Download Chapter 4: Adrenal Disorders

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.
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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
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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
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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
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Hypertension (HTN) and Hypokalemia
Delayed puberty in females and virilization in males
No salt-wasting occurs.
3-beta-hydroxysteroid dehydrogenase deficiency
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Ambiguous genitalia in both males and females
Salt-wasting (rare).
11-beta-hydroxylase deficiency
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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.
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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:
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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
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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
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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:
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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.
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Key points
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Primary adrenal insufficiency is defined as the impaired synthesis and/or release of
adrenocortical hormones on account of disease intrinsic to the adrenal cortex.
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Clinical manifestations are dependent on the type of hormonal class affected and the severity
of the defect(s).
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The hormones are divided into glucocorticoid (cortisol), mineralocorticoid (aldosterone), and
adrenal androgens (dehydroepiandrosterone).
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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.
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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
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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
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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
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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.
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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
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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.
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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
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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:
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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)
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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
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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
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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:
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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.
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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.
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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
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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.
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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.
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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.
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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
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
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
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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.
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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.
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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.

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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
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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:
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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
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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
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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
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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.
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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