cushing syndrome and addison disease
DESCRIPTION
The adrenal cortex produces three major classes of steroids: 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.TRANSCRIPT
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.
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-releasing hormone (CRH) from the hypothalamus
A constellation of clinical abnormalities due
to chronic exposure to excess of cortisol or
related corticosteroid
described by Harvey Cushing in 1932
Definition
CAUSES OF CUSHING’ S SYNDROME
ACTH-dependent causesACTH-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)
Etiology and Pathophysiology
COMMON CAUSES OF ECTOPIC ACTH SECRETION
Small cell carcinoma of the lung50%
Endocrine tumors of foregut origin35%Thymic carcinoidIslet cell tumor Medullary carcinoma thyroidBronchial carcinoid
Pheochromocytoma 5%Ovarian tumors 2%
Clinical FeatureHypercotisolism
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 weaknessDependent edema
Hypertension
Hypokalemic metabolic alkalosis
Frequency(%)
Weight gain 90“Moon facies” 75Hypertension 75
Violaceous striae 65Hirsutism 65Glucose intolerance 65Proximal muscle weakness 60Plethora 60Menstrual dysfunction 60Acne 40Easy bruising 40Osteopenia 40Dependent edema 40Hyperpigmentation 20Hypokalemic metabolic alkalosis 15
CLINICAL FEATURES OFGLUCOCORTICOID EXCESS
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.
Diagnosis
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.
Dexamethasone suppression test
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
Suppression tests
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
ACTH Stimulation test
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
CRH stimulation test
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
Metyrapone Test
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
Imaging diagnosis
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
Etiological diagnosis
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 )
Treatment
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
Medical therapy of Cushing’ s Disease
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
ADDISON’S DISEASE
PRIMARY ADRENAL INSUFFICIENCYCongenital adrenal hyperplasia Anatomic destruction of gland (chronic or acute)"Idiopathic" atrophy (autoimmune, adrenoleukodystrophy)Surgical removalInfection (tuberculous, fungal, viralæ especially in AIDS patients)HemorrhageInvasion: metastaticMetabolic failure in hormone production Enzyme inhibitors (metyrapone, ketoconazole, aminoglutethimide) Cytotoxic agents (mitotane) ACTH-blocking antibodiesMutation in ACTH receptor geneAdrenal hypoplasia congenitaSECONDARY ADRENAL INSUFFICIENCYHypopituitarism due to hypothalamic-pituitary diseaseSuppression of hypothalamic-pituitary axis By exogenous steroid By endogenous steroid from tumor
Classification of Adrenal Insufficiency
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,
INVESTIGATIONS
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.
ACTH stimulation test
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.
To assess mineralocortocoid status, Adrenal antibodies
Plasma reninactivity and aldosterone:
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.
AXR (plain abdominal films) and CXR:
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.
TREATMENT
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).
TREATMENT
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.
TREATMENT
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.
ADVERSE EFFECTS
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.
Special Therapeutic Problems
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.
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.
ACUTE ADRENOCORTICAL INSUFFICIENCY
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.
TREATMENT
