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Addison's disease definition

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patients with chronic adrenal insufficiency secondary to AI destruction of the adrenal glands

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adrenal insufficiency definition

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hypofunction of the adrenal cortex with impaired production and secretion of cortisol, aldosterone, and adrenal adrogents

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clinical manifestations f adreanl insufficiency

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*primarily due to the deficiency of cortisol* - essential for survival uring ties of stress

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two categories of adrenal insufficiency

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1. primary - disorder of the adrenal glands - anatomic destruction of these glands 2. secondary (central) - failure of the pituitary to secrete ACTH, leading to dadreanl cortico hypofunciton and eventual atrophy

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primary adrenal insufficiency etiologies: destruction of the gland (chronic or acute)

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1. AI adrenalitis - isolated, sporadic - associated with other AI disorders 2. infectious adrenalitis - think AIDS 3. infiltrative diseases - metastatic cancer - amyloid - sarcoid 4. bilateral massive adreanl hemorrhage 5. surgical resection

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primary adrenal insufficiency: metabolic defects

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1. congenital adrenal hyperplasia - less synth and release of cortisol 2. drug induced - ketaconazole - etomidate - inhbits 11Bhydroxylase activity, the final step in cortisol biosynthesis 3. adrenoleukiodystrophy

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secondary adrenal insufficiency: suppression of the HPA axis

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1. exogenous glucocorticoids - after withdrwal 2. excess endogenous glucocortiocids from a primary adrenal tumor after resection 3. high dose megestrol or chronic opiod use

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secondary adrenal insufficiency: hypopituitarism or pituitary diseas

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adenomas, mets, infection, infiltrative disease trauma aneurysm

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AI adrenalitis: mechanism

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1. cellular and humoral immune mechanisms to do this 2. other endocrine organs also affected in half patients

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autoimmune adrenalitis histology

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adrenal fibrosis and atrophy associated with lymphocytic infiltration anti-adrenal antibodies found in 70-90% of patients

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AI adrenalitis: common antibody

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anti-21 hydroxylase actiivty;

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polyglandular AI syndrome

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presence of 2+ AI endocrine disorers in one patient is called this

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polyglandular AI syndrome type I

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autoimmune polyendocrinopathy candidasis ectodermal dystrophy (APECED) 1. AR genetics 2. AIRE

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polyglandular AI syndrome type I clinic

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in childhood with either 1. hypoparathyroidism due to AI desruction of the parathyroids or against the calcium sensing surface receptors on the parathyroids - destruction decreases PTH - autoantibody to the surface receptor causes the PTH to shut down even at subnormal Ca levels 2. chornic mucocutaneous candidiasis due to defective T cell mediated antifungal immunity - autoantibodies to IL17 and IL22 impairing the Th17 resposne for fungus

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so APECED syndrome summary

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1. AR - mutation in the AIRE gene 2. primary hypoparathyroidism onset before age of 10 3. chronic mucocutaneous cnadidasis beore the age of 10 4. AI adrenalitis: onset age 10-15 eyars

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polyglandular AI syndrome type II: aka Schmidts syndrome

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much more prevalent 1. priary adrenal insufficiency is major and the initial manifestation 2. half caes are familial but no single mutation implicated 3. can present in 20-40 years

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polyglandular AI syndrome type II summary

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1. half of cases are familial 2 onset in young adults (20-40s) 3. AI adrenalitis with adrenal insuffciency presenting symptom 4. AI thyroid disease 5. T1DM

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infectious adrenalitis

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Tb, fungal, some viral TB is huge cause worldwide in US, more common in HIV/AIDS patients -- CMV with necrotizing adrenalitis -- mycobacterium avium intracellare: this as well *hypotension alone without the other symptoms/signs*

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bilateral massive spontaneous adrenal hemorrhage: acute

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acute destruction of both glands leading to acute primary adreanl insufficiency; *refractory hypertension* but can have 1. acute abdominal pain 2. fever 3. vomiting 4. delerium

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bilateral massive spontaneous adrenal hemorrhage: chronic

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sepsis, burns, trauma + predisposing condition ofr bleeding and thrombosis - anticoags, thrombocytopenia, DIC, antiphospholipid syndrome

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bbilateral massive spontaneous adrenal hemorrhage: patho

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severe stress leading to increased ACTH 1. enhanced adrenal arterial blood flow 2. catecholamine release from the medulla, leading to venoconstrictio nof the central vein 3. high pressure leads to rupture associa

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Waterhouse Fridericksen syndrome

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DIC with bacterial sepsis leading to destruction of the

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Congenital Adrenal Hyperplasia: what is it

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group of AR disorders that abolish the activity of a step essential to the biosynthesis of cortisol - decreased production of cortisol - compensatory increase in ACTH --- the chronic increase in circulating ACTH leads to the hyperplasia, increased production of steroids proximal to enzymatic defect, decreased prodcution of steroid hormone end products distal tot ht edefect

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pathophys of CAH

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1. gene mutations leadto reduction in enzyme activity for cortisol synthesis 2. decreased plasma cortisol, leading to chronically elevated ACTH by pituitarty 3. leads to - adrenal hyperplasia - increased production of steroids proxuimal to defective step - decreased prodcution of the steroids distal to the defect 4. clincial manifestations reflect the resultatn steroid hormone excesses and deficienceis.

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CAH: most common cause

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reduced or absence activity of CYP21A2 (21 hydroxylase) - required for both the cortisol synthesis and for the synthesis of aldosterone

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CAH: 21 hydroxylase: what occurs

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1. decreased cortisol production 2. increase in the ACTH chronically 3. increased prodcution of the hormones - DHEA - androstenedione 4. hyperplasia of the adrenal cortex

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CAH: 21 hydroxylase deficiency in females

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signs of excess androgen production so 1. hirsutism 2. ammenorrhea 3. acne *milder forms* severe deficiency: 1. male or sexually ambiguous external genitalia in XX female --- pseudohermaphroditism -- increased adrenal androgen production during the early fetal development

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CAH: 21 hydroxylase deficiency severe

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decreased aldosterone produciton 1. renal salt wasting, volume contration, hypotension, hyperkalemia *only with severe deficiency* decreased cortisol reserve predisposes to the development of adrenal cris: during periods of severe stress

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other CAD forms: and hallmark

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1. 11B hydroxylase deficiecy 2. 17 alpha hydroxylase deficiency hallmark of these is the increase in the production of the weak mineralocorticoid 11 deoxycorticosterone by the zona fasciculata

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overproduction of 11DOC

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1. 11B hydroxylase or 17 alpha hydroxylase deficiencies 2. increased production of 11DOC 3. hypertension and hypokalemia -- similar findings to that of primary hyperaldosteronism -- suppression of renin activity -- suppression of plasma aldo levels -- high levels of DOC

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differentiating features of 11Bhydroxylase deficiency and 17alpha hydroxylase

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11B: increased adrenal production of DOC accompanied by increased androgen production 17a: both adrenal and gonadal production of sex steroid impaired thus: M: DHEA and androstenedione and testicular production of testosterone impaired F: impared ovariean estrogen synthesis

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in F with 11 B hydroxylase deficiency

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hypertension with hypokalemia with suppression of renin and aldo increased DOC increased androgen, so presents similar to 21 hydroxylase (but not with increased DHEA and androstenedione)

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in M and F with 17alpha hydroxylase/17,20 lyase def

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hypertension with hypolkalemia with hypogonadism

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drugs that block 11B hydroxylase

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1. etomidate - anesthetic agent 2. ketoconazzole can lead to primary adrenal insufficiency

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abiraterone

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used for advanced prostate cancer leading to 17a hydroxylase 17,20 lyase blocking this leads to adrenal insufficiency, especially during stress -- can cause hypertension and hypokalemia due to excess DOC production

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adrenoleukodystrophy

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1. X linked 2. defective beta oxidation of fatty acids 3. high concentrations of very long chain fatty acids in the serum 4. progressive neurologic dysfunction 5. primary adreanl insufficiency

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secondary adrenal insufficiency: important cuases

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1. glucocorticoid withdrawal 2. neoplastic diseases 3. inflammatory diseases 4. abrupt onsent secondary failure

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glucocorticoid withdrwal pathophysiology

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1. chronic use of glucocorticoid therapy 2. suppression of CRH and ACTH release 3. ACTH deficiency chronically leads to atrophy of the zona fasciculata and reticularis of the cotex, sparing the glomerulosa -- thus aldo is ok 4. longer duration and higher doses associated with increasd risk

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glucocorticoid withdrawal recovery

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HPA axis can take up to a year; recorvery of hypothalamus and pituitary precede recovery of the zona fasciculata to secrete cortisol

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neoplastic diseases

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1. anything that destroys the pituitary, invades hypothalamus, the stalk, reducing CRH and ACTH can really causes this pituitary macroadenomas are important: loss of the pituitary ACTH reserve tends to occur late, usually after the loss of the reserve of other pituitary hormones

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inflammatory disease

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1. AI hypophysitis - enlargemento f the pituitary with panhypopituitarism - mimics adenomas but the pattern of loss idffers: loss of ACTH occurs early, sometimes as an isolated hormone deficiency

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AI hypophysitis associated wti

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women in the post partum period that

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abrupt onset secondary adrenal failure

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1. rapid destruction of pituitary or injury of the stalk so 1. post partum pituitary necrosis 2. hemorrhage 3. trauma 4. surgery to pituitary they lose ACTH immediately then, they use ACTH for weeks, getting normal cortisol response; this is how long it takes for adrenal cortical atrophy to occur after loss of endogenous ACTH

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adrenal insufficiency: clinic features of primary and secondary

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Occurs in 80-100% of pts 1. weakness 2. weight loss 3. anorexia, nausea, vomiting 4. hypotension (BP< 110/70) occurs in 10-40% of pts 1. abdominal pin 2. diarrhea, constipation 3. sexual dysfuction 4. behaviroal and psychiatric 5. hyponatremia 6. hypoglycemia

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adrenal insufficiency: clincial features seen only in the chronic primary form

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1. hyperpigmentation (90-100%) 2. hyperkalemia 3. hyperchloremic acidoses 4. salt craving

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when should adrenal insufficiency be on the DD

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unexplained (and/or situation here) 1. hypotension 2. hyponatremia 3. hypoglycemia

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acute adrenal insufficiency: hemodynamics

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1. low systemmic vascular resistance with 2. high or normal cardiac output similar to those in septic or anaphylactic shock

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chronic stable insufficiency hemodynamics

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1. CO tends to decline 2. blod pressure are not absolutely low but maybe in the low normal range

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secondary adrenal insufficiency: hemodynamics

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1. reduction in BP 2. normal or increased intravascular tone

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adrenal insufficiency: hypoglycemeia

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only after period of prolonged food deprivation; caused by ipaired hepatic gluconeogenesis; - primary defense against hypoglcemia during prolonged food deprivation

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adrenal insufficiency: hyponatremia

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seen in both secondary and primary forms: 1. cortisol: impairs renal excretion of free water -- SIADH because: cortisol has a tonic inhibitory effect on ADH and secretion and AQP2 expression in the cortical colecting duct so if ust a cortisol disease, then yponatremia without volume contraction (add in the aldo in Addison's, then you get a volume contraction)

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primary failure and renal issues

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1. impaired aldosterone 2. increased loss of sodium 3. volume contraction 4. decreased renal perfusion -- impaired renal excretion of free water 5. thus, hyponatremia that is *associated with volume depletion*

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summary: hyponatremia in secondary failure vs primary

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if failure is secondary (just cortisol bc ACTH doesnt really do much with aldo) then 1. chronic inhibition of ADH is lifted 2. SIADH 3. euvolemia4. normal BUN, serum creatinine, K level primary 1. decreased cortisol lifts the ADH inhibition 2. decreased aldo leads to salt and water wasting, increased K level, eventual volume contraction with consequent hypoperfusion and kidney damage 3. leads to hyponatremia with eleveated BUN, serum creatinine and K, and hyperchloremic acidosis

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hyperpigmentation

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in Addisons due to the increased ACTH - has melanocyte stimulating activity

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adrenal crisis

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1. adrenal insufficiency 2. cardiovascular collapse - BP < 90/60 - tissue underperfusion and ultimate failuire 3. hypotension unresponsive or only partially responsive to volume expansion or pressors

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clinical features of adrenal crissis

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1. often precipitated by acute severe intercurrent illness or other stressful events 2. CV collapse - marked hypotension - refractory to volume loading and pressors - manifestationso f multiple organ underperfusion 3. fever 4. abdominal pain 5. hypoglycemia 6. confusion/delirium *need to give stress doses of GC stat, as this is an emergency*

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Dx

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1. decreased cortisol secretion and/or imparied secretory reserve 2. is it ACTH dependnet

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8 am plasma cortisol

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if > 20 then you can exclude it if < 3 ug/dl, then some evidence, but no diagnsosis; need ACTH stimulation

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rapid ACTH stimulation test

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give the patient a synthetic ACTH prep; then, there are high levels of ACTH in the blood; - reserve capacity of adrenal cortex; - check levels before and after (30 and 60 minutes) - if greater than 20 ul increase then there is a normal response if primary: then there will be little to no incrase due to the facft that ACTH is already high in these pts if secondary: - subnormal incrase (<20), due to adrenal cortex arophic but not completely destroyed

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ACTH stimulation test in those that are in a special group

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if it is an acute issue (like a stalk transection) - the ACTH response may be normal for 3-4 weeks so that you need to wait before the atrophy occurs

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replacement therapy in pregnancy

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hydrocortisone is the agent of choice dont use dexamethasone

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Tx of CAH

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longer acting preps are preferred; this is because there want to suprresss the elebvated ACTH; this leads to the overproduction of androgens and the other things;

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aldo replacement

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not in secondary in those with addisons: reduce salt craving and the need for continuous high salt intake; fludrocortisone;

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