Transcript ADRENOCORTICAL INSUFFICIENCY

ADRENOCORTICAL
INSUFFICIENCY
THE ADRENAL
CORTEX
BASIS CONCEPTS
ADRENOCORTICAL HISTOLOGY
The adrenal cortex is composed of three
concentric zones with distinct steroid
biosynthetic capacities.
 Zona glomerulosa – biosynthesis of
mineralocorticoids
 Zona fasciculata – biosynthesis of
glucocorticoids
 Zona reticularis – biosynthesis of
adrenal androgens.
STEROID BIOSYNTHESIS
Steroidogenesis results from
specific sequential enzymatic
conversions of cholesterol
substrate into steroid hormones,
which exert a wide variety of
biological activities.

STEROID BIOSYNTHESIS

A series of steroidogenic enzymes are
compartmentalized either in the
mitochondria or in the endoplastic
reticulum.

Several of these enzymes belong to
the superfamily of mixed function
oxidase enzymes known as
cytochrome P450.
STEROID BIOSYNTHESIS
Approximately ~80% of adrenal
cholesterol sources are provided by
circulating low density lipoprotein
(LDL).


The adrenal cells can also synthesize
cholesterol de novo from acetyl
coenzyme A.
STEROID BIOSYNTHESIS
The first rate-limiting step in
steroidogenesis involves the removal
of six carbons from the lateral chain
of cholesterol by integral inner
mitochondrial membrane P450 side
chain cleavage (CYP11A1) enzyme to
generate pregnenolone.

Nomenclature for steroidogenic enzymes now utilized
Trivial name
Past
Current
Cholesterol side-chain cleavage
enzyme; desmolase
P450scc
CYP11A1
3β-Hydroxysteroid dehydrogenase
3β-HSD
3β-HSD
17α-Hydroxylase/17,20-lyase
P450c17
CYP17
21-Hydroxylase
P450c21
CYP21A2
11β-Hydroxylase
P450c11
CYP11B1
Aldosterone synthase;
P450C11AS CYP11B2
corticosterone 18-methylcorticosterone
oxidase/lyase
Main steroid biosynthetic pathways
(mineralocorticoids and glucocorticoids).
CYP17
cholesterol
CYP11A1
17,20-lyase
17α-hydroxylase
17αOH-pregnenolone
pregnenolone
17α OH-progesterone
progesterone
CYP21A2
CYP11B2
11-deoxycorticosterone
(DOC)
11-deoxycortisol
(S)
11β-hydroxylase
corticosterone
(B)
18-hydroxylase
CYP11B1
18OH-corticosterone
18-methyloxidase
ALDOSTERONE
CORTISOL
(F)
ZONA FASTICULATA
ZONA GLOMERULOSA
3β-HSD II
Main steroid biosynthetic pathways
(adernal androgens).
cholesterol
CYP11A1
pregnenolone
CYP17
17αhydroxylase
17β-HSD
17,20-lyase
17αOHpregnenolone
Dehydroepiandrosterone
Androstendiol
(DHEA)
3β-HSD II
progesterone
17α OHprogesterone
∆4androstendione
testosterone
estrone
estradiol
CYP19
ZONA
RETICULARIS
REGULATION OF
GLUCOCORTICOID SECRETION

The secretion of cortisol is
regulated by several levels of
signals and interactions between
the brain, the hypothalamus, the
pituitary, and the adrenal glands.
Regulation of the hypothalamic-pituitary-adrenal axis.
Cicardian rhythms
Feeding cycles
cytocines
stress
HIGHER BRAIN CENTERS
+
-
HYPOTHALAMUS
+
Neurotransmitters
-
neuropeptides
CRH-AVP
PITUITARY GLAND
ACTH
ADRENAL CORTEX
CBG
Cortisol-CBG
+
+
cytokines
-
Free-cortisol
PERIPHERIAL TISSUES
-
Inflammatry agents
CORTICOTROPIN-RELEASING HORMONE
(CRH)

41-aminoacid peptide synthesized by
neurons in the paraventricular
hypothalamic nucleus
 Action:


mRNA levels of pro-opiomelanocortin
(POMC),
the polypeptide precursor of ACTH
ADRENOCORTICOTROPIC
HORMONE [ACTH]

39-aminoacid peptide capable of
stimulating secretion of glucocorticoids,
androgenic steroids, and to a lesser
extent of mineralocorticoids from the
adrenal cortex.


In human ACTH stimulates melanin
synthesis in skin melanocytes.
ADRENOCORTICOTROPIC
HORMONE [ACTH]
The acute effect of The chronic effects
ACTH
of ACTH


activation exisiting
CYP11A1 to
convert cholesterol
to pregnenolone

increase in gene
trascription of most
of the steroidogenic
enzymes

(CYP11A1, CYP17,
CYP21A2, CYP11B1)
IN THE CHRONIC
ABSENCE OF ACTH ,
THE ADRENAL CORTEX
BECOMES ATROPHIC.
Glucocorticoid negative
feedback.
Glucocorticoids inhibit the release and
synthesis of ACTH primarily by decreasing
POMC gene transcription in pituitary
corticotroph cells.


Glucocorticoids inhibit the production and
secretion of CRH and vasopressin in
hypothalamic paraventricular nuclei.
ADRENOCORTICAL
INSUFFICIENCY
 Impairment
of the adrenal
production of glucocorticoids
(cortisol) and mineralocorticoids
(aldosterone) leads to a lifethreatening situation that is
often misinterpreted and
neglected.
ADRENOCORTICAL INSUFFICIENCY
PRIMARY
SECONDARY
(Addison’s disease)
inadequate ACTH
damage of the
adrenal glands
and/or CRH
secretion
BOTH PRIMARY AND SECONDARY
ADRENAL INSUFFICIENCY ARE
RARE DISEASES.
The prevalence of acquired primary
insufficiency is estimated at 39 to 60
cases per 1 million people, with most
the cases being diagnosed in the
third to fifth decade of life.
Iatrogenic adrenal insufficiency,
secundary to exogenous
glucocorticoid therapy, includes
large number of patients and
implies similar risks of acute
adrenal crisis.


Congenital adrenal hyperplasia (CAH)
is a family of inborn errors of
steroidogenesis, primarily
characterized by a specific enzyme
deficiency that impairs cortisol
production by the adrenal cortex.
Complete and near-complete blocks
of the 21-hydroxylase enzyme
(classical form of CAH) occurs in 1 in
15 000 live births worlwide.
ADRENOCORTICAL INSUFFICIENCY
For most cases of adrenal
insufficiency, impairment of
hormonal production can take place
over the course of many years, and
the clinical picture is insidiously
dominated by the features of the
disorder.

CAUSES OF PRIMARY
ADRENOCORTICAL INSUFFICIENCY
Autoimmune adrenalitis (80%)
Infectoius adrenalitis

tuberculosis (20%)
histioplasmosis, paracoccidioidomycosis,
blastomycosis, coccidioidomycosis, cryptococcosis

Invasive destruction



metastases
lymphoma
amyloidosis, sarcoidosis
CAUSES OF PRIMARY
ADRENOCORTICAL INSUFFICIENCY
AIDS (infectious or invasive destruction)
Adrenal hemorrhage
Iatrogenic (mitotane, ketoconazole,
aminoglutethimide, metyrapone,
etomidate, surgery)
Congenital and familiar

Adrenoleukodystrophy


Adrenal hypoplasia
Familial glucocorticoid deficiency
AUTOIMMUNE ADRENALITIS
The most common cause of Addison’s
disease.
 Humoral and cellular immunity are
both involved.
 Antibodies to the adrenal cortex are
detected in up to 70% of idiopathic
insufficiences;
they inhibit adrenal steroidogenesis in
vitro, and some of them are directed
against enzymes of steroidogenesis.

AUTOIMMUNE ADRENALITIS

Lymphocytic infiltration of the
adrenals

gradual destruction of cortical cells
and their replacement by fibrotic
tissue.
AUTOIMMUNE ADRENALITIS

In 50% of the cases

association to other autoimmune
endocrine or nonendocrine disorders

polyglandular autoimmune
syndromes
POLYGLADULAR AUTOIMMUNE
SYNDROME
Type I
 Often familial,
inhereted in an
autosomal recessive
pattern
 First manifestation:
hypoparathyroidism
and/or mucocutaneous
candidiasis occurring
during childhood
 Addison’s disease
develops in 60% of the
cases during
adolescence.
Type II
 The more frequent
 Familial in half of the
cases
 Occurs mostly between
20 and 40 years of age
 It often develops in a
sequence :
Insulin type 1
 Graves’ disease
 Addison’s disease


Hypoparathyroidism and
candidiasis are absent
INFECTIOUS ADRENALITIS
Adrenal tuberculosis is the secondmost common cause of Addison’s
disease in most countries (20%).
 The adrenal gland are completely
destroyed, including the medulla.


caseous necrosis

fibrosis
INFECTIOUS ADRENALITIS

Disseminated fungal infections can destroy
the adrenal glands

histoplasmosis
paracoccidioidomycosis
South American blastomycosis

Syphilis has also become a rare cause.
INVASIVE DESTRUCTION OF
ADRENALS

Metastatic involvement of the adrenals

lung cancer
 breast cancer
 stomach cancer
 colon cancer
 melanoma
Hodgkin and non-Hodgkin lymphoma



Amyloidosis and sarcoidosis are rare invasive
causes.
ACQUIRED IMMUNE DEFICIENCY
SYNDROME
Patients with AIDS may have adrenal
insufficiency through multiple mechanism:

Infection by cytomegalovirus, tuberculosis,
mycobacterium avium-intracellulare,
toxoplasmosis, cryptococcosis
 Invasion by Kaposi’s sarcoma and lymphoma
 Drugs (ketoconazole, rifampin, phenytoin)


Symptoms and signs of Addison’s disease may be
mistaken and imputed to AIDS itself.
IATROGENIC ADRENAL DEFICIENCY
Iatrogenic adrenal deficiency is a predicted situation
in medically treated Cushing’syndrome.
mitotane  blocks the synthesis of corticosteroids
and induces necrosis of the adrenal cortex
 aminoglutethimide, metyrapone, ketoconazole 
reversibly inhibit several steps of steroidogenesis.

Barbiturans, rifampin, phenytoin increases cortisol
metabolism

they may precipitate acute crisis in cases
undiagnosed adrenal insufficiency.
ADRENAL HEMORRHAGE
Adrenal hemorrage is a cause of rapid and total
destruction of adrenal glands, leading to acute
adrenal insufficiency.
In adults  patients on anticoagulant therapy;
usually after 50 years of age
 In patients with severe, often life-threatening
illnesses (infection with sepsis, burns, major
surgery, complicated pregnancy, trauma, severe
cardiovascular disease, acute renal disease).
 In children  meningococcal or pseudomonas
septicemia
 In neonates  after complicated delivery.

CONGENITAL AND FAMILIAL
ETIOLOGIES
Adrenoleukodystrophy
defective oxidation of very long chain
fatty acids (VLCFA) in peroxisomes

accumulation of VLCFA in central and
peripheral nervous tissue, adrenals,
gonads, and other organs.
CONGENITAL AND FAMILIAL
ETIOLOGIES
Adrenal hypoplasia
Adrenal failure shortly after birth

impaired development of the adult
adrenal cortex
CONGENITAL AND FAMILIAL
ETIOLOGIES
Familial glucocorticoid
deficiency
Rare autosomal recessive disorder

unresponsiveness to ACTH
(mutation of the ACTH receptor gene)
ADRENOCORTICAL INSUFFICIENCY-
PATHOPHYSIOLOGY
Glucocorticoids deficiency

 decreased sense of well-being
 hypoglycemia
 gastrointestinal disturbances
 water retention
 reduced vascular adrenergic tone
The decreased negative feedback by cortisol

increased synthesis and secretion of ACTH and
other POMC-derived peptides
ADRENOCORTICAL INSUFFICIENCY-
PATHOPHYSIOLOGY

mineralocorticoid deficiency

 increased sodium renal loss 
hyponatremia
increased renal retention of potassium and
hydrogen ions  hyperkaliemia and
acidosis

Adrenal androgen deficiency

decrease in axillary and pubic hair and
libido (in women)
ADRENOCORTICAL INSUFFICIENCY-
PATHOPHYSIOLOGY
In most cases the loss of adrenal function is
progressive.
Symptoms and signs appear when more
than 90% of the glands are destroyed.
Before that point, the increased ACTH and
renin maximally stimulate remaining
cortical tissue
normal basal amounts
of glucocorticoids and
mineralocorticoids
no sufficient
increase in
response to stress
During transient state of partial
steroid deficiency or decreased
adrenal reserve, an acute crisis may
be precipitated by surgery, trauma or
infection.
ADRENOCORTICAL INSUFFICIENCY-
CLINICAL FINDINGS
The clinical features of Addison’s
disease are often misleading and may
go unnoticed for months.
Most of the symptoms and signs
taken separately are non-specific.
Clinical and laboratory features of chronic
primary adrenal insufficiency
 Weakness, malaise
 depression, lack of initiative, impairment of
memory
 dizziness, postural hypotension, postural syncope
 myalgias, arthralgias
 anorexia, salt craving, weight loss
 hyperpigmentation
 hyponatremia, hyperkaliemia, azotemia
 eosinophilia, lymphocytosis, normochromic
anemia
 hypoglycemia
 ammenorrhea with decreased axillary and pubic
hair in women
 loss of libido in both sexes
ADRENOCORTICAL INSUFFICIENCY-
CLINICAL FINDINGS
Weakness, fatigue, malaise

constant complaints.
Weakness occurs for usual, routine tasks
and improves with rest, and it is
frequently associated with myalgias and
arthalgias.
ADRENOCORTICAL INSUFFICIENCY-
CLINICAL FINDINGS
Postural dizziness or (less often) syncope,
postural hypotension with tachycardia

are observed.
The existence of systolic hypertension is a strong
indication to exclude the diagnosis of adrenal
insufficiency (moreover, spontaneous improvement
of pre-existing hypertension is reported).
ADRENOCORTICAL INSUFFICIENCY-
CLINICAL FINDINGS
Gastrointestinal symptoms

are common.
Anorexia (with weight loss) is almost constantly
found among patients.
Salt craving, an increased thirst for iced liquids

are reported
ADRENOCORTICAL INSUFFICIENCY-
CLINICAL FINDINGS
Spontaneous hypoglycemia

is common in infants and children
(infrequent in adults)
It may be precipitated by infection,
fever, or alcohol ingestion.
ADRENOCORTICAL INSUFFICIENCY-
CLINICAL FINDINGS
hyperpigmentation

is a highly specific sign of chronic primary
adrenal insufficiency.
Vitiligo may coexist with hyperpigmentation
in10% of patients with autoimmune
Addison’s disease.
ADRENOCORTICAL INSUFFICIENCY-
DIAGNOSTIC PROCEDURES
The routine laboratory findings
Hyponatremia
 Hyperkaliemia
 Mild acidosis
Fasting blood glucose usually low to normal
 Mild elevation of urea and creatinine
(secondary to dehydratation)
 Moderate eosinophilia, lymphocytosis,
normochromic anemia
 Elevations of hepatic transaminases
 Mild hypercalcemia


ADRENOCORTICAL INSUFFICIENCY-
DIAGNOSTIC PROCEDURES
The diagnosis is confirmed by the rapid
ACTH stimulation test.
This test can be done at any time of the
day, since, in contrast to the circadian
rhythm of basal cortisol, the stimulated
cortisol concentration is independent of
the time of day.
Diagnostic approach to primary and secondary
adrenal insufficiency
CONCOMITANT
Baseline plasma ACTH
IN EARLY MORNING
Rapid ACTH stimulation test
Normal ACTH stimulation test
High plasma
ACTH
Abnormal ACTH stimulation test
ADRENAL INSUFFICIENCY
Metyrapone or
insulin test
INCIPIENT
PRIMARY
ADRENAL
INSUFFICIENCY
(rare)
Normal
Abnormal
NORMAL
HYPOTHALAMIC
PITUITARY
ADRENAL AXIS
Low or normal
plasma ACTH
High plasma
ACTH
PRIMARY
SECUNDARY
ADRENAL
INSUFFICIENCY
ADRENAL
INSUFFICIENCY
ADRENOCORTICAL INSUFFICIENCY-
DIAGNOSTIC PROCEDURES
Aldosterone concentration is low, nonresponsive to ACTH or to the upright
position, and is associated with high
renin activity.
Adrenal androgens
(dehydroepiandrosterone,
dehydroepiandrosterone sulfate, and
androsterone) are low.
ADRENOCORTICAL INSUFFICIENCY-
DIAGNOSTIC PROCEDURES
Adrenal CT scan should be perfomed.
If bilateral adrenal enlargement is
observed, futher evaluation is indicated
to determine the specific cause
(tuberculosis, other granulomatous
diseases, metastatic cancer, or
hemorrhage).
ADRENOCORTICAL INSUFFICIENCY-
DIAGNOSTIC PROCEDURES
Adrenal autoantibodies positive

autoimmune adrenalitis

(evaluation of presence of other
autoimmune diseases)
ADRENOCORTICAL INSUFFICIENCY-
TREATMENT
Treatment for chronic primary
adrenal insufficiency includes
substitutions for both glucocorticoid
and mineralocorticoid function.
ADRENOCORTICAL INSUFFICIENCY-
TREATMENT
The evaluation of glucocorticoid replacement is based
on clinical judgement of a patient’s subjective
feeling, and the aim of treatment should be to
administrate the smallest dose to keeps the patient’s
well-being at a normal level.
Mineralocorticoid adequacy is obtained when blood
pressure, sodium, potassium, and plasma renin levels
are normal without orthostatic hypotension and
tachycardia.
ADRENOCORTICAL INSUFFICIENCY-
TREATMENT
Glucocorticoid doses must be doubled or tripled
at the onset of minor illnesses for 24 or 48
hours.
Moderately stressful situations:
hydrocortisone i.v. (100 mg or more).
In cases of severe illness or trauma, patients
should be treated as in acute adrenal
insufficiency.
SECONDARY ADRENAL INSUFFICIENCY
Causes of secondary adrenal insufficiency
 Long-term glucocorticoid administration
 Selective cure of Cushing’s syndrome
 Pituitary adenomas
 Metastatic tumors
 Lymphocytic hypophisitis
 Sarcoidosis, histiocytosis
 Sheehan’s syndrome
 Pituitary surgery, radiotherapy
 Isolated ACTH deficiency
SECONDARY ADRENAL INSUFFICIENCY
Clinical findings
The clinical presentation of secondary
adrenal insufficiency is similar to those
suffering from Addison’s disease, with
the excepition of absent
hyperpigmentation.
 Dehydratation, and hyperkalemia are
usually absent.
SECONDARY ADRENAL INSUFFICIENCY
Diagnostic procedures
Abnormal cortisol response to
ACTH stimulation test (~70%)
+
normal or subnormal plasma ACTH
levels
SECONDARY ADRENAL INSUFFICIENCY
Diagnostic procedures
In ~30% of cases  normal cortisol response
to ACTH stimulation test

Metyrapone test or insulin-induced
hypoglycemia test:
 subnormal responce
+
 normal or low ACTH levels
SECONDARY ADRENAL INSUFFICIENCY
Treatment
Treatment for chronic secondary
adrenal insufficiency is similar to
that of primary deficiency, except
that mineralocorticoids are seldom
necessary.
ACUTE ADRENAL INSUFFICIENCY
 Acute adrenal insufficiency is a medical
emergency that is too often
misdiagnosed.
 It may occur in a patient with known and
treated adrenal insufficiency, in the
presence of a stressfull situation if:
 the dose of glucocorticoid treatment has
not been appropriately increased,
 or the patients cannot retain medication
because of vomiting.
ACUTE ADRENAL INSUFFICIENCY
 Acute adrenal insufficiency develops rapidly
 (not days but hours).
Symptoms and signs:
 gastrointestinal symptoms
 fever
 Hypotension
 hyponatremia, hyperkaliemia, lymphocytosis,
and eosinophilia
ACUTE ADRENAL INSUFFICIENCY
Gastrointestinal symptoms
anorexia
nausea
vomiting
abdominal pain

mimics an acute surgical abdomen
ACUTE ADRENAL INSUFFICIENCY
Fever is commonly associated
Hypoadrenalism
itself
infection
ACUTE ADRENAL INSUFFICIENCY
Hypotension may develop into
hypovolemic shock with apathy and
confusion.
ACUTE ADRENAL INSUFFICIENCY
In the previously undiagnosed
patient, clinical features are highly
misleading.
The presence of hyperpigmentation
(primary adrenal disease) suggests
the diagnosis.
ACUTE ADRENAL INSUFFICIENCY
In the cause of adrenal hemorrhage
causing acute destruction of the
glands, the presenting features are
abdominal or flank pain, in addition
to rapidly developing signs of acute
adrenal insufficiency
(hiperpigmentation is absent).
ACUTE ADRENAL INSUFFICIENCY
The confirmation of the
diagnosis should not delay
the institution of therapy.
ACUTE ADRENAL INSUFFICIENCY
In the majority of cases, it is
sufficient to obtain a plasma
sample

for assay of cortisol (and ACTH)
ACUTE ADRENAL INSUFFICIENCY
If the plasma cortisol level is below
20 g/dl (SI=0.56 mol/l)
in the face of hypovolemia or shock

the diagnosis is confirmed.
ACUTE ADRENAL INSUFFICIENCY
A rapid (30-minute) ACTH stimulation
test may be obtained,
without delaying the appropriate
therapy

by use of dexamethasone as a starting
glucocorticoid
ACUTE ADRENAL INSUFFICIENCY
TREATMENT
In the face of a strong clinical suspicion
for acute adrenal insufficiency, blood
is drown for the measurement of
electrolytes, glucose, cortisol and (if
possible) ACTH, and treatment is
instituted immediately, without
waiting for the results.
ACUTE ADRENAL INSUFFICIENCY
TREATMENT
Vigorous intravenous rehydration:
saline 0.9%
or 5% glucose in 0.9% saline

e.g., 2 liters in 3 hours;
continued at a lower rate for the next
24 to 48 hours
ACUTE ADRENAL INSUFFICIENCY
TREATMENT
Hydrocortisone iv 100 mg is injected as
soon as possible, and given every 6
hours iv or imm at the same dose for
the first 24 hours.
Mineralocorticoids are not necessary.
ACUTE ADRENAL INSUFFICIENCY
TREATMENT
Any precipitating illness should be
explored and appropriately
treated.
ACUTE ADRENAL INSUFFICIENCY
TREATMENT
In the absence of complications, treatment
can be tapered within 3 to 5 days and oral
mineralocorticoids
(9-fluorocortisol 0.1 mg/day)
are started when the patient is able to take
food and when hydrocortisone has been
decreased to less than 60 mg per day.