-step agents include thiazides diuretics, ACE inhibitors, calcium channel antagonists, and angiotensin II blockers. GRA is treated with physiologic doses of glucocorticoid, which correct the hypertension and hypokalemia. Surgical Care Laparoscopic adrenalectomy is favored, when possible. In patients with Conn syndrome, the blood pressure response to spironolactone preoperatively is a predictor of the blood pressure response to unilateral adrenalectomy. Surgical risk can be decreased by correcting the hypokalemia and controlling the blood pressure by administering spironolactone for at least 1-2 weeks, preferably 6 weeks, before surgery. Hypertension typically does not resolve immediately postoperatively but, rather, over 3-6 months; however, almost all patients have improved control of blood pressure after surgery. Long-term cure rates with unilateral adrenalectomy for Conn syndrome average 69%. Pheochromocytoma Catecholamine-secreting tumor derived from chromaffin cells. Pheochromocytoma and paraganglioma are rare neoplasms in children. Tumors that arise from the adrenal medulla are termed pheochromocytoma, and those with extraadrenal origins are called paraganglioma. Among hypertensive children, the incidence of surgically confirmed disease has ranged from 0.8 to 1.7 percent . The classic triad of symptoms consists of episodic headache, sweating, and tachycardia, usually accompanied by hypertension. However, only 50 percent of adult patients have one or more of 24 the "three classic symptoms". Symptoms caused by the mass effect of the tumor, such as abdominal pain and distension or back pain. In contrast to adults, in whom there is a high incidence of paroxysmal hypertension, most children have sustained hypertension. Malignant hypertension can occur with its associated complications (increased intracranial pressure, encephalopathy). Other signs and symptoms that occur less frequently include pallor, constipation, psychiatric disorders, blurred vision, weight loss, polyuria, polydipsia, increased erythrocyte sedimentation rate, hyperglycemia, and a dilated cardiomyopathy that may reflect the toxic effect of excess catecholamines. The clinical presentation is often different when pheochromocytoma is associated with the multiple endocrine neoplasia type 2 (MEN2) syndrome. Symptoms are present in only approximately one-half of patients, and only one-third have hypertension. A similar finding has been observed with pheochromocytoma associated with von Hippel-Lindau (VHL) disease, as 35 percent of patients have no symptoms, a normal blood pressure, and normal catecholamine tests. Compared to adults, children with pheochromocytomas have a higher incidence of bilateral adrenal tumors, extraadrenal tumors, and multiple tumors. In different series, extraadrenal tumors have been described in 30 to 60 percent of children (contrasted to 10 to 15 percent of adults), and multiple tumors have been described in up to 40 percent (compared to 5 to 10 percent in adults).Catecholamine-secreting paraganglioma are co-located with chromaffin tissues (along the para-aortic sympathetic chain, within the organs of Zuckerkandl at the origin of the inferior mesenteric artery, wall of the urinary bladder, and the sympathetic chain in the neck or mediastinum). Children and adolescents with pheochromocytoma or paraganglioma are at risk for malignant disease. Approximately 10 percent of pheochromocytomas in adults are malignant, whereas up to 47 percent of children in one series had malignant disease. In a series of 30 children with either pheochromocytoma or paraganglioma, statistically significant risk factors for malignancy included paraganglioma, apparent sporadic disease, and tumor size greater than 6 cm. Malignant pheochromocytomas and paragangliomas are histologically and biochemically the same as benign tumors. Thus, the only clue to the presence of a malignant pheochromocytoma is regional invasion or distant metastases, which may occur as long as 15 years after resection Stimulation of alpha-adrenergic receptors results in elevated blood pressure increased cardiac contractility, glycogenolysis, gluconeogenesis, and intestinal relaxation. Stimulation of betaadrenergic receptors results in an increase in heart rate and contractility. Symptoms include the following: headache, diaphoresis, palpitations, tremor , nausea, weakness, anxiety, epigastric pain, flank pain, constipation and weight loss Pheochromocytomas occur bilaterally in the MEN syndromes in as many as 70% of cases. MEN 2A (Sipple syndrome) is characterized by medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas, and Hirschsprung disease. 25 MEN 2B is characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal neurofibromatosis, intestinal ganglioneuromatosis, Hirschsprung disease, and a marfanoid body habitus. VHL disease is associated with pheochromocytoma, cerebellar hemangioblastoma, renal cell carcinoma, renal and pancreatic cysts, and epididymal cystadenomas. Neurofibromatosis, or von Recklinghausen disease, is characterized by congenital anomalies (often benign tumors) of the skin, nervous system, bones, and endocrine glands. Only 1% of patients with neurofibromatosis have been found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas have been found to have neurofibromatosis. Other neuroectodermal disorders associated with pheochromocytomas include tuberous sclerosis (Bourneville disease, epiloia) and Sturge-Weber syndrome. Familial pheochromocytoma The familial syndromes associated with pheochromocytoma have autosomal dominant inheritance. Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B von Hippel-Lindau (VHL) disease Neurofibromatosis type 1 (NF1) Succinate dehydrogenase mutations in subunits D, B, and C Approximately 50 percent of cases of multiple endocrine neoplasia include pheochromocytoma [35]. Between 10 and 20 percent of cases of VHL disease include pheochromocytoma [35]. Approximately 2 percent of patients with a disease-associated NF1 mutation develop catecholamine-secreting tumors, which may be adrenal pheochromocytomas or abdominal paragangliomas [36]. Catecholamine-secreting tumors may be associated with other neurocutaneous syndromes, including ataxia-telangiectasia, tuberous sclerosis, and Sturge-Weber syndrome Familial paraganglioma Familial paraganglioma is an autosomal dominant disorder characterized by paragangliomas that are located most often in the head and neck but also in the thorax, abdomen, pelvis, and urinary bladder Laboratory Studies Genetic testing — Although most patients with germline mutations that predispose to the development of pheochromocytoma or paraganglioma are typically not diagnosed until adulthood, onset during childhood can occur. A genetic cause should be sought in all children with pheochromocytoma or paraganglioma. Genetic testing can be complex. Testing one family member has implications for related individuals. Genetic counseling is recommended to help families understand the implications of 26 genetic test results, to coordinate testing of at-risk individuals, and to help families work through the psychosocial issues that may arise before, during, or after the testing process The diagnosis in the pediatric age group is best confirmed by measurement of 24-hour fractionated urinary metanephrines and catecholamines followed by radiographic localization of the tumor. In young children in whom an accurate 24-hour urine collection is not possible, measurement of plasma fractionated metanephrines is a reasonable alternative initial test The standard method for confirming the diagnosis of pheochromocytomas is to measure the following urinary catecholamines and their metabolites in a 24-hour specimen: epinephrine, norepinephrine, dopamine, metanephrine, homovanillic acid (HVA) and vanillylmandelic acid (VMA). creatinine levels should be determined for each 24-hour collection to assess the adequacy of the collection. If possible, the collection should be made while the patient is at rest, taking no medication, and without recent exposure to radiographic contrast medium. Urine should be acidified (pH <3) and kept cold during and after the collection. The diagnostic yield is increased if the patient is symptomatic during the collection period. Medications and foods that are known to interfere with the assay should be avoided. The major cause of false-positive catecholamine excretion results is administration of exogenous catecholamines, such as levodopa, methyldopa, and labetalol, which can elevate urine concentration for as long as 2 weeks. Certain foods can increase urinary catecholamines, including coffee, tea, bananas, chocolate, cocoa, citrus fruits, and vanilla. The following drugs can increase catecholamine measurements: Caffeine, acetaminophen (Tylenol) , Levodopa, Lithium, aminophylline, chloral hydrate, clonidine, erythromycin, insulin, methyldopa, nicotinic acid (large doses), Quinidine, tetracyclines, nitroglycerin. Drugs that can decrease catecholamine measurements include the following: clonidine, monoamine oxidase inhibitors (MAOIs), phenothiazines, salicylates and reserpine Other studies include the following: CBC count: This test is indicated when infection or abdominal pain is present. Electrolytes, BUN, creatinine, and glucose determinations: Evaluate for lactic acidosis; renal failure secondary to hypertension, renal damage, or both; and hyperglycemia or hypoglycemia caused by the impaired insulin response. Calcium measurement: High levels may be present because of excess of parathyroid hormone (PTH). Urinalysis: Proteins may be found in the urine because of hypertension. Measurement of plasma catecholamines is as follows: o Patients must be in a basal and calm state. o The measurement reflects only that single moment when the blood sample was obtained. o Basal levels of more than 2 ng/dL support the diagnosis, whereas values of less than 0.5 ng/dL make the diagnosis unlikely. o Suppression tests (phentolamine, clonidine) and stimulation tests (glucagon, histamine, metoclopramide) have both been proposed for improving diagnostic accuracy. Stimulation tests are dangerous. Administer with extreme caution. Consider a glucagon stimulation test if basal values are from 0.5-1 ng/dL. Patients demonstrate a significant rise in plasma catecholamine levels within minutes of glucagon administration; however, this can lead to severe hypertension. When the values are 1-2 ng/dL, a clonidine suppression test, which is highly sensitive and specific, is indicated. Mildly elevated levels of catecholamines in healthy individuals are suppressed by a dose a clonidine. The clonidine 27 o o o suppression test (0.3 mg) involves the collection of plasma free normetanephrine before and after oral administration of clonidine. Measurement of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to von Hippel-Lindau disease or MEN type 2. Free plasma metanephrines has been found to be a highly sensitive (100%) and specific (96.7%) measure, yielding a negative predictive value of 100%. Measurement of 24-hour urinary fractionated metanephrines using a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of Pheochromocytoma. Imaging Studies When the diagnosis has been established, the tumor must be located to facilitate its surgical removal. Although larger tumors can usually be located easily with sonography, the smallest tumors may require CT scanning or MRI, particularly when located outside the adrenal area. Scintigraphy with radiolabeled 131I-MIBG or 123I-MIBG is indicated. MIBG scintigraphy allows whole-body exploration. Owing to its high specificity (97%), this morphological study seems to be a valuable adjunct in the detection of extra-adrenal lesions. The main limitation of MIBG scintigraphy is its slightly lower sensitivity (adrenal, 84%; extraadrenal, 64%) than MRI (adrenal, 97%; extra-adrenal, 88%) or CT scanning (adrenal, 94%; extra-adrenal, 64%). However, despite the lower sensitivity, MIBG scanning offers the greatest specificity, and tumors seen on these images are almost certainly pheochromocytomas. If the MIBG scanning results are positive in a child, consider a diagnosis of neuroblastoma until proven differently. Positron emission tomography (PET) with radiopharmaceuticals provides functional imaging. It is designed to show substrate precursor uptake, cellular metabolism, or receptor binding in neoplasms with CT as a single modality; hybrid PET/CT directly correlates function and anatomy. It identifies localized pheochromocytoma with a sensitivity of 84.6%, a specificity of 100%, and an accuracy of 92%. Arteriography and selective venous sampling are almost never indicated. However, they may be helpful in patients predisposed to multiple tumors or when clinical and biochemical evidence is consistent with pheochromocytoma but are unsupported by other imaging modalities. Chest radiography can be used to evaluate for pulmonary edema. Medical Care Perform initial workup of pheochromocytoma using the history, physical examination, laboratory, and diagnostic test findings. Indications for evaluation include the following: o Patients with high blood pressure or recurrent hot flushes that are indicative of blood pressure peaks o Patients with an adrenal mass o Relatives of patients with MEN 2 or von Hippel-Lindau disease Schedule surgical removal only after successful pharmacotherapy to block the effects of catecholamine excess. Blockade of the alpha-adrenergic receptors in the preoperative phase is widely recommended, with additional beta-receptor blockade to treat cardiac dysrhythmias. During a hypertensive crisis, immediately institute alpha-blockade with phentolamine. Nitroprusside also should be used for uncontrolled hypertension. For further blood pressure control, initiate beta-blockade (esmolol-labetalol). A betablockade that is initiated without prior alpha-blockade can further exacerbate 28 hypertension. As vasoconstriction is relieved, use vigorous fluid resuscitation to maintain a normal blood pressure. Ventricular tachyarrhythmias can be treated with lidocaine and amiodarone. Chemotherapy and radiotherapy have been of questionable value in patients with unresectable disease. Unresectable disease may be rendered resectable by intensive chemotherapy. Chemotherapy currently has a response rate of approximately 50%. Sunitinib appears to be an active agent in the treatment of malignant pheochromocytomas based on limited cohort of patients and is currently in phase 2 trials. Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases, such as platelet-derived growth factor receptors, and vascular endothelial growth factor receptors, which play a role in both tumor angiogenesis and tumor cell proliferation. Patients with germline mutation and no evidence of active illness should have continued follow-up for pheochromocytoma. Surgical Care Surgery to remove pheochromocytomas is a high-risk procedure because of several reasons. Substantial comorbidity must be expected, including catecholamine-induced myocardiopathy. Intraoperative manipulation of the tumor may induce excessive catecholamine excretion, resulting in a life-threatening hypertensive crisis. Hypotensive crisis may occur because of a postoperative drop of catecholamines. Preoperative blockade of alpha-1 receptors has been used to reduce the risk of hypertensive episodes. Drugs such as urapidil has shown a significant reduction in hypertensive peaks. Transabdominal surgery has been the traditional approach; it allows early ligation of the adrenal vein to minimize systemic catecholamine release during manipulation. This approach also facilitates exploration of the sympathetic chain for multifocality. Other options include a subcostal or posterior extraperitoneal approach that offers rapid recovery and avoids the risk of transperitoneal surgery (adhesions, bowel obstruction). Alternatively, a laparoscopic adrenalectomy can be considered; tumors as large as 11 cm have been successfully removed. The contraindications to laparoscopy include evidence of soft-tissue or vascular extra-adrenal extension. Bilateral tumors develop in children with multiple endocrine neoplasia type 2 and pheochromocytoma, and bilateral adrenalectomy has been recommended at presentation. Careful and intensive monitoring of the patient's status throughout the perioperative period is imperative. Hypotension that develops after tumor removal reflects reversal of the volume-contracted state and should respond to judicious replacement of fluids. Some patients may develop pulmonary edema, possibly as a result of impaired myocardial function and the inability to tolerate intravenous fluids. When the tumor is removed, the blood pressure usually falls to approximately 90/60 mm Hg. Lack of a fall in pressure at the time of tumor removal indicates the presence of additional tumor tissue. When bilateral adrenal tumors are found and both adrenals are removed, adrenocortical lifelong steroid replacement is required. Significant morbility is associated with bilateral adrenalectomy. Because of these risks, some clinicians have recommended adrenalsparing surgery in patients who have bilateral tumors or who are at particular risk for a metachronous contralateral tumor. 29