Physiology of adrenal gland Glucocorticoids-Cortisolcoffeebreakcorner.weebly.com/.../adrenal_insufficiency_.pdfPhysiology of adrenal gland Anatomy ! Weight = 4g ! 2 adrenal gland,

Phys io logy o f adrena l g land

Anatomy

� Weight = 4g � 2 adrenal gland, right and left

� 2 component à inner adrenal medulla and outer adrenal cortex � situated near upper poles of kidney in retroperitoneum within Gerota’s capsule

Adrena l hormones

� Glucocorticoids-Cortisol � Mineralocorticoids-Aldosterone � Androgens-DHEA(S), testosterone, androstenedione   � Estrogens � Catecholamines-Epinephrine, Dopamine

Cor t iso l Da i ly

ACTH/Cor t iso l Trends

� ACTH is the principal regulator of Glucocorticoids secretion. � Secretion of ACTH and glucocorticoids exhibit a diurnal rhythm, s t imu la ted by stress and inh ib i ted by circulating glucocorticoids. � Endogenous production of cortisol averages 20 mg \ day.

Ac t ions o f G lucocor t ico ids

• Maintains metabo l ic homeostasis – Regulates blood glucose levels – Raises insulin levels – Increases catabolism/decreases anabolism – Inh ib i ts reproductive, thyroid and growth hormone

axes – Minera locor t ico id activity of cortisol

• Affects connect ive tissue – Causes loss of collagen – Loss of connective tissue – Inhibits fibroblasts – Inhibits bone formation/incr. resorption

• Maintains card iovascu lar function – Increases cardiac output – Increases vascular tone – Permissive effects on pressor hormones – Increases sodium retention

• Affects behav ior and cogn i t i ve function • Affects immune system

– Decrease # of circulating lymphocytes, monocytes, and eosinophils

– decrease migration of PMNs to sites of injury • Regulates about 25% of human genome

Ren in-Ang io tens in-A ldosterone

Act ions

• Angiotensin II – vasopressor – stimulates aldosterone

• Aldosterone – Activates sodium/potassium pump – Increases plasma sodium – Decreases plasma potassium – Decreases plasma hydrogen

*A ldosterone s t imu la ted by à RAS, ACTH, Hyperkalemia, hypovolemia, hypotension, CHF, Surgery

 Adrena l insu f f i c iency

S tages in Deve lopment o f Pr imary Adrena l

Insu f f i c iency

• Stage1- renin rises, aldosterone normal • Stage 2- ACTH rises, cortisol normal • Stage 3- impaired cortisol response to ACTH • Stage 4- aldosterone levels drop   • Stage 5- cortisol levels drop

E t io logy o f adrena l

insu f f i c iency

• Primary adrenal insufficiency • Secondary adrenal

insufficiency • Chronic adrenal insufficiency • Acute adrenal insufficiency

Ø Usually occurs after a prolonged of non specific complains

Ø Is more frequently observed in patients with primary adrenal insufficiency

D i f fe rent Types o f G lucocor t ico id

Insu f f i c iency

• Primary Adrenal Insufficiency – Glucocorticoid and Mineralocorticoid Insufficiency – Compensatory Increase in POMC (hyperpigmentation)

• Secondary (Central) Adrenal Insufficiency – Glucocorticoid Insufficiency On ly

• Glucocorticoid Withdrawal – Glucocorticoid Insufficiency On ly

Pr imary adrena l insu f f i c iency

1. Is most commonly caused by autoimmune adrenalitis § Isolated autoimmune adrenalitis accounts for 30 – 40

% § 60 – 70% develop adrenal insufficiency as part of

autoimmune polyglandular syndrome (APS) à APSH, APS2

2. Congenital adrenal hyperplasia 3. infection / hemorrhage/ infiltration/ tuberculous adrenalitis /

adrenal metastases (rarely caused adrenal insufficiency and this occurs only with bilateral bulky metastases)  

Secondary adrena l

insu f f i c iency

Is the consequence of dysfunction of hypothalamic – pituitary component of the HPA axis Majority of cases are caused by

§ Pituitary tumor § Pituitary irradiation § Pituitary apoplexy/hemorrhage § Pituitary infiltration § Drug induced § Congenital isolated ACTH deficiency

Glucocorticoid Withdrawal à Glucocorticoid Insufficiency On ly

C l in ica l presenta t ion

§ Pr imary adrena l insu f f i c iency are character ized by the loss o f both g lucocor t ico id and minera locor t ico id secre t ion

Ø Hyponatremia is a characteristic biochemical feature in primary adrenal insufficiency and is found in 80% of patient at presentation Ø Hyperkalemia is present in 40% of patient at initial diagnosis

§ Secondary adrena l insu f f i c iency. On ly g lucocor t ico id de f ic iency is present Ø Due to diminished inhibition of ADH by cortisol, resulting in mild symptoms of inappropriate secretion of antidiuretic hormone (SIADH) Ø Glucocorticoid deficiency à increased TSH

§ Adrenal androgen secretion is disrupted in both primary and secondary adrenal insufficiency

Chron ic adrena l insu f f i c iency

§ Non specific sign and symptoms such as fatigue and loss of energy § A distinguishing feature of primary adrenal insufficiency is hyperpigmentation, which is caused by excess ACTH stimulation of melanocytes.

Hyperpigmentation is most pronounced in skin areas exposed to increased friction or shear stress and is increased by sunlight § Conversely, in secondary adrenal insufficiency then skin has an alabaster like paleness due to lack of ACTH secretion

Adrena l Cr is is

• Usually in Patients with Primary Adrenal Insufficiency • Precipitated by Stress • Newly diagnosed vs. established patient

– stopped medicines – illness – vomiting

Presentation of Adrenal Crisis (usually primary adrenal insufficiency) • Hypotension/shock (90%) • Abdominal pain (80%) DD Acute abdomen • Fever (65%) • Anorexia/nausea/vomiting (60%) • Confusion (40%) • Hyponatremia/hyperkalemia/acidosis (80%) • Hypoglycemia (20%)

D iagnos is o f Adrena l

Insu f f i c iency

Laboratory Findings of Primary Adrenal Insufficiency • Hyponatremia • Hyperkalemia • Hypoglycemia • Lymphocytosis • Eosinophilia • Mild normochromic Anemia

Cosyntrop in tes t § A safe and reliable tool with excellent predictive diagnostic value § The cut off for failure is usually defined at cortisol levels of <500 –

550 nmol/L (18 – 20 micro g/ dL) sampled in 30 – 60 minutes after ACTH stimulation

Quick approach 1. Checking an 8AM fasting cortisol level can usually make or exclude the diagnosis in a patient levels of cortisol < 5 ug/dl or > 12 ug/dl

respectively. 2. Should on ly be done in subjects with signs/symptoms of adrenal insufficiency or history consistent with it. 3. Can be used in those patients with a moderate index of suspicion. 4. Measurement of ACTH levels can differentiate between primary and secondary insufficiency 5. Consistently high ACTH can be a sign of early adrenal insufficiency

Workup/Treatment for Suspected Adrena l Cr is is

• Establish IV access • Draw blood for electrolytes, glucose, cortisol, ACTH,

aldosterone and plasma renin activity • Infuse up to 3 liters of normal saline

• Follow fluid status • Give 100 mg of IV hydrocortisone • Supportive Measures

Treatment o f acute adrena l insu f f i c iency

1. Immediate initiation of rehydration, usually carried out by saline infusion at initial rates of 1L/H 2. Continuous cardiac monitoring 3. Glucocorticoid replacement should be initiated by bolus injection of 100mg hydrocortisone 4. Followed by the administration of 100 – 200 mg hydrocortisone over 24hours either by continuous infusion or provided by several IV or IM

injection 5. Mineralocorticoid replacement can be initiated once the daily hydrocortisone dose has been reduced to <50mg

Treatment o f chron ic adrena l

insu f f i c iency

1. 15 – 25 mg hydrocortisone in two or three divided doses 2. pregnancy may require an increase in hydrocortisone dose by 50% during the last trimester 3. in all patients, at least one half of the daily dose should be administered in the morning 4. Long acting glucocorticoids such as prednisolone or dexamethasone are not preferred