Cushingsyndromeandaddisondisease 130618105538-phpapp01

 The adrenal cortex produces three major classes
of steroids:
(1) glucocorticoids,
(2) mineralocorticoids, and
(3) adrenal androgens.
Consequently, normal adrenal function is important for
-modulating intermediary metabolism and immune
responses through glucocorticoids;
- blood pressure, vascular volume, and electrolytes
through mineralocorticoids;
- secondary sexual characteristics (in females) through
androgens.
- The adrenal axis plays an important role in the stress
response by rapidly increasing cortisol levels.
- Adrenal disorders include hyperfunction (Cushing's
syndrome) and hypofunction (adrenal insufficiency) as
well as a variety of genetic abnormalities of
steroidogenesis.
drpankajyadav05@gmail.com

When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid
hormones. ACTH is produced by the pituitary gland and released into the
petrosal venous sinuses in response to stimulation by corticotropin-releasingdrpankajyadav05@gmail.com

 A constellation of clinical abnormalities due
to chronic exposure to excess of cortisol or
related corticosteroid
 described by Harvey Cushing in 1932

CAUSES OF CUSHING’ S SYNDROME
ACTH-dependent causes
ACTH-secreting pituitary tumor ( Cushing’ s disease )
Pituitary CRH-secreting neoplasm ( ectopic CRP syndrome )
Nonpituitary ACTH-secreting neoplasm ( ectopic ACTH syndrome )
ACTH-independent causes
Adrenal adenoma
Adrenal carcinoma
Micronodular adrenal disease
McCune-Albright syndrome
Massive macronodular adrenal diease
Pseudo-cushing Syndrome
Factitious or surreptitious glucocorticoid administration (IATROGENIC)

COMMON CAUSES OF ECTOPIC ACTH SECRETION
Small cell carcinoma of the lung
50%
Endocrine tumors of foregut origin
35%
Thymic carcinoid
Islet cell tumor
Medullary carcinoma thyroid
Bronchial carcinoid
Pheochromocytoma 5%
Ovarian tumors
2%

Hypercotisolism
Lipid mobilization 
Lipid catabolism 
Lipid redistribution
Moon-face
buffalo hump
truncal obesity
Violaceous striae
Hepatic glucose
production
Insulin resistance
Glucose intolerance
protein metabolism negative
nitrogen balance
disruption of water and
electrocytes metabolism
Proximal muscle
weakness Dependent edema
Hypertension
Hypokalemic metabolic
alkalosis

Frequency(%)
Weight gain 90
“Moon facies” 75
Hypertension 75
Violaceous striae
65
Hirsutism 65
Glucose intolerance 65
Proximal muscle weakness
60
Plethora
60
Menstrual dysfunction 60
Acne 40
Easy bruising 40
Osteopenia 40
Dependent edema
40
Hyperpigmentation 20
Hypokalemic metabolic alkalosis
15

 Clinical manifestations
 Cortisol levels in blood are normally elevated at 8 A.M.
and decrease to less than 50% by midnight except in
infants and young children in whom a diurnal rhythm is
not always established.
 In patients with Cushing syndrome this circadian
rhythm is lost, and cortisol levels at midnight and 8
A.M. are usually comparable.
 Urinary excretion of free cortisol is increased. This is
best measured in a 24-hr urine sample and is
expressed as a ratio of micrograms of cortisol excreted
per gram of creatinine.

 Dexamethasone is an exogenous steroid that provides negative
feedback to the pituitary to suppress the secretion of ACTH.
 This steroid is unable to pass the blood brain barrier which
allows this test to assess a specific part of the hypothalamic-
pituitary-adrenal axis. Specifically, dexamethasone binds to
glucocorticoid receptors in the pituitary gland, which lies outside
the blood brain barrier, resulting in regulatory modulation
 A single-dose dexamethasone suppression test is often helpful;
a dose of 25–30 μg/kg (maximum of 2 mg) given at 11 P.M.
results in a plasma cortisol level of less than 5 μg/dL at 8 A.M.
the next morning in normal individuals but not in patients with
Cushing syndrome.
 A low dose dexamethasone suppresses cortisol in individuals
with no pathology in endogenous cortisol production. A high
dose dexamethasone exerts negative feedback on pituitary ACTH
producing cells but not on ectopic ACTH producing cells or
adrenal adenoma.

 Low-dose
 A normal result is decrease in cortisol levels
upon administration of low-dose
dexamethasone.
 Cushing's disease involve no change in
cortisol on low-dose dexamethasone, but
inhibition of cortisol on high-dose
dexamethasone

 Large dose DX suppression test
◦ D.X 2mg q6h P.O 2 days
◦ Urinary free cortisol reduced 50%: Cushing’s
disease (Pituitary adenoma)
◦ Urinary free cortisol NOT reduced 50%:Adrenal
tumor, carcinoma, ectopic ACTH Syndrome

 ACTH 25u intravenously 8h
 2-5 fold increase in urinary free cortisol in
Cushing’ s disease
 Plasma cortisol and urinary free cortisol
increase in half of adrenal adenoma patients
 No response in adrenal carcinoma

 Etiology diagnose (especially for pituitary ACTH-
dependent or ectopic ACTH syndrome)
 A newer approach is to combine a CRH stimulation
test with a dexamethasone suppression test(4mg ).
 method :
1 µg / kg of CRH is administered intravenously.
ACTH and cortisol levels are measured before
CRH injection and 15, 30, 45, 60, 90 and 120
minutes after injection.
 A rise in the cortisol value of 20 percent or more
above basal level or a rise in the ACTH value of at
least 50 percent above basal level is considered
evidence for an ACTH-dependent lesion

 Etiology diagnose (especially for pituitary or
adrenal)
◦ Metyrapone (30mg/kg) P.O at midnight
◦ Urinary 17-OHCS, Plasma ACTH,11-deoxycortisol
more above basal level : Cushing’s disease
(Pituitary adenoma)
◦ No response in adrenal carcinoma , tumor,
ectopic ACTH Syndrome

 Pituitary CT has a sensitivity of about
50% for identifying microadenomas
 MRI has increased sensitivity but is not
100% predictive
 If diagnostic doubt need bilateral inferior
petrosal sinus sampling for ACTH
 Adrenal ultrasonography---first choice
 Abdominal CT will allow identification of
adrenal pathology
 Somatostatin scintigraphy to identify
sites of ectopic hormone production

 Cushing’ s disease:
 Adrenal adenoma:
 Adrenal carcinoma:
 Ectopic ACTH
Syndrome:
 Chronic, moderate clinical
features can be suppressed by
large dose test
 Shorter course , mild features
can NOT be suppressed by large
dose test
 Acute onset, progressive course,
hyperandrogenic effect
predominate, palpable mass,
low ACTH
 Appear suddenly, progress
rapidly, not typical manifestation
of Cushing’s syndrome,
hyperpigmentation, hypokalemia,
high ACTH

 Cushing’s disease
◦ Transsphenoidal microadenomectomy
◦ Pituitary radiation
◦ Bilateral total adrenolectomy
◦ Drugs
 Adrenal adenoma and carcinoma
◦ Surgical removal
◦ Drugs ( mitotane, metyrapone, ketoconazole ) for
nonresectable or metastatic carcinoma
 Ectopic ACTH Syndrome
◦ Surgical removal of the ectopic tumor
◦ Chemotherapy, radiotherapy
◦ Drugs ( mitotane, metyrapone, ketoconazloe )

 Purpose
◦ Correct metabolic abnormalities before
attempted surgical cure
◦ Palliate surgically noncurable disease
◦ Achieve remission in patients for whom surgery
is unlikely to achieve satisfactory long term
results

 Steroidogenic inhibition
◦ Mitotane
◦ Metyrapone
◦ Aminoglutethimide
◦ Ketoconazole
 Neuromodulatory treatment
◦ Bromocriptine
◦ Cyproheptadin
◦ Valproic acid
◦ Octreotide
 Glucocorticoid receptor antagonist
◦ RU486

 The original description of Addison's
disease"general languor and debility,
feebleness of the heart's action, irritability
of the stomach, and a peculiar change of
the color of the skin"summarizes the
dominant clinical features.
 Addison's disease results from progressive
destruction of the adrenals, which must
involve >90% of the glands before adrenal
insufficiency appears

PRIMARY ADRENAL INSUFFICIENCY
Congenital adrenal hyperplasia
Anatomic destruction of gland (chronic or acute)
"Idiopathic" atrophy (autoimmune, adrenoleukodystrophy)
Surgical removal
Infection (tuberculous, fungal, viralæ especially in AIDS patients)
Hemorrhage
Invasion: metastatic
Metabolic failure in hormone production
Enzyme inhibitors (metyrapone, ketoconazole, aminoglutethimide)
Cytotoxic agents (mitotane)
ACTH-blocking antibodies
Mutation in ACTH receptor gene
Adrenal hypoplasia congenita
SECONDARY ADRENAL INSUFFICIENCY
Hypopituitarism due to hypothalamic-pituitary disease
Suppression of hypothalamic-pituitary axis
By exogenous steroid
By endogenous steroid from tumor

Frequency of Symptoms and Signs in Adrenal
Insufficiency
Sign or Symptom Percent of Patients
Weakness 99
Pigmentation of skin 98
Weight loss 97
Anorexia, nausea, and vomiting 90
Hypotension (<110/70) 87
Pigmentation of mucous membranes 82
Abdominal pain 34
Salt craving 22
Diarrhea 20
Constipation 19
Syncope 16
Vitiligo 9

General:
K+↑ Na+↓ glucose ↓ uraemia,
mild acidosis,
Ca2+ ↑
eosinophilia,
neutropenia.
lymphocytosis.
anaemia,
abnormal LFTs,

 The short test compares blood cortisol levels
before and after 250 micrograms of
tetracosactide (intramuscular or intravenous) is
given.
 If, one hour later, plasma cortisol exceeds 170
nmol/l and has risen by at least 330 nmol/l to at
least 690 nmol/l, adrenal failure is excluded.
 If the short test is abnormal, the long test is used
to differentiate between primary adrenal
insufficiency and secondary adrenocortical
insufficiency.

 The long test uses 1 mg tetracosactide
(intramuscular). Blood is taken 1, 4, 8, and 24
hr later.
 Normal plasma cortisol level should reach
1000 nmol/l by 4 hr. In primary Addison's
disease, the cortisol level is reduced at all
stages, whereas in secondary corticoadrenal
insufficiency, a delayed but normal response
is seen.

In Addison’s disease ACTH is
iniappropriately high
Low in secondary causes.

To assess mineralocortocoid status,
Adrenal antibodies

Look for signs of previous TB, eg calcification.
Have a low threshold far further investigations
for TB, especially if autoantibodies are negative,
eg CT adrenal glands.

 All patients with adrenal insufficiency should
receive specific hormone replacement.
 Replacement therapy should correct both
glucocorticoid and mineralocorticoid deficiencies.
 Hydrocortisone (cortisol) is the mainstay of
treatment. The dose for physiologic replacement
(~10 mg/M2/24 hr of hydrocortisone).
 Patients are advised to take glucocorticoids with
meals or, if that is impractical, with milk or an
antacid, because the drugs may increase gastric
acidity and exert direct toxic effects on the gastric
mucosa.
 To simulate the normal diurnal adrenal rhythm,
two-thirds of the dose is taken in the morning, and
the remaining one-third is taken in the late
afternoon.

 Since the replacement dosage of
hydrocortisone does not replace the
mineralocorticoid component of the adrenal
hormones, mineralocorticoid
supplementation is usually needed. This is
accomplished by the administration of 0.05
to 0.1 mg fludrocortisone per day by
mouth. Patients should also be instructed to
maintain an ample intake of sodium (3 to 4
g/d).

 In female patients with adrenal insufficiency,
androgen levels are also low. Thus, some
physicians believe that daily replacement with
25 to 50 mg of DHEA orally may improve
quality of life and skeletal density.

 Complications of glucocorticoid therapy, with the
exception of gastritis, are rare at the dosages
recommended for treatment of adrenal
insufficiency.
 Complications of mineralocorticoid therapy
include hypokalemia, hypertension, cardiac
enlargement, and even congestive heart failure due
to sodium retention. Periodic measurements of
body weight, serum potassium level, and blood
pressure are useful.

 During periods of intercurrent illness,
especially in the setting of fever, the dose
of hydrocortisone should be doubled.
 With severe illness it should be increased
to 75 to 150 mg/d.
 When oral administration is not possible,
parenteral routes should be employed
 Likewise, before surgery or dental
extractions, supplemental glucocorticoids
should be administered.

Table 331-9. Glucocorticoid Preparations
Estimated Potencyb
Commonly Used Namea Glucocorticoid Mineralocorticoid
SHORT-ACTING
Hydrocortisone 1 1
Cortisone 0.8 0.8
INTERMEDIATE-ACTING
Prednisone 4 0.25
Prednisolone 4 0.25
Methylprednisolone 5 <0.01
Triamcinolone 5 <0.01
LONG-ACTING
Paramethasone 10 <0.01
Betamethasone 25 <0.01
Dexamethasone 30-40 <0.01
a The steroids are divided into three groups according to the duration of biologic activity. Short-acting preparations have a biologic half-life <12
h; long-acting, >48 h; and intermediate, between 12 and 36 h. Triamcinolone has the longest half-life of the intermediate-acting preparations.
b Relative milligram comparisons with hydrocortisone, setting the glucocorticoid and mineralocorticoid properties of hydrocortisone as 1. Sodium
retention is insignificant for commonly employed doses of methylprednisolone, triamcinolone, paramethasone, betamethasone, and
dexamethasone. drpankajyadav05@gmail.com

A Checklist for Use Prior to the Administration
of Glucocorticoids in Pharmacologic Doses
-Presence of tuberculosis or other chronic infection (chest x-ray,
tuberculin test)
-Evidence of glucose intolerance or history of gestational diabetes
mellitus
-Evidence of preexisting osteoporosis (bone density assessment in
organ transplant recipients or postmenopausal patients)
-History of peptic ulcer, gastritis, or esophagitis (stool guaiac test)
Evidence of hypertension or cardiovascular disease
-History of psychological disorders

Supplementary Measures to Minimize Undesirable Metabolic Effects of
Glucocorticoids
-Monitor caloric intake to prevent weight gain.
-Restrict sodium intake to prevent edema and minimize hypertension and potassium loss.
-Provide supplementary potassium if necessary.
-Provide antacid, H2 receptor antagonist, and/or H+,K+-ATPase inhibitor therapy.
-Institute alternate-day steroid schedule if possible. Patients receiving steroid therapy over a prolonged
period should be protected by an appropriate increase in hormone level during periods of acute stress. A
rule of thumb is to double the maintenance dose.
-Minimize osteopenia by
Administering gonadal hormone replacement therapy: 0.625-1.25 mg conjugated estrogens given
cyclically with progesterone, unless the uterus is absent; testosterone replacement for hypogonadal men
-Ensuring high calcium intake (should be approximately 1200 mg/d)
-Administering supplemental vitamin D if blood levels of calciferol or 1,25(OH)2 vitamin D are reduced
-Administering bisphosphonate prophylactically, orally or parenterally, in high-risk patients

1. Adrenal crisis may be a rapid and
overwhelming intensification of chronic adrenal
insufficiency, usually precipitated by sepsis or
surgical stress.
2. Alternatively, acute hemorrhagic destruction of
both adrenal glands can occur in previously well
subjects.
3. In children, this event is usually associated with
septicemia with Pseudomonas or meningococcemia
(Waterhouse-Friderichsen syndrome).
4. In adults, anticoagulant therapy or a coagulation
disorder may result in bilateral adrenal
hemorrhage.

 Treatment is directed primarily toward
repletion of circulating glucocorticoids and
replacement of the sodium and water
deficits.
 intravenous infusion of 5% glucose in
normal saline solution should be started
with a bolus intravenous infusion of 100 mg
hydrocortisone followed by a continuous
infusion of hydrocortisone at a rate of 10
mg/h.

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