Rahaf Jereisat

Pyramidal in shape. 3- 5 cm in height , 3 cm in width , less than 1 cm thicK, Mass 3.5 - 5 g

The adrenal gland is divided into 2 areas, the cortex and medulla.

The cortex is divided into 3 areas: GFR

the outer zone (glomerulosa): aldosterone synthesis

the central zone (fasciculata): cortisol synthesis

the inner zone (reticularis): androgen biosynthesis.

The adrenal medulla is an extension of the sympathetic nervous system that secretes catecholamines into capillaries rather than synapses.

Glucocorticoids:

Cortisol is the major glucocorticoid in humans.

Levels are highest in the morning on waking and lowest in the middle of the night.

Cortisol levels rises dramatically during stress.

95% protein bound (cortisol-binding globulin/transcortin) which is increased by estrogens, free fraction is biologically active

Mineralocorticoids:

Aldosterone is the most important one.

Stimulated by angiotensin 2.

Water and Na retention, K and H excretion

Adrenal Androgens:

Secreted in response to ACTH

Probably important in initiation of puberty

Catecholamines:

Small proportion of NA from medulla, remaining from sympathetic nerve endings

Major source of Adrenaline

Conversion of NA to Adrenaline by Catechol-O-MethylTransferase (COMT), which is induced by glucocorticoids.

A group of clinical abnormalities caused by prolonged exposure to increased amounts of cortisol or related corticosteroids.

Causes: 1.Exogenous: iatrogenic causes are the most common overall causes of Cushing syndrome 2.Endogenous -uncommon

About 15% of Cushing cases are from ACTH from a source that cannot be located.

Striae: Purple, >1cm

1. deposition of adipose tissue in characteristic sites: moon facies; interscapular buffalo hump; and mesenteric bed, truncal obesity.

2. hypertension, muscle weakness, and fatigability related to mobilization of peripheral supportive tissue; osteoporosis caused by increased bone catabolism; cutaneous striae; and easy bruisability.

3. Women may have acne, hirsutism, and oligomenorrhea /amenorrhea (increased adrenal androgen secretion.)

4. Emotional changes range from irritability or emotional lability to severe depression or confusion; even psychosis can occur as well.

5. Glucose intolerance is common, with 20% of patients having diabetes.

6. hypokalemia (mineralocorticoid effect) and leukocytosis. Clinically significant hypokalemia is uncommon.

7. delayed wound healing, renal calculi from increased calcium levels, and glaucoma. Polyuria is from hyperglycemia.

8. There is increased susceptibility to infections because neutrophils exhibit diminished function because of high glucocorticoid levels.

Diagnosis

The 1-mg overnight dexamethasone suppression test is used to rule out the diagnosis of Cushing syndrome or glucocorticoid excess: If you give a milligram of dexamethasone at 11 p.m., the cortisol level at 8 a.m. should come to normal if there is the normal ability to suppress ACTH production over several hours.

The problem with this test is that there can be falsely abnormal or positive tests. Any drug that increases the metabolic breakdown of dexamethasone will prevent its ability to suppress cortisol levels, like phenytoin, carbamazepine, and rifampin.

Stress increases glucocorticoid levels. The 1-mg overnight dexamethasone suppression test can be falsely positive in stressful conditions such as starvation, anorexia, bulimia, alcohol withdrawal, or depression.

An abnormality on the 1-mg overnight test should be confirmed with a 24-hour urine-free cortisol. The 24-hour urine-free cortisol is more accurate and is the gold standard for confirming or excluding Cushing’s syndrome.

A third screening test for Cushing is the midnight salivary cortisol. Cushing patients, cortisol is abnormally elevated at midnight.

The precise etiology of the Cushing syndrome is established by using ACTH levels, sometimes in combination with high-dose dexamethasone suppression testing. ACTH levels are elevated with either a pituitary source of ACTH such as an adenoma or with an ectopic source.

High dose dexamethasone suppression testing can distinguish the difference. The output of a pituitary adenoma will suppress with high-dose dexamethasone. The output of an ectopic source will not suppress with high-dose dexamethasone.

If the ACTH level is low, then the etiology is most likely from an adrenal tumor. When the adrenal gland is the source of increased cortisol production, there is feedback inhibition on the pituitary and the ACTH level is suppressed.

When there is a low ACTH level, the precise etiology is confirmed with a CT scan of the adrenals.

When there is a high ACTH level, the precise etiology is confirmed with an MRI of the pituitary looking for an adenoma or a CT scan of the chest looking for an ectopic focus.

If neither of these show a lesion or the MRI of the brain is equivocal, then inferior petrosal sinus sampling should be done to see if there is increased ACTH coming out of the brain.

Single random cortisol levels are not reliable.

• High plasma ACTH levels = pituitary or ectopic source

• Low plasma ACTH levels = adrenal tumors or hyperplasia

Management

Nelson syndrome: abnormal hormone secretion, enlargement of the pituitary gland, and the development of large and invasive growths known as adenomas. It occurs in people who undergo surgical removal of the adrenal glands for Cushing disease.

Hypersecretion of the major adrenal

mineralocorticoid, aldosterone.

Hyperaldosteronism can be divided into the

following:

• Primary aldosteronism, in which the

stimulus for the excessive aldosterone

production is within the adrenal gland

• Secondary aldosteronism, in which the

stimulus is extraadrenal

The most common cause of primary

hyperaldosteronism is a unilateral adrenal

adenoma (70%).

Bilateral hyperplasia accounts for 25–30%.

Excessive black licorice ingestion can mimic

this effect. Licorice has aldosterone-like

qualities.

Primary hyperaldosteronism is characterized by hypertension and low potassium levels. Most of the other symptoms, such as muscle weakness, polyuria, and polydipsia, are from the hypokalemia.

Metabolic alkalosis occurs because aldosterone increases hydrogen ion (H+) excretion.

Edema is uncommon with primary hyperaldosteronism because of sodium release into the urine (Aldosterone escape mechanism).

Adrenal adenomas are removed surgically.

Bilateral hyperplasia is treated with spironolactone.

Persistent HTN after surgery may occur due to primary HTN or due to vascular changes caused by HTN .

PRIMARY (Addison’s Disease)

Endogenous Failure of adrenal gland to secret hormones, slow progressive

Presence of hyperpigmentation due to stimulation of melanocytes by high ACTH .

SECONDARY

most common cause and its due to ACTH deficiency usually due to inappropriate steroids withdrawal , or pituitary tumor, sheehan, sarcoidosis, histocytosis

TERTIARY

Hypothalamic causes

ADRENAL CRISIS

Potentially fatal and variable in its presentation , usually precipitated by acute illness or replacement of thyroid hormone in un recognized chronic adrenal insufficiency

Primary adrenal insufficiency (High ACTH)

1-Addison’s disease

Autoimmune ( most common in west) destruction of all 3 layers , most pt have positive 21 – hydroxylase antibodies .

50 % of these pt may develop autoimmune endocrine disorder (primary hypothyrodism , celiac disease type 1 DM , hypoparathyrodism )

2-Other causes :

TB (mc in developing world), fungal infection

HIV/AIDS

Sarcoidosis , hemochromatosis

Metastatic carcinoma ( lung cancer , renal cell cancer ) lymphoma

Bilateral adrenal hemorrhage, sepsis and DIC , anticoagulation protein C deficiency . (e.g. Water-friderichen syndrome)

Weight loss

Anorexia

Fatigue

Nausea and vomiting

Diarrhoea or constipation

Hypoglycemia

Skin pigmentation (diffuse brown, tan, or bronze darkening of both exposed and unexposed body parts)

CLINICAL FEATURES in primary disease

(MINERALOCORTICOID INSUFFICIENCY)

Hypotension .

Shock .

Hyponatremia .

Hyperkalemia.

Chronic: small heart

Decreased body hair

Loss of libido especially in female

All symptoms mentioned above .

Pt don’t develop hyperpigmentation .

no hyperkalemia .

-Primary acute hypoadrenalism.

severe fatal symptoms

-Causes: stress, rapid withdrawal of steroids, adrenal hemorrhage, surgery and infection.

-Circulatory shock with severe hypotension, hyponatremia, hyperkalemia.

In some instances hypoglycemia .

Laboratory findings include white blood cell count with moderate neutropenia, lymphocytosis, and eosinophilia; elevated serum potassium and urea nitrogen; low sodium; low blood glucose; and morning low plasma cortisol.

The definitive diagnosis is the cosyntropin or ACTH stimulation test. A cortisol level is obtained before and after administering ACTH. A normal person should show a brisk rise in cortisol level after ACTH administration.

Differences between primary and secondary adrenal insufficiency:

• Hyperpigmentation (occurs only with primary insufficiency)

• Electrolyte abnormalities

• Hypotension

Adrenal CT scan in case of primary disease Brain MRI in case of secondary disease in absence of steroids intake

Treatment should not be delayed to wait for results in patients with suspected acute adrenal crisis.

If the patient’s condition permits, it may be appropriate to perform a short ACTH stimulation test before administering hydrocortisone.

Investigations should be performed before treatment is given if the patient’s symptoms suggest chronic adrenal insufficiency

-Glucocorticoid replacement (always): oral hydrocortisone 15-20 mg daily in divided doses.

-Mineralocorticoid replacement (usually): Fludrocortisone 0.05-0.15 mg daily.

-Androgen replacement (beneficial in women): DHEA (DeHydro EpiAndrosterone) 50mg/day

During stress or illness corticosteroids should be in increase 2 to 3 times. (STRESS DOSE)

• Pateints with primary adrenal insufficiency require glucocorticoid and mineralocorticoid replacement , but those with central disease require glucocorticoid replacement only

CAH is a syndrome associated with increased adrenal androgen production because of enzymatic defects.

CAH is the most common adrenal disorder of infancy and childhood.

CAH arises from autosomal recessive mutations, which produce deficiencies of enzymes necessary for the synthesis of cortisol.

Pediatric subject

C-21 hydroxylase deficiency in 95% of all cases.

C-21 hydroxylase deficiency is associated with reduction in aldosterone secretion in one-third of patients.

Adrenal virilization occurs with or without an associated salt-losing tendency, owing to aldosterone deficiency, which leads to hyponatremia, hyperkalemia, dehydration, and hypotension.

Patients are female at birth with ambiguous external genitalia (female pseudohermaphrodism), enlarged clitoris, and partial or complete fusion of the labia.

Postnatally CAH is associated with virilization. Patients may be male at birth with macrogenitosomia; postnatally this is associated with precocious puberty.

C-11 hydroxylase deficiency

The mineralocorticoid manifestations in C-11 deficiency can be ‘biphasic.’ In early infancy, despite having excessive mineralocorticoid hormones, patients sometimes present with relative ‘salt wasting’ (aldosterone deficiency).

This is because some infants have inefficient salt conservation as well as immature aldosterone production. During this phase, infants can present with hypotension and hyperkalemia (very similar to 21 hydroxylase deficiency). Later in life (childhood and adulthood), there is better ability to hold onto salt, so the patient develops the typical C-11 deficiency syndrome: hypertension and hypokalemia.

C-17 hydroxylase deficiency

characterized by hypogonadism, hypokalemia, and hypertension resulting from increased production of 11-deoxycorticosterone.

Diagnosis. CAH should be considered in all infants exhibiting failure to thrive, especially those with episodes of acute adrenal insufficiency, salt wasting, or hypertension.

The most useful measurements are of serum testosterone, androstenedione, dehydroepiandrosterone, 17-hydroxyprogesterone, urinary 17-ketosteroid, and pregnanetriol.

A rare, usually benign, tumor that arises from the chromaffin cells of the sympathetic nervous system.

The rule of 10%: 10% being extraadrenal, 10% malignant, 10% in children, 10% bilateral or multiple (>right side). 10% are not associated with hypertension.

Surgical subject

Familial pheochromocytoma occurs in 5% of cases, and is transmitted as an autosomal dominant trait alone or in combination with MEN type II or III, von Recklinghausen neurofibromatosis, or von Hippel-Lindau retinal cerebellar hemangioblastomatosis.

In adults, 80% of pheochromocytomas occur as a unilateral solitary lesion with 10% being bilateral and 10% extraadrenal. Solitary lesions favor the right side.

Extraadrenal pheochromocytomas are mostly located within the abdomen and near the celiac, superior mesenteric, and inferior mesenteric ganglia.

Catecholamine Secretion. Secretion of dopamine occurs more in familial syndromes and is not associated with hypertension. Epinephrine secretion causes tachycardia, sweating, flushing, and hypertension. Norepinephrine is secreted by all extraadrenal tumors.

Paroxysms or crisis:

The attack has a sudden onset, lasting from a few minutes to several hours or longer. Headache, profuse sweating, palpitations, and apprehension are common in this setting.

Pain in the chest or abdomen may be associated with nausea and vomiting. Blood pressure is elevated with tachycardia in crisis. 40% have elevated blood pressure elevation only during the attack. Anxiety, tremor, and weight loss are also found.

>33% of pheochromocytomas cause death prior to diagnosis; death is often due to cardiac arrhythmia and stroke.

Other clinical features include orthostatic hypotension and glucose intolerance.

Increased amounts of catecholamines or catecholamine metabolites in a 24-hour urine collection.

Recently, plasma metanephrine levels have been used in conjunction with urinary tests.

Overall, metanephrines are the most sensitive and specific individual test.

Smoking can increase plasma-free metanephrines. The patient must not smoke at least 4 hours before the test.

Clonidine should suppress epinephrine levels. Failure of epinephrine levels to fall after clonidine administration is highly suggestive of pheochromocytoma. A clonidine-suppression test is used when the above screening tests are equivocal.

When the catecholamine or metanephrine levels are abnormal, the tumor is confirmed with CT or MRI scan.

Note: Beta blockers are used if significant tachycardia occurs after alpha blockade; beta blockers are not administered until adequate alpha blockade has been established, since unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis.

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