Adrenocortical Insufficiency
Deficient production of cortisol or aldosterone result from
lesions of the hypothalamus,
pituitary gland,
adrenal cortex
symptoms may be
severe
mild,
appear
abruptly
insidiously,
Onset -
infancy
later
May be permanent or temporary.
Corticotropin
Deficiency. (ACTH)
hypoplasia or aplasia of the pituitary
These congenital defects are associated with abnormalities
of the skull and brain
anencephaly and
holoprosencephaly.
adrenals are small with normal structure,
autosomal recessive inheritance
craniopharyngioma, is the most common causes of ACTH
deficiency
Adrenal Hypoplasia
Congenita.
onset of hypo-adrenalism usually begins
in the neonatal period
may be delayed until 10 yr of age
presenting manifestations
Increasing pigmentation
salt-losing symptoms
low levels of all adrenal
steroids
Affects - boys
caused by a mutation of the DAX-1
gene, - located on Xp21.
boys with adrenal hypoplasia
congenita (AHC) do not undergo puberty owing to hypogonadotropic hypogonadism
(HHG),
both AHC and HHG are caused by
the same mutated DAX-1 gene. Cryptorchidism, is seen in these boys, is – a
manifestation of HHG.
AHC also occurs in
Duchenne muscular dystrophy
glycerol kinase deficiency
mental retardation
Prenatal diagnosis of AHC is possible.
Inborn Defects of
Steroidogenesis.
The most common causes of adrenocortical insufficiency in
infancy are the salt-losing forms of congenital adrenal hyperplasia
21-hydroxylase defect
lipoid adrenal hyperplasia
deficiency of 3b-hydroxysteroid
dehydrogenase manifest salt-losing symptoms in the newborn period.
Here there is a deficiency in the
synthesis of both cortisol and aldosterone
There are elevated levels of
steroids that are formed prior to the enzymatic defect.
Hemorrhage into Adrenal Glands.
1. Occur in the
neonatal period because of difficult labor or asphyxia.
Scrotal hematoma may be the presenting sign.
Identified by calcification of the adrenal gland
2. Waterhouse-Frederickson
syndrome - shock resulting from meningococcemia
3. Adrenal
hemorrhage may also occur because of child abuse.
Abrupt Cessation
of Administration of Corticotropin or a Corticosteroid.
Likely to occur if steroid is been given in large doses for
a long time to patients( asthma, Nephrotic syndrome) who are subjected to
stressful situations such as severe infections or surgical procedures.
CLINICAL
MANIFESTATIONS.
At birth -
Symptoms characteristic of salt loss-
-
Failure to thrive
-
Vomiting
-
Lethargy
-
anorexia
-
dehydration
-
Circulatory collapse may be fatal.
In older children with Addison
disease,
onset is more gradual
-
muscular weakness
-
lassitude
-
anorexia
-
loss of weight
-
general wasting
-
low blood pressure
-
Abdominal pain may simulate an acute surgical condition,
-
an intense craving for salt.
-
adrenal crisis – may be fatal - suddenly becomes
cyanotic, the skin is cold, and the pulse is weak and. blood pressure falls,
and respirations rapid and labored.
-
crises is precipitated by infection, trauma, excessive
fatigue, or drugs such as barbiturates, laxatives, thyroid hormone, or insulin.
Increased
pigmentation of the skin should make you think of possibility of
adrenocortical insufficiency.
This manifestation occurs in due
to excessive secretion of ACTH
-
primary adrenal hypoplasia
-
adrenoleukodystrophy
-
Addison disease.
Pigmentation first on the face
and hands
Most intense around the genitals,
umbilicus, axillae, nipples, and joints
Scars may be especially pigmented
Areas of depigmentation
(vitiligo) may be interspersed with dark areas.
The exposed areas of the skin are
the most intensely affected
failure of a suntan to disappear
may be the first clue to the condition.
buccal mucosa -pigmentation is
bluish brown.
Other features-
hypoglycemia, in the neonate with congenital adrenal hypoplasia.
Pigmentation does not occur in patients with a deficiency
of ACTH.
Hypoglycemia is the usual presenting manifestation.
Hyperkalemia does not occur because of preserved aldosterone
secretion, but hyponatremia may be present.
LABORATORY FINDINGS.
- serum sodium and chloride are low
- levels of potassium elevated
- increased plasma Renin activity
- Urinary excretion of sodium and chloride is increased
- urinary potassium is decreased
- pH & ABG - acidosis.
- Plasma Urea is elevated if dehydration is present.
- Hypoglycemia
- Blood eosinophils - increased in number.
- X ray of the abdomen - calcifications in the area of the adrenals – in hemorrhage, adrenal cysts, or tuberculosis
- Ultrasonography of the abdomen ]
- computed tomography of the abdomen ] -- to show adrenals
- magnetic resonance imaging of the abdomen ]
- X ray Chest – Microcardia - A small and narrow shadow of the heart reflects hypovolemia.
- Electrocardiography- changes reflect potassium levels
- measurement of the plasma or serum levels of cortisol before and after administration of ACTH- resting levels are low
No increase
occurs after administration of ACTH.
17. Measurement of plasma or serum levels of cortisol precursors - in
infants in whom congenital adrenal hyperplasia is suspected.
TREATMENT.
Treatment - for adrenal crisis must be immediate and
vigorous.
- Blood
sample should be obtained before therapy for determination of levels of ACTH,
cortisol
aldosterone
PRA(plasma renin activity)
17a-hydroxyprogesterone
adrenal androgens. - Intravenous administration of 5% glucose in 0.9% saline solution - to correct the hypoglycemia and the sodium loss.
- water-soluble form of hydrocortisone- should be given intravenously. - large doses can be given safely. - 25 mg for infants and 75 mg for older children -given intravenously at 6-hr intervals for the first 24 hr. - dose may be reduced during the next 24 hr
- After the first 48 hr, if oral intake is satisfactory, intravenous fluids may be discontinued
- corticosteroid given orally as cortisol in doses of 5–20 mg at 8-hr intervals.
- Florinef (9a-fluorohydrocortisone), a mineralocorticoid, added orally at 0.05–0.3 mg daily.
chronic
replacement therapy for aldosterone and cortisol deficiencies.
cortisol given orally in daily doses of 5–10 mg/24 hr in two
or three divided doses
Fluorhydrocortisone is continued orally in doses of 0.05–0.3
mg daily.
During situations of stress, such as infection or operative
procedures, the dose of hydrocortisone should be increased.
Overdosage with fluorhydrocortisone results in
hypertension
cardiac enlargement
edema
because of excessive retention of sodium chloride and water
Excessive loss of potassium may produce weakness or
paralysis
elevated levels of very long chain fatty acids are
diagnostic of adrenoleukodystrophy. antiadrenal antibodies suggests an
autoimmune pathogenesis;
Infants with congenital adrenal hypoplasia should undergo
chromosomal analysis to search for a mutation or deletion of the Xp21 region
elevated levels of creatine phosphokinase indicate an
association with Duchenne muscular dystrophy
elevated levels of triglycerides suggest glycerol kinase
deficiency.
Deficiency of
21-hydroxylase
accounts for 90% of affected patients.
This P450 enzyme (P450c21) hydroxylates progesterone and
17-hydroxyprogesterone (17-OHP) to
yield
11-deoxycorticosterone
(DOC) and 11-deoxycortisol
There steroid 21-hydroxylase genes are on the short arm of
chromosome 6
classic disorder occurs in salt-wasting and simple
virilizing forms.
Newborn screening programs
Uses -capillary
heel blood on filter paper disks
75% of affected infants have the salt-losing, virilizing
form
25% have the simple virilizing form
CLINICAL MANIFESTATIONS.
The clinical manifestations in CAH depend on
which
hormones are deficient
and which
are overproduced
Most patients with CAH have the defect in 21-hydroxylation
75% of
infants are salt losers,
Non-Salt–Losing Congenital Adrenal Hyperplasia.
In the male with 21-hydroxylase deficiency,
clinical
manifestations are of premature isosexual development.
The infant isnormal at birth,
-
signs of sexual and somatic precocity may appear within
the first 6 mo of life
-
evident at 4–5 yr of age or later.
-
Enlargement of the penis, scrotum, and prostate
-
appearance of pubic hair
-
development of acne and a deep voice
-
Muscles are well developed
-
bone age is advanced for chronological age.
-
premature closure of the epiphyses causes growth to
stop early
-
testes appear small in contrast to the enlarged penis
-
Mental development is normal
-
abnormal physical development may result in behavioral
problems.
In the female, CAH due to 21-hydroxylase deficiency results
in
-
female pseudohermaphroditism
-
there is almost always evidence of masculinization at
birth.
-
enlargement of the clitoris and varying degrees of
labial fusion.
-
vagina usually has a common opening with the urethra
(urogenital sinus).
-
The clitoris may be so enlarged that it resembles a
penis,
-
because the urethra opens below this organ, a mistaken
diagnosis of hypospadias and cryptorchidism is sometimes made.
-
complete labial fusion, a phallic urethra, and an
external meatus at the tip of the penis.
-
internal genital organs are of a normal female
-
Salt losing may or may not be seen
After birth
-
Pubic and axillary hair develop prematurely
-
acne appears
-
voice assumes a masculine quality.
-
tall for their age
-
ossification is advanced;
-
body build of a
boy
-
the internal genitals are female
-
breast development and menstruation do not occur
-
erroneously reared as males
LABORATORY FINDINGS
salt-losing disease
-
low serum concentrations of sodium and chloride
-
elevated levels of potassium and blood urea nitrogen.
-
Plasma levels of renin are elevated
-
serum aldosterone is inappropriately low for the renin
level.
-
In classic 21-hydroxylase deficiency, serum levels of
17-OHP are elevated
-
Blood levels of cortisol are usually low in patients
with the salt-losing type of disease.
-
Levels of urinary 17-ketosteroids and pregnanetriol are
elevated
DIAGNOSIS.
-
adrenal tumor may be palpable
-
may be seen on IVP by displacement of the adjacent
kidney.
-
Ultrasonography, computed tomography (CT), or magentic
resonance imaging (MRI) may be necessary if hormonal studies have ruled out
CAH.
-
Urinary 17-ketosteroid excretion and plasma levels of
dehydroepiandrosterone sulfate (DHEAS) are elevated with CAH and cortical
tumors,
-
very high values favor the diagnosis of neoplasm.
Administration of hydrocortisone quickly reduces elevated
steroid levels to normal in patients with CAH but does not do so in those with
a virilizing tumor.
By inhibiting secretion of corticotropin, corticosteroids
reduce the stimulation of the adrenals in patients with CAH, whereas
adrenocortical tumors are not subject to pituitary regulation.
In males with CAH,
-
testes are small for the degree of virilization,
-
in true precocious puberty or with Leydig cell tumors,
the testes are enlarged for age.
Females with CAH -adrenal cortical steroid levels elevated.
Molecular techniques can now be used for genetic counseling
for all forms of CAH.
Prenatal Diagnosis and Treatment.
Prenatal diagnosis of 21-hydroxylase
in 1st trimester
DNA
analysis and HLA genotyping of chorionic villus cells.
In 2nd trimester
1. measuring 17-OHP and androstenedione in
amniotic fluid
2. HLA typing and DNA analysis of amniotic
fluid cells.
Prenatal treatment
-
maternal dexamethasone administration
-
dexamethasone, readily crosses the placenta,
-
First-trimester chorionic villus biopsy is performed to
determine the sex and genotype of the fetus
-
therapy is continued only if the fetus is a female.
-
Maternal side effects - edema, excessive weight gain,
hypertension, glucose intolerance, cushingoid facial features, and severe
striae with permanent scarring.
DNA analysis
of chorionic villus cells can be used for the prenatal diagnosis of all forms
of CAH.
TREATMENT.
glucocorticoids inhibits excessive production of androgens
prevents progressive virilization.
-
hydrocortisone (10–20 mg/m2 /24 hr) orally in two or
three divided doses
-
Infants require 2.5–5 mg two to three times daily
-
children 5–10 mg two to three times daily.
-
Doses must be individualized by monitoring growth and
hormonal levels.
-
salt-losing disease- require a mineralocorticoid and
sodium supplementation in addition to the glucocorticoid. - therapy with
9a-fluorohydrocortisone (0.05–0.3 mg daily) and sodium chloride, 1–3 g
-
non–salt-losing disease may also manifest elevated
plasma renin activity and require a mineralocorticoid.
Serum levels of 17-OHP, androstenedione, testosterone, and renin,
measured at
8–9 A.M
prior to
taking the morning medication
monitor for
signs of
cortisol
or androgen excess
growth
and weight gain
pubertal
development
osseous
maturation
administration of hydrocortisone must be continued
indefinitely
Increased doses are indicated during periods of stress such
as infection or surgery because they have defective adrenal reserve.
The enlarged clitoris of female infants - requires surgical
correction
Timing is 6–12 mo.
Vaginoplasty and correction of the urogenital sinus also
done at the time of clitoral surgery
complete sexual gratification, including orgasm, can be
achieved.
menarche occurs at the appropriate age
delay is related to suboptimal dose.
sex assignment of infants with intersex - -easy to make a
female.
Destruction of the adrenal cortex during childhood
Tuberculosis
Autoimmune
destruction
Usually the medulla is not destroyed
All adrenal cortical function is lost
Antiadrenal antibodies seen in plasma
inherited
as an autosomal recessive disorder,
gene in chromosome 21q22.3
Type I autoimmune polyendocrinopathy - autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy.
Chronic
mucocutaneous candidiasis is the first manifestation,
Hypoparathyroidism
Addison
disease
Other features -
gonadal
failure
alopecia
vitiligo
keratopathy
enamel
hypoplasia
nail
dystrophy
intestinal
malabsorption
chronic
active hepatitis
Hypothyroidism
type I
diabetes mellitus
Type II autoimmune polyendocrinopathy
autoimmune
thyroid disease or insulin-dependent diabetes.
Gonadal
failure
Vitiligo
alopecia
chronic
atrophic gastritis
pernicious
anemia
HLA-D3 and
HLA-D4 predominate in these patients
common in
females
Antiadrenal
antibodies, steroid cell antibodies, and antibodies to 21-OH, 17a-OH, and P450
scc enzymes are also found in these patients.
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