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ENDOCRINE PBL TRIGGER 3

1) Cushings Syndrome

Defi niti on :

a) Etiology / Pathophysiology

ACTH-dependent Non-ACTH-dependent Pituitary adenoma secreting ACTH

(Cushings disease) Ectopic ACTH syndrome (bronchial

carcinoid , small-cell lung carcinoma, other neuro-endocrine tumours)

Iatrogenic (ACTH therapy )

Iatrogenic - chronic glucocorticoidtherapy

Adrenal adenoma Adrenal carcinoma

b) Clinical features / Sign and Symptoms

i. Characteristic feature of this disease is thedisproportionate distribution of body fat, resultingin some abnormal features:

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a. Moon face: The edematous facial appearance due to fat accumulation and retention ofwater and salt

b. Torso: Fat accumulation in the chest and abdomen. Arms and legs are very slim in proportion to torso (torso means trunk of the body)c. Buffalo hump: Due to fat deposit on the back of neck and shoulderd. Pot belly: Due to fat accumulation in upper abdomen (Fig. 70.9).ii. Purple striae: Reddish purple stripes on abdomen due to three reasons:a. Stretching of abdominal wall by excess subcutaneous fat

b. Rupture of subdermal tissues due to stretchingc. Deficiency of collagen fibers due to protein depletion.

iii. Thinning of extremities

iv. Thinning of skin and subcutaneous tissues due to protein depletion caused by increased

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catabolism of proteins

v. Aconthosis: Skin disease characterized by darkened skin patches in certain areas such asaxilla, neck and groin

vi. Pigmentation of skin, especially in ACTHdependent type due to hypersecretion of ACTHwhich has got melanocyte-stimulating effect

vii. Facial plethora: Facial redness

viii. Hirsutism: Heavy growth of body and facial hair

ix. Weakening of muscles because of protein depletion

x. Bone resorption and osteoporosis due to protein depletion. Bone becomes susceptible toeasy fracture

xi. Hyperglycemia due to gluconeogenesis (from proteins) and inhibition of peripheralutilization of glucose. Hyperglycemia leads to glucosuria and adrenal diabetes

xii. Hypertension by the mineralocorticoid effects of glucocorticoids retention of sodiumand water results in increase in ECF volume and blood volume, leading to hypertension

xiii. Immunosuppression resulting in susceptibility for infection

xiv. Poor wound healing.

c) Diagnosis and Investigation

A cortisol test, which may be done on a sample of blood or on a sample of urine collectedover a 24-hour period.

An overnight dexamethasone suppression test using a low dose of steroid (often done toreconfirm a cortisol test). This test is most commonly done on a sample of blood, but a moreextensive form of the test may involve both blood and urine samples.

A test to measure cortisol in the saliva in the evening may be done.

If the above tests show you have Cushing's syndrome, the following blood tests can help yourdoctor find out the amount of adrenocorticotropic hormone (ACTH) in your body andwhether you have a tumor on the adrenal glands, the pituitary gland, or an organ:

ACTH testCorticotropin-releasing hormone (CRH) stimulation testIf the first tests show that too much ACTH is causing Cushing's syndrome, other tests may beneeded to find out its source. These include:

Inferior petrosal sinus sampling (IPSS) to find out whether too much ACTH is being releasedfrom the pituitary gland. During IPSS, a small tube (catheter) is used to collect samples from

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blood vessels near the brain. If these blood samples show high levels of ACTH, it usuallymeans that the pituitary gland is the source of excess ACTH. The IPSS is often used with theCRH stimulation test.Computed tomography (CT scan) and magnetic resonance imaging (MRI) of the chest or

pituitary gland, which may help locate a tumor producing ACTH. But sometimes the tumor

may be too small to detect with a CT scan or an MRI. A CT and MRI of the adrenal glandmay also be used to locate adrenal tumors.Blood test results showing changes in body chemistry also may point to Cushing's syndrome.These include:

An increase in the number of white blood cells (leukocytosis).A low potassium level (hypokalemia).High blood sugar (hyperglycemia).Increased levels of cholesterol (hypercholesterolemia) and high blood fats(hypertriglyceridemia).A decrease in the time it takes for blood to clot.A high testosterone level.

d) Treatment and Management

SURGERY

Selective transsphenoidal resection of pituitary adenoma indicated in Cushing disease, afterwhich remainder of pituitary usually returns to normal function

However, corticotrophs require 6 36 months to recover normal function

Thus, hydrocortisone replacement is required temporarily

Bilateral laparoscopic adrenalectomy if no remission (or recurrence) after pituitary surgery

Laparoscopic resection for adrenal neoplasms secreting cortisol

Because contralateral adrenal is suppressed, postoperative hydrocortisone replacement isrequired until recovery

Surgical resection of ectopic ACTH-secreting tumors

Regulation of Corti sol Secretion

Cortisol regulates its own secretion through negative feedback control by inhibiting therelease of corticotropin-releasing hormone from hypothalamus and ACTH from pituitarygland.

ACTH secretion follows circadian rhythm- it varies in different periods of the day. The rateof secretion of both ACTH and CRF is high in the morning and low in the evening.

Causes of hypercortisolism

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Effects of corticosteroids on the HPA axis

Role of cortisol in regulation of blood pressure (b.p) and blood glucose level.

Stimulation of gluconeogenesis. A major action of cortisol is to promote gluconeogenesis and

storage of glycogen. Overall, the effects of cortisol are catabolic and diabetogenic. Cortisolaffects protein, fat, and carbohydrate metabolism in a coordinated fashion to increaseglucoseView drug information synthesis as follows: Cortisol increases protein catabolism inmuscle and decreases new protein synthesis, thereby providing additional amino acidsViewdrug information to the liver for gluconeogenesis. Cortisol increases lipolysis, which providesadditional glycerol to the liver for gluconeogenesis. Finally, cortisol decreases glucoseViewdrug information utilization by tissues and decreases the insulin sensitivity of adipose tissue.Glucocorticoids are essential for survival during fasting, because they stimulate thesegluconeogenic routes. In hypocortisolism (e.g., primary adrenal insufficiency, Addison'sdisease), there is hypoglycemia. In hypercortisolism (e.g., Cushing's syndrome), there ishyperglycemia. explains why random blood sugar is raised above normal range !!!

Drug regulation in Malaysia

Role of lab investigations in diagnosing Cushings syndrome.

Obesity, chronic illness, chronic alcoholism and depression can cause false-positive results(pseudo-Cushing's syndrome) on the 1-mg dexamethasone suppression test and mildlyelevated free cortisol values on the 24-hour urine collection.

Danger of prolonged use of exogenous steroids

(1) The possibility of suppression of the hypothalamic pituitary adrenal (HPA) axis andresulting secondary adrenal insufficiency,

(2) The possibility of worsening of the underlying disease for which steroid therapy wasinitiated, and

(3) A phenomenon, sometimes called the steroid withdrawal syndrome, in which some patients encounter difficulty, and even significant symptoms, discontinuing or decreasingsteroid doses despite having demonstrably normal HPA axes.

Cortisol withdrawal syndrome, even when given replacement corticosteroids for adrenalinsufficiency; manifestations include

Hypotension

Nausea

Fatigue

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Arthralgias

Myalgias

Pruritus

Flaking skin