Adrenal Medicine

HTN

Does Cushing cause hypotension or HTN?

loss

Does aldosterone cause hydrogen retention or loss?

loss

Does aldosterone cause potassium retention or loss?

retention

Does aldosterone cause sodium retention or loss?

boys

Does congenital adrenal hyperplasia take longer to diagnose in girls or boys?

What advice should be given to patients with primary adrenal insufficiency about their medication?

Double the dose of steroid during illness and continue on doubled dose until after their illness resolves Need to be administered IV/IM during surgery or in cases of prolonged diarrhoea or vomiting Provide emergency steroid card

Which of the following is NOT seen in Adrenal insufficiency? A) weight loss B) fatigue and weakness C) nausea vomiting D) orthostatic hypotension E) hirsuitism F) hyperpigmented skin G) salt cravings

E (hirsuitism - this is cortisol excess)

Which of the following is NOT consistent with secondary adrenal insufficiency? A) low cortisol B) low ACTH C) rapid cortisol increase on cosyntropin test D) normal sodium and potassium levels E) orthostatic hypotension

E (orthostatic hypotension - not present as aldosterone secretion is preserved)

Mortality from MEN 2 of Medullary Thyroid Carcinoma can be prevented by doing what?

Early Thyroidectomy

Investigating primary adrenal insufficiency

Electrolytes - hyponatraemia (MC), hyperkalaemia, raised urea FBC - normocytic anaemia Glucose - hypoglycaemia ACTH - elevated Plasma renin - elevated Adrenal antibodies - +ve Synacthen test (needed to confirm) - cortisol post Synacthen <500nmol/L TFTs - hypo or hyperthyroid

What happens to the aldosterone/renin ratio in primary hyper-aldosteronism?

Elevated - over-secretion of aldosterone by adrenals - (-) FDBK on renin release (suppression)

What are catecholamines?

Epinephrine, Norepinephrine

Alternative aldosterone antagonist to spironolactone but without testosterone antagonist SEs

Eplerenone, however it has not been fully evaluated yet.

Synthetic glucocorticoids

Ex prednisone and dexamethasone. They have antinflammatory and immunosuppressive effects at high levels. So it can inhibit local rxn to injury, inhibit release of degredative enzymes, etc. And immunosuppressively inhibit production of T and B cells and induce their death.

Cushing's syndrome

Excess cortisol secretion --> glucocorticoid excess Loss of circadian rhythm

Clinicals of Congenital Hyperplasia?

-INC ACTH CAUSING BILATERAL HYPERPLASIA -CORTISOL AND ALDOSTERONE DEFICIENCY, ANDROGEN EXCESS -FEMALES: Ambiguous genitalia, cliteromegaly, normal ovaries and fallopian tubes. NO FERTILITY PROBLEMS, Genitalia must be treated -MALES: No genital abnormalities, present with salt wasting Accelerated linear growth, advanced skeletal maturation

Diagnostic work up of adrenal incidentaloma

Exclude hormone hypersecretion: - plasma/ urinary metanephrines => Phaeochromocytoma - aldosterone: renin ratio => primary hyperaldosteronism - 1mg over night dexamethasone suppression test => Cushings syndrome Assess likelihood of metastasis: - full hx + examination - poorly demarcated on CT/MRI? - CXR in smokers Unenhanced CT scan - low density lesions (Hounsfield units) = benign, lipid rich adenoma If vascular, calcified or heterogeneous then unlikely to be benign

Screening for Hyperaldosteronism shows...?

-Increased serum aldosterone and increased urine aldosterone -Inc. Plasma aldosterone to renin ratio

Causes of Cushing Syndrome - ACTH independent (LOW ACTH)

Exogenous glucocorticoids* (most common) - suppresses entire HPA axis (B/L atrophy adrenal cortex) Adrenal (1°) adenoma (rare) Adrenal hyperplasia

How do you diagnose addison's disease?

-Low Cortisol levels -ACTH: In primary adrenal, ACTH HIGH. In secondary pituitary, ACTH LOW 1. ACTH Test: Give ACTH. IF cortisol low, then primary deficiency. -Cosyntropin Stimulation: DETECTS PRIMARY. Synthetic ACTH prep, if cortisol still low, then + - Metyrapone Stimulation: DETECTS SECONDARY. Should decrease cortisol and increase ACTH, but here, failure of ACTH to rise

Clinical Manifestations of pheochromocytoma?

-Paroxysmal, come and go -HTN (during attack) - Panic attack/MI symptoms

Secondary Hyperaldosteronism etiology

Extra-adrenal etiology

Glucocorticoids cause all of the following EXCEPT: A) increased destruction and reduced production of inflammatory cells B) reduced migration of neutrophils C) decreased lymphocytes and monocytes D) inhibition of the function of antigen presenting cells E) inhibition of eicosanoids F) increased mast cell degranulation and histamine release

F (DECREASED mast cell degranulation and histamine release)

Which of the following is NOT a complication of corticosteroid use? A) iatrogenic Cushing's B) HPA axis suppression C) peptic ulcer D) psychosis E) glaucoma F) all of the above are possible complications

F (all of the above are possible complications) (be sure to frequently check blood sugars and blood pressure, encourage glaucoma screening, and give osteoporosis prophylaxis - calcium with vitamin D and bisphosphonates)

Hypernatremia Hypokalemia Hypertension Suspect primary hyperaldosteronism when a patient is diagnosed with hypertension and is found to have hypokalemia. Check renin:aldosterone ratio Get CT of adrenal glands to r/o adenoma or carcinoma

Features of Hyperaldosteronism

cortisol- catabolic actions

-predominates - stimulates protein breakdown in muscle, bone etc (amino acid mobilisation) - increases fat mobilisation- lipolysis, releases fatty acids & glycerol

Physiologic dose of: Fludrocortisone (mineralocorticoid)

0.1 mg DAILY

Clinical presentation of CAH

1) "Classic" CAH - present in neonatal period or infancy - virilisation (e.g. causing ambiguous genitalia in girls) +/- salt wasting (b/o lack of aldosterone) 2) "Non classic" CAH - partial enzyme activity - presents later in life similar to PCOS (hirsuitism, oligomenorrhea)

Equivalent Doses: 1) Cortisone 2) Hydrocortisone 3) Prednisone 4) Prednisolone 5) Triamcinilone 6) Dexamethasone

1) 25 mg 2) 20 mg 3) 5 mg 4) 5 mg 5) 4 mg 6) 0.75 mg

Management of adrenal crisis

1) ABCDE 2) Assess BP + fluid balance 3) Take PMHX, check drugs for steroid exposure 4) Bloods - FBC, U&E, TFTs, cortisol, ACTH (consider Synacthen test ONLY if pt haemodynamically stable) 5) Give 1 L 0.9% saline over 1-2 hrs (be careful in cardiac/ renal failure) 6) Give 100mg IV hydrocortisone bolus 7) Correct hypoglycaemia c glucose (if present) 8) Continue IV fluids until clinical recovery - continue hydrocortisone (either 200mg continuous infusion or 50mg IV/IM injection every 6 hrs) 9) ID and Rx precipitants 10) Pt education - sick day rules etc

Screen: Addison's disease

1) ACTH 2) Serum Cortisol

Investigating phaeochromocytoma

1) Biochemistry - 24hr urinary fractionated metanephrines +/- catecholamines screening Ix - >2 collections may be needed if suspicion high b/o episodic nature of secretions - plasma metanephrines - serum chromogranin A (marker of neuroendocrine hypersecretion) elevated in phaeochromocytoma AND paraganglioma 2) Radiology - CT/ MRI abdomen - whole body MRI if tumour not localized - 1231 - meta-iodobenzylguanidine (MIBG) detects tumours not visible on MRI; useful pre op to exclude multiple tumours 3) Genetic testing: - syndromic presentations - sporadic tumours (30% germline mutations in susceptibility genes) - mutations MC in young, multiple, extra adrenal disease - annual screening of index cases + 1st degree relatives

Dexamethasone suppression test

1) Get baseline cortisol 2) Give DM at midnight 3) Redraw Cortisol at midnight

Which two corticosteroids also have mineralocorticoid activity?

1) Hydrocortisone 2) Cortisone

LABS: Primary hyperaldosteronism 1) Renin 2) Aldosterone 3) Bicarb 4) Na+ 5) K+

1) LOW 2) HIGH 3) HIGH (to compensate for metabolic acidosis) 4) HIGH 5) LOW

Adrenal Insufficiency LABS: 1) Na+ 2) K+ 3) BUN/Cr 4) Blood Sugar 5) ADH

1) Low (no aldosterone) 2) High (K+ not exchanged for Na+) 3) High (volume depletion...AKI) 4) Low (low cortisol) 5) High (volume depletion...low BNP...high ADH)

Investigation of hyperaldosteronism

1) Plasma renin + aldosterone - ambulant aldosterone:renin ratio, anti-hypertensives should be discontinued for 4wks prior to testing (esp. BBs, ACEi); serum K+ should be normalised c supplements - serum Na+, K+, bicarbonate 2) Confirmation in specialist clinic - e.g. failure of aldosterone suppression following IVI c NS or fludrocortisone 3) Determine cause, abdo CT/MRI - localise aldosterone producing adenoma (Conn's), non functioning adenomas present in 20% of hypertensives - adrenal vein sampling; confirm bilateral hyperplasia

How do glucocorticoids cause HYPER-glycemia?

1) They increase Liver protein synthesis - of enzymes for gluconeogenesis/glycogenesis 2) They also antagonize peripheral effects of insulin

Diagnosis of Pheochromocytoma

1. 24 hour urine collection of metanephrine, VMA (vanillylmandelic acid), total catecholamines, creatinine 2. Abdominal CT scan=85-95% sensitivity 3. Abdominal MRI=99% sensitivity

What are the common signs of Cushing's syndrome?

1. Buffalo hump 2. Moon face 3. Central adiposity 4. Purple/red striae 5. Increase infections 6. Poor wound healing 7. Osteroporosis and pathologic fractures

Functions of cortisol?

1. Counters insulin; increases glucose 2. Increases protein catabolism & catecholamine activity 3. Increased during stress 4. Immunosuppresant 5. Suppresses gonadotropic release hormones

What are the four major causes of Hypercortisolism?

1. Cushing's Syndrome 2. Adrenal Tumor 3. Cushing's Disease 4. Ectopic Tumor

What are the classic findings of Primary Hyperaldosteronism?

1. Diastolic HTN 2. Hypokalemia 3. Metabolic alkalosis 4. Low plasma renin

Criteria for Diagnosis of Primary Hyperaldosteronism

1. Diastolic HTN without edema 2. Decreased stimulation of renin when stimulated -stimulate with volume depletion 3. Increase secretion of aldosterone that cannot be suppressed -try to suppress with volume expansion NO Diuretic use

What are two conditions secondary hyperaldosteronism are associated with?

1. Edema state 2. Associated with HTN

MEN 2 treatment for hyperparathyroidism

1. Excise 3.5 remnant in neck 2. Full excision with remnant implanted back in forearm

What is the diagnostic testing for Primary Hyperaldosteronism?

1. Failed aldosterone suppression with volume expansion 2. Renin hypo secretion with volume depletion

Treatment for Primary Adrenal Insufficiency/Addisons and Secondary Adrenal Insufficiency

1. Glucocorticoid-Hydrocortisone 2. Mineralocorticoid-Fludrocortisone 3. Education 4. Adequacy of Therapy

What are the 3 classic triads of pheochromocytoma?

1. Headache 2. Diaphoresis 3. Palpitations

How to Diagnose hypercortisolism?

1. High 24 hr urinary cortisol OR 2. Low Dose Dexamethasone Suppression: Normally, cortisol should go down with LDD. IF IT REMAINS HIGH, THEN HYPERCORTISOLISM! 3. Check ACTH levels: IF LOW, THEN SYNDROME/ADRENAL TUMOR. IF HIGH, THEN DISEASE/ECTOPIC. (Is PT taking steroids? Test +, ACTH low = SYNDROME. If not taking steroids and Test +, ACTH low = ADRENAL) 4. HIGH DOSE DEXAMETHASONE TO DIFFERENTIATE BETWEEN ADRENAL OR ECTOPIC TUMOR. If cortisol suppressed, then ADRENAL. If not suppressed, then ECTOPIC. 5. CT/MRI, especially of lung

What two conditions can lead to aldosterone release?

1. Hyperkalemia directly releases aldosterone 2. Hypovolemia increases renin, which releases angiotensin I which is converted to angiotensin II, which releases aldosterone

Multiple Endocrine Neoplasm 1

1. Hyperparathyroid 2. Pancreatic islets 3. Pituitary

What if surgical resection failed or is C/I?

1. Ketoconazole-decreases cortisol production 2. Metyrapone-blocks final step of cortisol synthesis-used with ketoconazole if it fails

Multiple Endocrine Neoplasms for MEN2 are most commonly what?

1. Medullary Thyroid Carcinoma 2. Pheochromocytoma

Diagnosis of Cushing's

1. Start with 24 hours urine cortisol IF greater than 300mcg/dL BOOM you are diagnosed IF less than 90 mpg/dL you DON'T have it yay!!! 2. 1 mg Dexamethasone suppression test (negative feedback loop)-Dexamethasone at 11pm and then cortisol measured at 8am 3. CRH/Dex suppression test if above inconclusive--if cortisol is greater than 50-Diagnositc

How to diagnose Hyperaldosteronism?

1. Take off hypertensives 2. 24 hour urine aldosterone and serum aldosterone for screening 3. Aldosterone Suppression Test 4. CT/MRI

What are three causes of acute hemorrhagic destruction of the bilateral adrenal glands?

1. Waterhouse-Friderichsen syndrome 2. Anticoagulation 3. Pregnancy complication

What is the clinical presentation of Addison's disease?

1. Weakness/Fatigue (initially asthenia) 2.Hypotension/Orthostasis/Dehydration 3. Weight loss/Anorexia 4. +/- Hyperpigmentation (skin, mucosa) 5.Nausea/Vomiting/Diarrhea/Abdominal pain

What are the two most common stressors to cause an adrenal crisis?

1. infection 2. vomiting/diarrhea

Waterhouse-Friderichsen syndrome is a common cause of acute hemorrhagic destruction of the bilateral adrenal glands and is associated with what?

1. pseudomonas 2. meningococcemia septicemia

What are two exacerbation of chronic adrenal insufficiency?

1. stress participant 2. sudden withdrawal/noncompliance of chronic steroid

Pheochromocytoma "Rule of Tens"?

10% bilateral 10% familial 10% malignant 10% in children 10% no hypertension 10% recur 10% extra adrenal*

Rule of 10s for phaeochromocytoma

10% malignant 10% extra-renal (paragangliomas) 10% familial 10% bilateral 10% hereditary (MEN2, vHL, neurofibromatosis)

Rule of 10s with Pheochromocytoma

10% part of MEN 2(a/b) 10% Bi-lateral 10% Extra-adrenal 10% Malignant

what amplifies cortisol action

11β-HSD 1, converts cortisone back to cortisol present eg. in liver, adipose tissue

Causes of hypokalaemia

1o hyperaldosteronism Vomiting + metabolic alkalosis Diarrhoea or other fluid loss from lower bowel: - ileostomy - villous adenoma of rectum Diuretic use Hypomagnesaemia Insulin infusion Rare causes - e.g. RTA, defects in renal tubular function - Gitelman syndrome (usually normotensive) - Liddle syndrome (hypertensive) - Bartter syndrome (usually hypo or normotensive) - Hypokalaemic periodic paralysis

Treatment of Cushing's syndrome

1st line - surgery; adrenalectomy (adenoma/ carcinoma) if adrenal; transphenoidal if pitutary 2nd line - medical; metyrapone, ketoconazole then surgery if tumour locatable and not metastasised 3rd line - pituitary radiotherapy

Treatment of type 1 familial hyperaldosteronism

1st: Dexamethasone to inhibit production of ACTH. 2nd: Spironolactone.

Other causes of Primary Hyperaldosteronism?

2ND MCC: bilateral cortical hyperplasia Carcinoma

Triad of MEN-1

3 P's: Parathyroid hyperplasia/adenoma Pancreas endocrine tumour (gastrinoma/insulinoma) Pituitary tumour

Steroids are more likely to cause central adrenal insufficiency (through hypothalamic-pituitary-adrenal axis feedback suppression) for people who have been on them longer than ____________

3 weeks

Age for phaeochromocytoma

30-60 is most common but can occur in children.

How long does it take a person to regain normal HPA axis function after chronic steroid use?

6-12 months (after d/c steroids)

Cushing's disease or benign adrenal adenomas have a 5yr survival rate of (#)% and a 10yr survival rate of (#)%

95(%); 90(%) (ectopic ACTH prognosis: 5yr rate of 65% and 10yr rate of 55%) (death not necessarily due to cancers, but due to co-morbidities and increased risk of infection)

Prognosis of phaeochromocytoma

96% 5 yr survival for benign tumours Surgical removal cures HTN in majority of pts Malignant disease - Rx c radio or chemotherapy

DISORDERS OF ADULT ADRENAL FUNCTION

:)

DISORDERS OF FETAL ADRENAL FUNCTION

:)

Secondary hyperaldosteronism

= Renin secretion increased due to renal hypoperfusion - e.g. cardiac failure, liver failure etc Renin secreting renal tumours rare cause High renin and aldosterone

Adrenal crisis

= acute adrenal insufficiency, life threatening cortisol deficiency Precipitants: - infection - sudden cessation of glucocorticoid therapy - failure to incr. glucocorticoid dose during intercurrent illness, after trauma or surgery requiring GA

Adrenal incidentaloma

= adrenal mass >1cm in size, discovered incidentally in work up of clinical disorders unrelated to adrenal gland Common - >4% >50s using CT Majority benign and inactive - ALL require workup (exclude malignancy + hormone excess)

Cushing's disease

= bilateral adrenal hyperplasia from ACTH secreting pituitary tumour Peak age 30-50s

Phaeochromocytoma

= catecholamine secreting tumours, occur in 0.1% of pts c HTN 90% arise in adrenal medulla 10% arise in extra-adrenal chromaffin tissues ("paragangliomas") Majority sporadic - genetic basis occurs in 30% of pts; esp. bilateral, extra-adrenal or malignant tumours (<10%)

Congenital adrenal hyperplasia (CAH)

= family of inherited (autosomal recessive) disorders of adrenal steroidogenesis 21 hydroxylase deficiency MC form: - defect --> block in cortisol (+/- aldosterone) synthesis --> hypersecretion of ACTH --> build up of precursors upstream of defect (e.g. 17-OH) AND excess hormone synthesis (e.g. androgens) in pathways unimpaired by enzyme defect

Primary hyperaldosteronism

= tumours or bilateral hyperplasia of zona glomerulosa --> excess aldosterone c normal cortisol Low renin, high aldosterone Aldosterone secretion independent of renin Causes: - 2/3 aldosterone producing adenoma (Conn's syndrome) - 1/3 bilateral adrenal hyperplasia

Which of the following describes MEN 2a (Sipple's syndrome)? A) Autosomal dominant disorder causing medullary carcinomas of the thyroid, pheochromocytomas, and/or hyperplasia or multiple adenomas causing hyperparathyroidism B) familial autosomal dominant multiglandular syndrome causing tumors of the pituitary adenomas, pancreatic tumors, and / or parathyroid tumors C) Manifests as tumors of the medullary carcinomas of the thyroid, mucosal neuromas, bilateral adrenal pheochromocytomas and / or Marfan-like habitus

A (Autosomal dominant disorder causing medullary carcinomas of the thyroid, pheochromocytomas, and/or hyperplasia or multiple adenomas causing hyperparathyroidism) (screen patients for ret proto-oncogene; those + should have siblings and children tested)

Which of the following is NOT a consequence of a pheochromocytoma? A) hypoglycemia B) seizures C) psychosis D) hypertensive crisis E) cardiomyopathy F) pulmonary edema

A (HYPERglycemia)

How is Cushing's syndrome due to primary adrenal tumors treated? A) adrenalectomy of cortisol secreting adenomas and carcinomas B) transsphenoidal resection the pituitary tumor C) dexamethasone supplementation D) Ketoconazole or Metyrapone to block 11-hydroxylase enzyme in the pathway of cortisol production

A (adrenalectomy of cortisol secreting adenomas and carcinomas)

Which hormone is responsible for the reabsorption of sodium and excretion of potassium? A) aldosterone B) cortisol C) androgens D) norepinephrine

A (aldosterone) (secreted with low BP to retain sodium and water)

How should you treat secondary adrenal insufficiency? A) hydrocortisone acetate B) prednisone C) fludrocortisone D) cortisol, renin, potassium, and BP monitoring

A (hydrocortisone acetate) (no need for aldosterone replacement with fludrocortisone)

The zona glomerulosa secretes: A) mineralcorticoids B) androgens C) glucocorticoids D) catecholamines

A (mineralcorticoids - aldosterone) (salt)

Which of the following is NOT a symptom of primary hyperaldosteronism? A) oliguria B) headache C) muscle weakness, fatigue, lethargy D) may be asymptomatic

A (polyuria and polydipsia in cases of severe hypokalemia)

A patient presents to your office following discovery of an incidental adrenal mass. Work up shows the mass to be non-functional and <5cm. What would be the appropriate next step? A) repeat CT in 3 months B) surgical excision C) fine needle biopsy D) any of the above

A (repeat CT in 3 months)

>1000 ng.mL

A DHEA level of what excludes the diagnosis of Addison's?

50%

A child born to a parent who has MEN, what is the percentage chance of the child also having it?

What is Adrenal Insufficiency?

A decrease in adrenal hormones

Test for adrenal function

ACTH (cosyntropin) Stimulation test 1) get baseline cortisol (8 am) 2) get baseline plasma ACTH 3) ACTH stimulation test *cosyntropin = ACTH business end

LABS: 1° adrenal insufficiency - from auto-immune adrenal destruction

ACTH - HIGH Cortisol - LOW Aldosterone - LOW

LABS: 1° adrenal insufficiency

ACTH - HIGH (no - FDBK on HPA axis by Cortisol) Cortisol - LOW Aldosterone - LOW HYPO-natremia (renal salt wating) HYPER-kalemia (not traded for Na+) ADH - HIGH

LABS: 2° adrenal insufficiency - from chronic glucocorticoid therapy (-) FDBK

ACTH - LOW Cortisol - LOW (adrenal atrophy) Aldosterone - Normal********

How do you confirm adrenal insufficiency?

ACTH Stimulation test - 250 mg ACTH (co-syntropin) - Should 2x Cortisol within 60 minutes - If cortisol is still < 20 = (+) Test for 1° adrenal insufficiency

Aetiology of Cushing's syndrome

ACTH dependent = pituitary overproduction of ACTH --> stimulating adrenal gland to produce cortisol - Cushing's disease, ectopic ACTH (SCLC, carcinoid) ACTH independent = autonomous cortisol secretion - adrenal adenoma/ carcinoma/ hyperplasia, exogenous (iatrogenic, excess alcohol, depression) - McCune-Albright

Two main groups of causes of CS and examples of them.

ACTH dependent e.g. excess ACTH from pituitary adenoma (Cushing's DISEASE), ectopic ACTH producing tumours, excess ACTH administration. Non ACTH dependent e.g. adrenal adenomas, adrenal carcinomas, excess glucocorticoid administration.

Gold standard for diagnosing Addison's

ACTH stimulation (Synacthen) test: absence of usual rise in cortisol levels following administration of ACTH.

increases

ADH _______________ ACTH release

What is addison disease?

AI due to autoimmune disease

Physiologic dose of: Hydrocortisone

AM - 20 mg PM - 10 mg

Physiologic dose of: Prednisone

AM - 5 mg PM - 2.5 mg

Clinicals of addisonian crisis?

AMS, Confusion, Psychosis, dehydration, weakness

Causes of Addison's diseaes

ANATOMIC DESTRUCTION OF THE GLAND Autoimmune, usually against the 21-hydroxylase enzyme (most common cause cause). Surgical removal. Trauma. Infections, particularly TB. Also CMV in AIDS patients. Haemorrhage (Waterhouse-Friderichsen syndrome is haemorrhage of adrenals secondary to septicaemia). Infarction e.g. antiphospholipid syndrome. Invasion e.g. neoplastic, sarcoidosis, amyloidosis. METABOLIC FAILURE IN HORMONE PRODUCTION Congenital adrenal hyperplasia e.g. 21-hydroxylase or other enzyme deficiencies. Cytotoxics. ACTH/glucocorticoid resistance. Increased hepatic metabolism of cortisol (caused by some drugs). Enzyme inhibition by some drugs. Congenital adrenal insufficiency.

neutrophils elevated (In adrenal crisis, just eosinophils are elevated)

Acute abdomen is a Ddx for adrenal crisis, what lab value would distinguish this from adrenal insufficiency?

Symptoms of adrenal insufficiency

Acute cause e.g. infection, surgery, trauma, haemorrhage: Hypotension. Hypovolaemic shock. Acute abdominal pain. Low-grade fever. Vomiting. Chronic cause. Symptoms develop gradually and diagnosis is often delayed: Fatigue and weakness (most common). Anorexia. Nausea. Vomiting. Weight loss. Abdominal pain. Diarrhoea. Constipation. Cravings for salt. Muscle cramps and joint pain. Syncope (due to hypotension). Confusion/personality change/irritability. Loss of pubic/axillary hair in women. Delayed puberty.

Low BP; Addisonian crisis: severe hypotension and vascular collapse Weakness and easy fatigability Anorexia, nausea, vomiting, diarrhea, abd. pain Hypoglycemia Hyperpigmentation (only if ACTH is increased) Vitiligo - often occurs in patients with Addison's

Addison's Disease Signs and Symptoms

What is primary adrenal insufficiency?

Addison's Dz: Decrease in CORTISOL, ALDOSTERONE, and ADRENAL ANDROGENS due to the chronic destruction of the adrenal cortex.

1° adrenal insufficiency is also known as...

Addison's disease

Tuberculosis is a common cause of this endocrine disease - calcifications in the adrenal glands

Addison's disease (primary adrenal insufficiency) - TB is the main cause of primary adrenal insufficiency in developing countries - Most require life-long glucocorticoids and mineralocorticoids, even if TB is cured

30-60 yo

Addison's primarily occurs in what age range?

Pseudo-Cushing syndrome

Additional factors raise serum cortisol and complicate DDx of Cushing's E.g. - obesity - alcoholism - depression Distinction from Cushings syndrome: - diurnal variation retained - cortisol falls when alcohol abuse stopped - cortisol rises c insulin induced hypoglycaemia

How to prevent adrenal crisis

Adjust hydrocortisone intake to demands e.g. illness. Don't stop steroids suddenly after using them for >2 weeks. This applies to all patients, not just those with adrenal insufficiency.

Excess can be caused by adrenal tumor of Cushingoid association Hyposecretion = not clinically significant Hypersecretion of estrogens: Gynecomastia, testicular atrophy, decreased libido Hypersecretion of androgens: hirsutism, deepening of the voice, amenorrhea, acne, breast atrophy

Adrenal Androgens and Estrogens of the Zona Reticularis

ACUTE adrenal insufficiency Abrupt withdrawal from pharmacologic steroids -- result: hypotension/shock ** takes place when Addison pt's: -- fail to take meds -- experience major stress Txt: "stress doses" of IV steriods

Adrenal Crisis

What part of the body produces and releases cathecholamines (epinephrine, norepinephrine, dopamine)?

Adrenal Medulla

Causes of primary hyperaldosteornism

Adrenal adenoma (Conn's syndrome) (most common) - suspect in young women. Bilateral adrenal hyperplasia. Familial hyperaldosteronism type 1 (AD): the ACTH regulatory part of the 11beta-hydroxylase gene merges with the aldosterone synthase gene so that ACTH release leads to excessive production of aldosterone Familial hyperaldosteronism type 2: inherited aldosterone-producing adenoma or inherited bilateral adrenal hyperplasia. Adrenal carcinoma.

Other tests to identify causes of adrenal insufficiency

Adrenal antibodies. CXR: neoplasia. AXR: adrenal calcification can indicate previous TB infection. CT of adrenal glands indicated if autoantibodies are -ve and primary cause is suspected. MRI of hypothalamus and pituitary if secondary cause suspected. Measure other hormone HPA axis hormones.

What can prolonged exogenous use of a steroid in Cushing's disease cause

Adrenal atrophy d/t HPA suppression

Complications of adrenal insufficiency

Adrenal crisis - due to increased steroid requirements due to illness, trauma or sudden withdrawal from steroids. Presents as severe insufficiency leading to hypovolaemic shock and coma. Reduced QOL. Osteoporosis (due to steroid treatment.

addison's disease

Adrenal failure - glucocorticoid and mineralocorticoid deficiency primary cause- adrenal damage or auto-immune disease secondary cause- pituitary dysfunction- low ACTH or failure to take corticosteroid function

What is critical illness related corticosteroid insufficiency

Adrenal insufficiency in patients who are seriously ill e.g. septic. Cause unknown, but suspect when hypotension isn't responding to treatment.

Suspected Primary hyperaldosteronism - Plasma Aldosterone:Renin ratio of 45:1 (LOW renin) - (+) Adrenal suppression test - CT does not show discrete unilateral mass What is next?

Adrenal vein sampling: differentiate between... - unilateral (adenoma) - tx with surgery - B/L (hyperplasia) - tx with medical therapy

What is the last line treatment for Cushing's if surgical resection and radiation fail

Adrenalectomy

Treatment of Conn's syndrome

Adrenelectomy. Aldosterone antagonists (spironolactone) whilst waiting.

Which of the following lab values is NOT consistent with primary adrenal insufficiency (Addison's)? A) decreased serum cortisol B) elevated ACTH C) hypoglycemia D) decreased aldosterone E) hyperkalemia F) hyponatremia G) decreased renin

G (ELEVATED renin - secreted from the kidneys with hypotension)

• Commonly prescribed ARBs: - candesartan (Atacand) - eprosartan (Teveten) - irbesartan (Avapro) - losartan (Cozaar) - olmesartan (Benicar) - telmisartan (Micardis) - valsartan (Diovan) Same precautions as ACEI's OK to use with diuretic

Angiotensin Receptor Blockers ("sartans")

Secondary adrenal insufficiency

Any cause of hypopituitarism Similar S&S to 1o adrenal insufficiency - pigmentation absent, ACTH not raised and mineralocorticoid deficiency not present (aldosterone secretion not significantly influenced by ACTH) Diagnosis - raised cortisol after Synacthen + innappropriately low/ low-normal plasma ACTH level - insulin stress test alternative Mx: - hydrocortisone replacement and dose adjustment same as 1o adrenal failure - fludrocortisone not needed (mineralocorticoid function intact)

What can cause addisonian crisis?

Any stressor, surgery, pregnancy, trauma, infection, rapid steroid withdrawal, etc

equal

Are pheochromocytomas more common in men or women?

low

Are the serum ACTH levels low, normal, or high in secondary hypocorticolism?

Stenosis of arteries requires blood to pump harder and faster for it to get through the narrowed vessels -- Angiotensin II helps constrict the post-glomerular vessels to increase BP and restore filtration If BP is "too low", there will not be adequate force to push blood through the glomerulus of the kidneys --> filters out less creatinine-->high retention of creatinine in blood Because ACE inhibitors interfere with the production of angiotensin II, auto-regulation is impaired, glomerular perfusion falls, renal ischemic nephropathy develops, and renal failure ensues.

Artery Stenosis and ACEI's

zones of the cortex

G- mineralocorticoids F- glucocorticoids R- sex steroids

If there is both thyroid and glucocorticoid deficiency, which should be replaced first

Glucocorticoid - otherwise it can precipitate an adrenal crisis.

Management of Addison's disease

Glucocorticoid replacement: Hydrocortisone (oral) Doses need to be increased during illnesses. Mineralocorticoid replacement: Fludricortisone (oral). Monitor symptoms, signs, BP and electrolytes to titrate doses. Screen for other autoimmune diseases.

reduces humoral and cell-mediated immunity

Glucocorticoids suppress the immune system. How do they do this?

Presentation of CS

Gluconeogenesis --> DM. Increased protein breakdown --> muscle wasting, thin easily bruised skin. Lipolysis --> redistribution of fat to face and trunk e.g. moon face, buffalo hump, abdominal striae. Reduced immune system --> infections. Mineralocorticoid effects -->hypertension and heart failure. Altered Ca metabolism --> osteoporosis. Negative feedback of other pituitary hormone production e.g. GH, GNRH --> growth suppression in children, gonadal dysfunction. Also has psychiatric effects e.g. depression, insomnia, psychosis. Also hirsutism and acne.

What antibodies do you find in DM type 1?

Glutamic Acid Decarboxylase GAD65***

Clinical features of primary adrenal insufficiency

Gradual onset, symptoms non-specific - fatigue, weakness, anorexia, weight loss, nausea, abdo pain Dizziness and postural hypotension - mineralocorticoid deficiency Hypoglycaemia b/o glucocorticoid loss Hyperpigmentation b/o ACTH excess (--> melanocyte stimulation) 2o loss of cortisol -ve feedback Androgen deficiency in women --> loss of libido and accessory hair

What is congenital adrenal hyperplasia

Group of AR disorders of deficiency of enzymes used in the production of steroid hormones, most commonly 21-hydroxylase. Results in cortisol+/- aldosterone deficiency and androgen excess depending on severity of deficiency. Look at the 1st flashcard to help understand this.

S/S Conn's

HTN Polyuria/polydipsia Weakness Hypokalemia Alkalosis

Prez for pheochromocytom?

HTN unresponsive to meds Normal electrolytes Thin HA, palpitations

What is the triad seen in Addisonian Crisis?

HYPONATREMIA, HYPOGLYCEMIA HYPERKALEMIA

Causes of secondary adrenal insufficiency

HYPOTHALAMIC: Congenital deficiency of CRH production. Trauma e.g. base of skull fracture/surgery. Radiotherapy. Neoplasia/infiltration/infection (TB, meningitis). SUPPRESSION OF H-P-axis. Exogenous steroid administration (most common cause). Antiphsychotics. Steroid production from tumours. PITUITARY: Congenital aplasia. Tumours. Sheehan's syndrome. Infection (TB)/infiltration. Radiotherapy/surgery/trauma. Isolated ACTH deficiency.

Treatment of adrenal crisis

High dose perenteral hydrocortisone + IV fluids. Patients can be given self-injection kits.

How do you confirm Addison's disease?

High-dose ACTH stimulation test

Pattern of cortisol secretion

Highest in morning Lowest middle of the night Rises during stress

hair on chin, upper lip, abdomen, chest acne, menstrual irregularities, defeminization (reduced breast size, loss of feminine adipose tissue), and virilization (frontal balding, muscularity, deep voice)

How do patients with hirsutism present?

HTN, Hypokalemia, neuromuscular manifestations, no edema ( in primary), and metabolic syndrome

How does primary hyperaldosteronism present?

90%

How much of the adrenal glands cortex must be destroyed before the clinical manifestations of Addison's disease occur?

Clinical presentation of adrenal crisis

Hx pre-existing adrenal insufficiency or recent discontinuation of steroids; some pts present de novo Underlying conditions: - 1o adrenal insufficiency - 2o adrenal insufficiency - chronic exogenous glucocorticoid Rx (dose >5mg predisolone equivalent for >4wks) - can include long term, nasal, topical or inhaled steroids S&S: - fever, confusion, somnolence - hypotension - pre renal failure, hyponatraemia, hyperkalaemia - altered pigmentation (1o hyperpigmented, 2o pale) - abdo pain, n+v, weight loss

Treatment of CAH

Hydrocortisone and fludricortisone. Salt supplementation. Surgical correction of genitalia.

Are MEN's (Multiple Endocrine Neoplasms) a Autosomal Dominant or Recessive Disease?

Autosomal Dominant

What is Von Hippel - Lindau Syndrome?

Autosomal dominant disorder w/ hemangiomas of Retina, Cerebellum, Brain Stem, and SC. -Pancreatic, renal cysts -adenomas and carcinomas

What is congenital adrenal hyperplasia?

Autosomal recessive MCC: 21 HY DEFICIENCY 2ND MCC: HYDROXYLASE DEFICIENCY

Children who test positive for the RET mutation should have a prophylactic thyroidectomy by the age of: A) 6yo B) 6mo C) 1yo D) 16yo

B (6mo) (a/w MEN 2 A and B) (as medullary carcinomas of the thyroid seen in MEN 2B are generally aggressive and present early in life)

Which of the following causes of Cushing's syndrome is termed Cushing's disease? A) primary adrenal tumors B) ACTH pituitary tumor C) iatrogenic D) ectopic ACTH

B (ACTH pituitary tumor) ("central") (40% of spontaneous causes)

All of the following are seen in hyperaldosteronism EXCEPT: A) hypertension B) hyperkalemia C) low plasma renin D) elevated plasma and 24-hour urine aldosterone

B (HYPOkalemia) (increased aldosterone drives up blood pressure due to increased sodium uptake and increased potassium excretion)

What is the appropriate treatment for an acute adrenal crisis? A) IVF and IV prednisone B) IVF and IV hydrocortisone C) fludrocortisone

B (IVF and IV hydrocortisone) (also get blood cultures and start IV antibiotics)

Which of the following is the most common cause of primary hyperaldosteronism? A) localized hyperplasia B) adrenal adenoma C) bilateral hyperplasia

B (adrenal adenoma - Conn's syndrome)

Secondary adrenal insufficiency affects secretion of all of the following EXCEPT? A) cortisol B) aldosterone C) androgens D) all of the above

B (aldosterone secretion is preserved) (low pituitary ATCH production)

The zona reticularis secretes: A) mineralcorticoids B) androgens C) glucocorticoids D) catecholamines

B (androgens - sex)

How is ACTH deficiency treated? A) endogenous ACTH replacement B) cortisol replacement C) radiation and chemotherapy D) no treatment

B (cortisol replacement)

Which hormone is secreted in stressful situations causing inhibition of inflammation as well as in times of hypoglycemia, causing an increase in hepatic gluconeogenesis? A) aldosterone B) cortisol C) androgens D) norepinephrine

B (cortisol)

Which of the following describes MEN 1 (Wermer's syndrome)? A) Autosomal dominant disorder causing tumors of the medullary carcinomas, pheochromocytomas, and/or hyperplasia or multiple adenomas causing hyperparathyroidism B) familial autosomal dominant multiglandular syndrome causing tumors of the pituitary adenomas, pancreatic tumors, and / or parathyroid tumors C) Manifests as tumors of the medullary carcinomas of the thyroid, mucosal neuromas, and / or bilateral adrenal pheochromocytomas

B (familial autosomal dominant multiglandular syndrome causing tumors of the pituitary adenomas, pancreatic tumors, and / or parathyroid tumors) (three P's) (pancreatic tumors may be nonsecretory, gastrinomas, or insulinomas) (can also see adrenal adenomas and non-endocrine tumors)

Which of the following corticosteroids is the LEAST potent? A) prednisone B) hydrocortisone C) methylprednisone D) betamethasone

B (hydrocortisone) (used to treat adrenal insufficiency as it can be measured and monitored -- most similar to natural cortisol)

Which of the following should you NOT use as treatment for primary adrenal insufficiency? A) hydrocortisone acetate B) prednisone C) fludrocortisone D) cortisol, renin, potassium, and BP monitoring

B (prednisone - use hydrocortisone as cortisol replacement)

Which of the following is utilized in the diagnosis of pheochromocytoma? A) serum epinephrine and norepinephrine levels B) serum normetanephine and metanephrine levels C) clinical diagnosis only D) PET scan

B (serum normetanephine and metanephrine levels) (CT or MRI of abdomen with focus on adrenals - CT contrast can precipitate HTN crises) (if suspected, refer to endocrinology)

A patient presents to your office following discovery of an incidental adrenal mass. Work up shows the mass to be non-functional and >5cm. What would be the appropriate next step? A) repeat CT in 3 months B) surgical excision C) fine needle biopsy D) any of the above

B (surgical excision) (excise if found to be functional, >5cm, or if there is evidence of growth on f/u CT)

How is Cushing's disease treated? A) adrenalectomy of cortisol secreting adenomas B) transsphenoidal resection the pituitary tumor C) dexamethasone supplementation D) Ketoconazole or Metyrapone to block 11-hydroxylase enzyme in the pathway of cortisol production

B (transsphenoidal resection the pituitary tumor) (Cushing's disease refers to an ACTH secreting pituitary tumor)

broad spectrum abx and treat electrolyte abnormalities, hypoglycemia, and dehydration

Besides hydrocortisone, what else is used to treat adrenal crisis?

Management of primary hyperaldosteronism

Bilateral adrenal hyperplasia - aldosterone receptor antagonist (e.g. spironolactone, eplenerone) Unilateral adenoma (Conn's syndrome) - laparoscopic adrenelectomy - cures hypokalaemia in 100% - cures HTN in 70% - adrenal vein sampling may be needed to confirm unilateral aldosterone excess

What are clinical manifestations of Cushing's Disease?

Buffalo hump, moon face, thin extremities, purple striae (hyperpigmentation), may develop DM, glucose intolerance, hypogonadism, lanugo hair, masculinization

What is the most common cause of adrenal insufficiency? A) infections B) adrenal hemorrhage C) Addison's disease D) meningococcemia

C (Addison's disease - autoimmune destruction of the adrenal gland) (can also be caused by drugs, malignancy, and infiltrative disease such as hemochromatosis)

Which of the following is FALSE regarding Cushing's syndrome screening tests? A) high estrogen states can increase free urine cortisol and inhibit the ability of dexamethasone to suppress cortisol B) Alcoholism, depression, and anorexia nervosa can raise cortisol levels causing false positives C) Certain drugs such as phenytoin, phenobarb, and primidone can decrease the metabolism of dexamethasone, resulting in false tests D) all of the above are true

C (Certain drugs such as phenytoin, phenobarb, and primidone can INCREASE the metabolism of dexamethasone, resulting in false tests) (chronic corticosteroid use can also influence tests)

Which disease process is characterized by excess ACTH secretion by the pituitary gland? A) Cushing's syndrome B) Addison's disease C) Cushing's disease D) acromegaly

C (Cushing's disease - many things can cause Cushing's syndrome)

Which of the following is NOT a sign consistent with a phemochromocytoma? A) headache B) diaphoresis C) hypotension D) tachycardia E) pallor and cyanosis F) sense of "impending doom"

C (HYPERtension)

Which of the following describes MEN 2B? A) Autosomal dominant disorder causing medullary carcinomas of the thyroid, pheochromocytomas, and/or hyperplasia or multiple adenomas causing hyperparathyroidism B) familial autosomal dominant multiglandular syndrome causing tumors of the pituitary adenomas, pancreatic tumors, and / or parathyroid tumors C) Manifests as tumors of the medullary carcinomas of the thyroid, mucosal neuromas, bilateral adrenal pheochromocytomas and / or Marfan-like habitus

C (Manifests as tumors of the medullary carcinomas of the thyroid, mucosal neuromas, bilateral adrenal pheochromocytomas and / or Marfan-like habitus) (screen for ret proto-oncogene)

Which of the following is FALSE regarding serum aldosterone testing? A) plasma should be taken with the patient recumbent at 8am and again 4 hours later with the patient upright B) Patients should have a liberal NaCl diet C) Patients should be testing only after fasting D) all of the above are true

C (Patients should be testing only after fasting) (patients require a liberal NaCl diet as a low Na diet can reduce renal potassium secretion and inhibit manifestation of hypokalemia)

Which of the following is TRUE regarding aldosterone? A) Promotes resorption of Na+ and water and excretion of K+ in the proximal convoluted tubule B) Promotes excretion of Na+ and water and reabsorption of K+ in the proximal convoluted tubule C) Promotes resorption of Na+ and water and excretion of K+ in the distal convoluted tubule D) Promotes excretion of Na+ and water and reabsorption of K+ in the distal convoluted tubule

C (Promotes resorption of Na+ and water and excretion of K+ in the distal convoluted tubule)

What is the appropriate treatment for a pheochromocytoma? A) surgical excision B) administration of beta blockers, followed by alpha blockers (pheonoxybenzamine); then surgery C) administration of alpha blockers (pheonoxybenzamine), followed by beta blockers; then surgery D) administration of alpha blockers and beta blockers only

C (administration of alpha blockers, followed by beta blockers; then surgery) (alpha blockers work to decrease blood pressure; beta blockers work by decreasing heart rate) (want to decrease blood pressure before heart rate to avoid inducing heart failure)

Which of the following is used in primary adrenal insufficiency and idiopathic orthostatic hypotension due to low levels of aldosterone? A) prednisone B) hydrocortisone C) fludrocortisone D) betamethasone

C (fludrocortisone) (dosing based on sodium levels, blood pressure, and serum renin)

Cushing's syndrome is a syndrome of _______ excess A) mineralcorticoid B) androgen C) glucocorticoid D) catecholamine

C (glucocorticoid)

The zona fasiculata secretes: A) mineralcorticoids B) androgens C) glucocorticoids D) catecholamines

C (glucocorticoids - cortisol) (sugar)

What is the most common cause of Cushing's syndrome? A) primary adrenal tumors B) ACTH pituitary tumor C) iatrogenic D) ectopic ACTH

C (iatrogenic)

ACTH deficiency causes adrenal insufficiency and decreased levels of all of the following EXCEPT: A) cortisol B) androgens C) mineralcorticoids D) all of the above are decreased

C (mineralcorticoids - salts / aldosterone)

Which of the following is FALSE regarding cortisol replacement with hydrocortisone acetate? A) must increase dose in times of acute stress or illness B) continue increased dose until resolution of the stressor C) monitor with serum cortisol levels D) administer as a divided dose

C (monitor with 24 hour urine free cortisol)

What should be checked prior to using blood based investigations to diagnose Cushing's syndrome?

CBG (cortisol binding globulin) E.g. in severely ill pts serum CBG decr. Testing conducted OFF oral contraceptive pill - incr. CBG --> incr. total serum cortisol levels

In patients with a history of heart failure (who are often on these drugs), this side effect could be misinterpreted as a symptom of pulmonary congestion, especially if the patient tends to be orthopneic often seen in: Women Asians Nonsmokers Patients can switch to an angiotensin II receptor blocker (ARB).

CHF and ACE Inhibitors

When is fludrocortisone needed in the management of adrenal crisis?

Hydrocortisone at high doses has mineralocorticoid activity Fludrocortisone not needed until hydrocortisone doses <50mg /day and ONLY in pts c primary adrenal insufficiency

Trx Addisons

Hydrocortisone, DHEA as well for women

Results in high BP, high Na+, low K+ -- High Na+ --> excessive water retention Primary: adrenal adenoma/carcinoma Secondary: renin producing tumor of kidney; ACTH secreting tumor (pituitary, ectopic) **Reactive: stimulation due to elevated K+, low Na+, low BP, hypovolemia -- this form is transient**

Hyperaldosteronism

benign functional adrenal adenoma

Hyperaldosteronism is typically due to an abnormality in the cortex of the adrenal gland, what typically causes this abnormality?

Clinical features suggesting adrenal Cushing's

Hyperandrogenism +/- virilisation if adrenal androgens co secreted by adrenal adenoma/ carcinoma - androgenic alopecia, deepeing of voice, cliteromegaly Severe hirsuitism + virilisation assoc. c large (>10cm) adrenal tumour strongly suggestive of CARCINOMA

Dexamethasone suppression test RESULTS - Something wrong in (-) FDBK loop 1) High ACTH (cortisol did not suppress ACTH) 2) High Cortisol

Central cause (ACTH tumor in Pituitary) - or - ACTH-secreting tumor in the lungs

What is pheochromocytoma characterized by?

Characterized by *paroxysmal or prolonged HTN

Signs of adrenal insufficiency

Hyperpigmentation in creases and buccal mucosa. (POMC is a precursor to ACTH that is produced in the pituitary however it stimulates melanocytes). Therefore only present in primary deficiency as the negative feedback causes overproduction of pituitary hormones. Hypotension/postural hypotension. Low sodium and high potassium levels.

What is the most common feature of pheochromocytoma?

Hypertension

ARBs = angiotensin receptor blockers Function: block the activity of AT II, thus blocking its vasoconstrictor effect Because ACE isn't involved, cough is (usually) not a side effect Equally effective as ACEI's, but should not be used together.

Hypertension and ARBs

One main effect of RAAS: increase in BP For those with HTN, this can be harmful. ACE inhibitors: drugs that block ACE activity, thereby blocking production of AT II from AT I SE: cough (lung endothelium) and angioedema (kidney endothelium)

Hypertension and RAAS

Complications of Cushing's Disease?

Hypertension, Diabetes, Glaucoma/Cataracts, Aseptic necrosis of femoral head, impaired immunity, adrenal crisis

Presentation of hyperaldosteronism

Hypertension. Metabolic alkalosis. Raised Na or lowered K although this is not always present. Polyuria/polydipsia due to reduced ability to concentrate urine. Weakness due to hypokalaemia. Headaches and lethargy.

Results in low BP, low Na+, high K+ Primary: damaged adrenal gland (autoimmune, infections [TB, HIV], congenital, ketoconazole) Secondary: -- Low ACTH -- Low renin secretion: kidney damage (diabetes, other kidney disease, meds: ACE/ARB/DRI) -- Decreased tissue response to aldosterone -- Aldosterone receptor unresponsiveness (congenital) -- Medications (esp. ACEIs and spironolactone)

Hypoaldosteronism

Person w/ TB: (CXR-RUL cavitary lesion, fever, cough) - Non-anion gap metabolic acidosis - Hyperkalemia*** - Hyponatremia - Shock-like symptoms (hypotension)*** - Abdominal tenderness - HYPO-glycemia - Unexplained fever - N/V, weight loss and anorexia*** - Pigmentation*****

Chronic 1° adrenal insufficiency***** (adrenal crisis) - "Addison's disease" - decreased cortisol (Low Cortisol; HIGH* ACTH) - decreased adrenal sex hormone - decreased aldosterone secretion **Main cause of Addison's is auto-immune adrenalitis - Ab vs all 3 zones of adrenal cortex

What is pseudo-CS

Clinical features and biochemical evidence of CS caused by: Chronic severe anxiety and/or depression. Prolonged excess alcohol consumption. Poorly controlled diabetes. HIV infection.

4 main causes: -- Iatrogenic -- adrenal gland failure (high ACTH) [primary] -- pituitary failure (low ACTH) [secondary] -- hypothalamic failure (low ACTH) [much less common]

Hypocortisolism

Suspected Primary hyperaldosteronism - Plasma Aldosterone:Renin ratio of 45:1 (LOW renin) Q: What test do you do?

Confirm - Adrenal suppression test - After load of oral saline - It should suppress aldosterone, unless pathology is present - IF NOT (+): Do CT of adrenals

How can we diagnose addisionian crisis?

INC. POTASSIUM DEC. CALCIUM DEC. GLUCOSE INC. BUN DUE TO DEHYDRATION

How do you diagnose Addison's disease?

Cortrosyn Stimulation Test: Tests functional ability of adrenal cortex to synthesize cortisol 1. Check baseline plasma cortisol and aldosterone levels 2. Inject IV ACTH 0.25mg 3. 30min and 60min post-injection check plasma cortisol and aldosterone levels Dx = minimal to no change in levels

obesity, HTN, glucose intolerance, and hyperlipidemia

Cushing causes metabolic syndrome. What is associated with metabolic syndrome?

Prolonged exposure to glucocorticoids endogenous or exogenous

Cushing's Syndrome

SX: 35 yo F - fatigue - overweight; central obesity - easy bruising - hirsutism - Acne - Cataracts - moon facies - abdominal striae (purplish) - HYPER-tension*** - Glucose intolerance (HYPER-glycemia)*** - Osteopenia and osteoporosis - Skin hyperpigmentation - Proximal muscle weakness*** - Susceptibility to infections - HYPO-kalemia*** - HYPER-natremia*** TEST?

Cushing's Syndrome - excessive systemic Cortisol levels TESTS 1) Urine free cortisol 2) ACTH (serum) - if ACTH elevated ->Dexamethasone suppression test - if ACTH Low -> Stop steroids/Adrenal CT If ACTH elevated - secondary tumor (central) If ACTH low - primary tumor - OR exogenous steroids

increase

Cytokines _______________ ACTH release

Which of the following is NOT part of the 10% rule of Pheochromocytomas? A) 10% bilateral B) 10% malignant C) 10% extraadrenal D) 10% benign E) 10% pediatric F) 10-15% familial (MEN syndrome)

D (10% benign)

Clinical manifestations of Addisons

INCR SKIN PIGMENTATION Weakness Hyperkalemia Hyponatremia Low BP Axillary hair increase

Primary Aldosteronism shows ____ aldosterone and _____ renin.

INCREASED ALDOSTERONE AND DECREASED RENIN

Secondary Aldosteronism shows _____ aldosterone and _____ renin.

INCREASED ALDOSTERONE AND INCREASED RENIN

high

IS the plasma ACTH low, normal, or high in adrenal crisis?

What is the treatment of Adrenal crisis?

IVF resuscitation 2L normal saline followed by D51/2NS If no improvement with IVF resuscitation- do KEY TREATMENT STRESS Hydrocortisone 100mg IV Q6hr or Dexamethasone 4mg q24hr Vasopressors?-don't work well

What is the most common etiology of Addison's Disease?

Idiopathic autoimmune (80%)

Management of adrenal incidentaloma

If > 4cm - incr. risk of malignancy --> unilateral adrenalectomy If <4cm and NO hormone hypersecretion and not suspicious on imaging --> f/u c repeat Ix in 6mnths and potentially annually if no change

50%

If Cushing is left untreated, what percentage of patients will die within 5 years?

hyponatremia and hyperkalemia (Remember: aldosterone causes sodium and water retention and potassium excretion. no aldosterone here to do this.)

If a patient has Addison's disease and decreased aldosterone, what electrolyte abnormalities will they have?

hyperparathyroidism

If a patient has a tumor of the parathyroid in MEN 1, what will this cause?

hyperinsulinemia and fasting hypoglycemia

If a patient has an insulinoma with MEN 1, what will this cause?

pheochromocytoma

If a patient has familial MEN 2A (Sipple syndrome), what should they be screened for?

MTC

If a patient has familial MEN 2A (Sipple syndrome), what will they only have?

OCP (note: Clomiphene can also be used if patient has PCOS)

If a patient has hirsutism and desires fertility, what medication should you put them on?

pelvic US

If a patient has hirsutism and the total and free testosterone come back elevated, what is the next step?

CT of adrenals

If a patient has hirsutism and the total and free testosterone come back negative, what is the next step?

ovarian failure (remember: and FSH/LH ratio >2.0 is common in PCOS)

If a patient has hirsutism and their FSH/LH ratio is >2.0 and they have amenorrhea, what might this suggest?

Mitotane, ketoconazole, and metyrapone

If a patient with Cushing has an adrenal tumor that cannot be resected or ectopic cushing syndrome, what is the treatment?

cortisol until body can manage the productino

If a patient with Cushing has their tumor removed, what is the treatment?

gastrin

If a patient with MEN 1 has a gastrinoma, what will this secrete?

<3 mcg/kL

If a patients serum, urine total cortisol is this, then this is diagnostic of Addison's disease. What is this value?

suppressed

If dexamethasone is given, should cortisol be suppressed, unchanged, or increased?

stay low (Because the adrenals are not able to produce. secrete the cortisol. there is plenty of ACTH and the problem is not with ACTH. Remember Addison's is a primary disease)

If doing the ACTH stimulation test to test for Addison's disease, what would be expected to happen with the cortisol level?

Imaging (CXR- TB, cancer, fungal infection) and CT of abdomen

If the cause of Addison's is clearly not autoimmune, what is the next step?

sodium wasting and electrolyte disorders by the fifth day of life

If the mineralocorticoids (aldosterone) are under secreted in congenital adrenal hyperplasia, what will this lead to?

Treatment of CS

If there is a tumour then resect it. Drugs that suppress adrenal gland function whilst waiting for definitive treatment: metyrapone, ketoconazole, mitotane.

ACTH secreting tumor (?? Cushing disease (secondary)??)

If you do the AM ACTH level when testing for Cushing, and the ACTH level is normal or elevated what does this suggest?

Cortisol secreting tumor or other source or cortisol (Cushing Syndrome (primary) or Ectopic cushing syndrome)

If you do the AM ACTH level when testing for Cushing, and the ACTh level is low what does this suggest?

autoimmune

In females, Addison's is most likely to be caused by what?

elevated

In hyperaldosteronism, would aldosterone be decreased, normal, or elevated?

estrogen

In secondary hyperaldosteronism, if renin is stimulated outside of the pressure initiated response, what will there be extra of in pregnancy?

How is Cushing's syndrome due to primary adrenal tumors treated for non-resectable tumors? A) adrenalectomy of cortisol secreting adenomas and carcinomas B) transsphenoidal resection the pituitary tumor C) dexamethasone supplementation D) Ketoconazole or Metyrapone to block 11-hydroxylase enzyme in the pathway of cortisol production

D (Ketoconazole or Metyrapone to block 11-hydroxylase enzyme in the pathway of cortisol production)

still high (The loop is not shut down like it normally would be when dexamethasone is given)

In the dexamethasone suppression test used to test for Cushing, what happens to the cortisol level after the dexamethasone is given?

40-60 yo

In what age group are pheochromocytomas usually found?

Prognosis of incompletely controlled CS

Increased mortality from increased risk of vascular disease, DM and infections.

Where does the HYPER-pigmentation come from in 1° adrenal insufficiency?

Increased pituitary secretion of (no - cortisol FDBK) - ACTH - Melanocyte stimulating hormone

Symptoms of Cushing's syndrome

Increased weight gain Poor wound healing Recurrent infections Depression Menstrual disturbances Hirsuitism Osteoporosis

Action of cortisol

Increases breakdown of carbohydrates, proteins and fats. Increases blood sugar through gluconeogenesis. Reduces inflammation and immune response by inhibiting phospholipase A2. Also has a weak mineralocorticoid activity. Increases calcium resorption from bones as well as increasing renal excretion and reducing GI absorption. Converted to cortisone (inactive) by the liver and can then be activated again by target tissues.

Action of aldosterone

Increases reabsorption of Na and Cl and loss of K and H at kidneys.

Things which can precipitate a hypertensive crisis in people with a phaeochromocytoma

Induction of anaesthesia. Opiates. Dopamine antagonists. Decongestants such as pseudoephedrine. Drugs that inhibit the reuptake of catecholamines, including tricyclic antidepressants and cocaine. X-ray contrast media. Childbirth.

Which of the following is FALSE? A) Surgical excision of aldosterone secreting adenomas is curative B) Spironolactone is a potassium sparing diuretic used in the treatment of adrenal hyperplasia causing hyperaldosteronism C) Spironolactone is used in poor surgical candidates D) all of the above are true

D (all of the above are true)

Primary adrenal insufficiency affects secretion of which of the following? A) cortisol B) aldosterone C) androgens D) all of the above

D (all of the above) (low adrenal activity)

The adrenal medulla secretes: A) mineralcorticoids B) androgens C) glucocorticoids D) catecholamines

D (catecholamines - from chromaffin cells)

Under which category of causes of Cushing's syndrome would a paraneoplastic syndrome due to lung malignancy fall? A) primary adrenal tumors B) ACTH pituitary tumor C) iatrogenic D) ectopic ACTH

D (ectopic ACTH - most often seen with small cell lung cancer) (25% of spontaneous causes)

Which of the following indicates a positive overnight dexamethasone suppression test? A) suppression of AM ACTH levels B) suppression of AM cortisol levels C) failure to suppress AM ACTH levels D) failure to suppress AM cortisol levels

D (failure to suppress AM cortisol levels - indicative of Cushing's syndrome) (check serum ACTH and refer)

Which of the following is NOT seen in Cushing's syndrome? A) obesity B) abnormal fat distribution C) easy bruising D) hyperpigmentation E) hirsuitism F) sexual dysfunction G) emotional lability

D (hyperpigmentation- this is Addison's) (will also see purple striae, moon face, muscle atrophy and weakness, HTN, osteopenia, glucose abnormalities, menstrual disorders, and hyperlipidemia)

Which of the following causes of adrenal insufficiency is an acute failure of the adrenal gland due to meningitis? A) infections B) adrenal hemorrhage C) Addison's disease D) meningococcemia

D (meningococcemia - AKA Waterhouse-Friderichsen)

Which of the following is NOT a physiologic effect of corticosteroids? A) increased gluconeogenesis and glycogen synthesis B) increased insulin levels C) increased lipid levels D) increased sodium and water excretion E) delayed growth F) muscle wasting and skin atrophy G) osteoporosis

D (sodium and water RETENTION)

Androgens and potency

DHEA and androstenedione. DHEA is secreted more but DHEA and androstenedione are both weak in potency compared to testosterone.

What test is elevated in patients with androgen-producing adrenal tumors?

DHEA-S Made in Adrenals: Androstenedione, DHEA, T, DHEA-S* Made in Ovaries: Androstenedione, DHEA, T Androstenedione, DHEA, DHEA-S - none of these interact with the androgen receptor - all converted to Testosterone, which acts on receptors

What is the most abundantly secreted steroid?

DHEAS

which DM develops diabetic ketoacidosis? Tx?

DM type 1 1st: FLUID resuscitation*** monitor: acidity (tx bicarb), electrolytes

Describe DM1 age onset? immunity?habitus?resistance? FH? Insulin/C-reactive protein?

DM type 1 age:<10yoa, Immunity:+Ab, Habitus:normal/underwt, resistance:none, FH: slight, Insulin/CRP: low or none

Describe DM2 age of onset?immunity?habitus? resistance? FH Insulin/C-reactive protein

DM type 2 onset: usually in 50s but can be any age. immunity:none, habitus:obese, resistance: + insulin resistance, FH: strong, Insulin/CRP- high, even fasting

Urinary free cortisol (17-hydroxycorticosterol) higher than 100 μg/24 hr Check ACTH levels, see if suppressible with dexamethasone Pituitary MRI for pituitary tumor Abdominal CT for adrenal mass

Diagnosing Cushing Syndrome (Clinically)

Determine if due to H-P-A problem or if secondary to other disease (mostly kidney disease) or drugs If H-P-A problem is suspected, check plasma renin activity, aldosterone, CT adrenals r/o mass, ACTH, evaluate for pituitary problem as indicated -- This type of problem usually occurs in conjunction with Addison's Disease -- Mineralocorticoid replacement might be needed (fludrocortisone [Florinef])

Diagnosing Hypoaldosteronism

Must have a high index of suspicion!!! Demonstrate inappropriately low cortisol: timed serum/salivary/urinary cortisol subnormal response to ACTH stimulation Determine if endogenous ACTH is high or low Decide if the adrenal or pituitary is the problem.

Diagnosis of Adrenal Insufficiency

A 24 hour urine collection for VMA and Metanephrine will help make the diagnosis of pheochromocytoma. MAO inhibitors prevent excess metabolism of epinephrine (be sure to avoid serotonin syndrome though)

Diagnosis of Pheochromocytoma

hyperfunction

Is Cushing a hypofunctino or hyper function of the adrenal cortex?

ACTH dependent

Is Cushing disease (secondary hypercortisolism) ACTH dependent or independent?

ACTH independent

Is Cushing syndrome (primary hypercortisolism) ACTH dependent or independent?

increased

Is potassium excretion increase or decreased in Cushing?

retained

Is sodium excreted or retained in Cushing?

Kinins: group of structurally related polypeptides Ex: Bradykinin, kallikrein Act locally to induce vasodilation, vascular permeability, and contraction of bronchial smooth muscle (causing bronchoconstriction, which stimulates cough). ** Note: kinins stimulate VASODILATION; ACEs break down kinins, which is why VASOCONSTRICTION occurs

Kinins, Cough, and ACE

What happens to aldosterone levels in: - 1° adrenal insufficiency (peripheral)

LOW - renal sodium wasting In absence of Aldosterone, there is a compensatory release of ADH - water retention - dilutional HYPO-natremia

What are symptoms of addison's?

LOW NA AND WATER, HIGH K+ "Bronzing" of the skin (ACTH high)

How to diagnose Congenital Adrenal Hyperplasia?

LOW SODIUM LOW GLUCOSE HIGH POTASSIUM LOW CORTISOL AND ANDROGEN HIGH 17 HP

Trx Conn's

Laparascopic adrenalectomy or lifelong spironolactone

How to treat Bilateral Hyperplasia

Lifelong Spironolactone

Maintenance treatment of primary adrenal insufficiency

Lifelong glucocorticoid + mineralocorticoid replacement therapy - hydrocortisone 1st line: daily doses of 15-30mg, divided into two or three doses - mineralocorticoid replacement given as fludrocortisone, 50-200ug/day

CRH stimulation test

Localising test If pituitary --> cortisol rises If ectopic/ adrenal --> no change in cortisol

High dose dexamethasone test

Localising test Distinguishes pituitary from ectopic/ACTH causes Only pituitary causes respond to dexamethasone - ectopic and adrenal causes produce ACTH/ cortisol autonomously If cortisol suppressed --> MRI pituitary, consider bilateral inferior petrosal sinus sampling If not - CT chest/ abdo/ pelvis + contrast

What is secondary adrenal insufficiency caused by?

Long term steroid therapy leading to CHRONIC suppression of adrenal axis. THIS IS THE MCC OF ADRENAL INSUFFICIENCY!

Risks of Synthetic glucocorticoids

Lots of risks like susceptibility to infxn, loss of bone mass, and ADRENAL SUPPRESSION VIA NEG FEEDBACK. Thus we taper them long term to allow the adrenals to kick back in.

Laboratory abnormalities in adrenal insufficiency

Low Na and high K. Raised Ca. Anaemia, lymphocytosis. Hypoglycaemia (particularly in children). Raised liver transaminases. Low cortisol (taken at 8-9am when levels should be highest). ACTH: raised in primary, lowered in secondary. Renin and aldosterone: renin=high and aldosterone=low in Addison's but often unaffected in secondary insufficiency.

How does malnourishment affect CBG?

Lower total protein- lowers CBG as well (which means low cortisol)

gastrinomas

MEN 1 (Wermer's syndrome) can cause 25% of _____.

Common familial causes of phaeochromocytoma or paraganglioma

MEN 2: - RET gene - medullary thyroid carcinoma, hyperparathyroidism Von Hippel-Lindau: - VHL - renal cell carcinoma, cerebellar haemangioblastoma, retinal/spinal angiomas Neurofibromatosis type 1: - NFL gene - cafe au lait patches, neurofibromas Succinate dehydrogenase subunit B and D mutations: - phaeochromocytoma, paragangliomas in neck, thorax or abdomen

MEN-2b

MEN-2a + mucosal neuromas + Marfanoid appearance.

Inherited syndromes associated with phaeochromocytomas

MEN2 von Hippel-Lindau Neurofibromatosis 1

Medullary Thyroid Carcinoma and Pheochromocytoma develops earlier and is more aggressive in what disease state?

MEN2b

What triggers release of aldosterone

Mainly angiotensin 2. To a lesser extent, raised plasma potassium and ACTH.

Circulation of cortisol

Majority bound to cortisol binding globulin (CBG) (80-90%) and albumin (5-10%) - only small % exists as free, biologically active form Cortisol immunoassays measure total (bound and free) cortisol - conditions that stimulate CBG levels (e.g. oestrogen therapy) can incr. measured cortisol levels WITHOUT affecting biologically active levels

Causes of primary adrenal failure

Many! Autoimmune adrenalitis MCC - +ve adrenal antibodies Other causes rare - consider when antibody testing -ve: - genetic: CAH, adrenoleucodystrophy - iatrogenic: bilateral adrenalectomy, drugs (metryapone, ketoconazole, phenytoin, rifampicin) - infarction/ haemorrhage: antiphospholipid syndrome - infection: TB, fungal, AIDS - infiltration: amyloid, haemchromatosis - malignancy: breast, lung, kidney

Side effects of spironolactone

Men - gynaeocmastia (b/o weak androgen receptor activity) Females - contraception needed, risk of feminising male fetus if pregnant

what is the first line tx for DM type II?

Metformin- decrease hepatic glucose synthesis, decrease GI glucose absorption, increases sensitivity. advantages: wt Lose**, little risk of hypoglycemia se: lactic acidosis, esp in renal impairment** can't use in renal dysfunction

Treatment for Primary Hyperaldosteronism

Diet w/ Na+ restriction & Aldosterone antagonist (spironolactone)

Aliskiren (Tekturna) 150 - 300 mg/d is the only direct renin inhibitor approved by the FDA Blocks the conversion of angiotensinogen to angiotensin 1 (AT I) Effective but expensive $100+/mo, no generic available at this time Main side effects are diarrhea, angioedema. Contraindicated in pregnancy OK to add diuretic

Direct Renin Inhibitors

When treating diabetic ketoacidosis when should stop administrating IV insulin?

Discontinue when anion gap from the metabolic acidosis has normalized and pt can tolerate oral intake

Causes of hypertension with low renin AND low aldosterone

Mineralocroticoid receptor pathway in distal nephron activated, even if aldosterone low Ectopic ACTH syndrome, liquirice misuse, 11 deoxycorticosterone secreting adrenal tumour or Liddle's syndrome

Primary adrenal insufficiency = Addison's disease; often coexists with hypoaldosteronism -- usually adults ages 30 to 60 years -- more common in women -- Autoimmune or infectious destruction -- Ketoconazole and steroid drugs can suppress adrenal function -- clinical manifestations seen only after 90% of adrenal gland is destroyed.

More About Hypocortisolism

Sex and age of onset for Addisons

More common in women. 30-50.

Where does the HYPO-kalemia come from in Cushings? Q: How could you treat it?

Most corticosteroids - also have mineralocorticoid activity - bind to aldosterone receptors in kidney - cause K+ exchange for Na+/H2O (HTN) TX: ALdosterone receptor antagonist (Spironolactone)

What triggers release of cortisol

Mostly ACTH which in turn is triggered by stress and low blood-glucose concentrations.

If steroids have only been given for 5 days, do you need to taper?

NO

Is bronzing seen in secondary adrenal insufficiency?

NO, ACTH LOW, BECAUSE ONLY CORTISOL IS LOST.

Is ACTH elevated in adrenal insufficiency?

NO; ACTH LOW

What happens to aldosterone levels in: - 2° adrenal insufficiency (central)

NORMAL - aldosterone levels are primarily regulated by the RAAS (Renin-angiotensin-aldosterone system)

Complications of Cushing's treatment

Nelson's syndrome Post adrenalectomy Increase pigmentation, increase pituitary size (adrenalectomy removes -ve feedback) Post transphenoidal surgery - hypopituitarism

Act as ____ in CNS and _____ in bloodstream

Neurotransmitter, Hormone

Pheochromocytomas secrete more (Epinephrine / Norepinephrine)

Norepinephrine (4:1 ratio) (as per Burns' corrected email)

Man presents for surgery - Hx of HTN, h/a, and anxiety - After anesthesia, he has severe HTN (250/140) with tachycardia and pallor - ECG: NSR

Occult Pheochromocytoma - with catecholamine surge (due to anesthesia) - chromaffin cell tumors (Adrenal Medulla) - could be prevented with prophylactic Beta-blocker

What is Cushing's Syndrome?

Occurs with an increase in cortisol due to prolonged use of steroids. HIGH CORTISOL, LOW ACTH, NO HYPERPIGMENTATION!

Presentation of phaeochromocytoma

Often occur in episodes lasting up to an hour. MOST COMMONLY: Headache Profuse sweating Palpitations Tremor Hypertension Postural hypotension MORE RARELY: Nausea Weakness Anxiety Sense of doom Epigastric pain Flank pain Constipation Weight loss Fever

autoimmune workup

Once Addison's disease is confirmed, what should be the next step?

Weight gain: -- truncal obesity -- moon facies -- buffalo hump Hypertension: made worse by sodium and water retention (due to mineralocorticoid-like effect) Hypokalemia Glucose intolerance: insulin resistance, increased gluconeogenesis and glycogen storage by the liver Cortisol interferes with GH action on long bones Osteoporosis occurs due to loss of protein matrix

Other Findings of Cushing's Syndrome

Hormones of the Adrenal Cortex by the 3 layers

Outer Zona Glomerulosa - Aldosterone Middle Zona Fasiculata - Cortisol Inner Zona Reticularis - Androgens Adrenal medulla - epinephrine

Clinical features of primary hyperaldosteronism

PC: HTN + hypokalaemic alkalosis (incr. urinary K+ excretion) - hypokalaemia NOT always present, esp. in bilateral adrenal hyperplasia HTN => blurred vision, headaches Hypokalaemia => muscle fatigue or tiredness

Clinical features of phaeochromocytoma

PC: headache, sweating, pallor, palpitations - anxiety, panic attacks and pyrexia LC HTN present in 90% cases Complications - hypertensive crisis, encephalopathy, hyperglycaemia, pulmonary oedema, cardiac arrhythmias, death

What must be done before testing renal function, renin activity and aldosterone levels for suspected hyperaldosteronism

Patient must be off: Diuretics - 4 weeks. BBs and dihydropyrodine CCBs - 2 weeks. Steroids. Potassium supplements. Laxitives. ACEi AIIRAs

androgens

Patients with hirsutism have an excess of what hormone?

primary hyperaldosteronism (Definition- Excessive aldosterone production by the adrenal cortex)

Periods of wet/dry and aldosterone wasting occur with what type of hyperaldosteronism?

Dexamethasone suppression test RESULTS 1) LOW ACTH (FDBK worked at Pituitary) 2) High Cortisol

Peripheral cause 1) Cushing's - adrenal hyperplasia 2) Adrenal adenoma

Management of phaeochromocytoma

Phenoxybenzamine (non competative alpha blocker) - needs adequate blockade prior to beta blockade (paradoxical rise in BP) Give 6wks before surgery - laparoscopic adrenalectomy gold standard

In Primary hyperaldosteronism - often the HYPO-kalemia is not significant until the person is given a _______ to treat the HTN

Diuretic (Thiazide)

In order to diagnose Primary Hyperaldosteronism what should you NOT use?

Diuretics

Triad of MEN-2a

"TAP": Thyroid medullary carcinoma Adrenal (phaeochromocytoma) Parathyroid hyperplasia

Striae (stretch marks) Hyperpigmentation: ACTH is similar to MSH (in the case of Cushing's disease) or because both are released in excess if there is too much CRH from the hypothalamus. Elevated cortisol--> vasoconstriction and hypertension Protein wasting: catabolic effects of cortisol on muscle Altered Mental Status Infection (too much cortisol --> lowered immunity) Increased andrenal androgen levels (in women) -- acne -- hirsutism -- oligomenorrhea

** Cushing's Syndrome (Symptoms)

- stimulates sympathetic outflow from the CNS (Raises BP) - stimulates the kidney to resorb sodium - stimulates the adrenal gland to release aldosterone -stimulates release of ADH from the posterior pituitary gland. (a direct vasoconstrictor of peripheral arteries)

** How Does Angiotensin II Work?

What are some etiologies of adrenal insufficiency? MC?

*- Addison's (autoimmune) - most common* - adrenal or pituitary hemorrhage - CAH - chronic steroid administration (neg feedback to pituitary)

How should glucocorticoids be given during times of stress?

*- double doses with acute illness * - IV for emesis, trauma and surgery - consider emergency kit for when they cannot be taken to the hospital to get IV

What is the mineralocorticoid treatment for adrenal insufficiency? How do you follow up?

*- fludrocortisone * (for primary AI only) (100-150 mcg daily) - goal is high normal renin level (down from high) - consider giving an adrenal androgen with DHEA F/U with eval of vascular volume and orthostatic BP measurement

What kind of electrolyte imbalance is seen in primary adrenal insufficiency

*- hyponatremia and hyperkalemia * (these two values are AI until proven otherwise) - low glucose - elevated BUN/Cr - *vitiligo* and other autoimmune diseases - deficiency of all steroids

What is adrenal crisis in people with primary adrenal insufficiency caused by?

*- mineralocortioids deficiency* when stressed (causes hypoNa and hyperK) *- hypotension*

*the three things that diagnose AI*

*HYPONA, HYPERK, HYPOTENSION*

What is the glucocorticoid treatment for adrenal insufficiency? How do you monitor this?

- *hydrocortisone* replacement for glucocorticoids - titrate to the oral dose of hydrocortisone to the usual daily dose of *15-25mg daily dosing in 2-3 divided doses* throughout the day - monitor glucocorticoid replacement by follow-up evaluation of weight and blood pressure - follow up with electrolyte evaluation - do NOT follow up with ACTH and urine cortisol values (not reliable)

medulla of the adrenal glands

- 10% of the gland - part of the SNS - secretes catecholamines (adrenaline & noradrenaline)

How is free cortisol measured?

- 24 hour *urine* collection (used to detect excess cortisol) - exogenous steroids will alter the serum and urine cortisol levels (they will lower cortisol due to feedback inhibition)

What lab tests should be done to diagnose pheochromocytoma?

- 24 hour urine fractionated catecholamines, metanephrines VMA (should be several times normal)

cortex of the adrenal glands

- 90% of the gland - secretes steroid hormones (glucocorticoids, mineralocorticoids, sex steroids) - controlled hormonally

What sort of imaging should be done in cushing syndrome?

- CT or MRI of the adrenals - if ectopic, localize the source such as a chest CT in general, imaging is not that useful (tumor may be too small, tumor may not even be the source)

What labs should you check if a patient presents with hirsutism?

- DHEAS (adrenal origin) - malignant if twice normal - total testosterone (ovarian origin) - malignant if > 200ng/dl

How will a patient present with primary hyperaldosteronism?

- HTN - hypokalemia - thin - no familial HTN - metabolic alkalosis

What is the gold standard for imaging to diagnose a pheo>

- MIBG (metalogobenzylguanidine) nuclear imaging tracer concentrates in catecholamine producing cells

What sort of imaging should be done in Cushing disease?

- MRI of the pituitary in general, imaging is not that useful (tumor may be too small, tumor may not even be the source)

What are the findings of adrenal crisis in those with primary adrenal insufficiency

- abdominal tenderness - fever - postural hypotension - look for precipitating infection - careful with consideration for surgical abdomen because it could precipitate adrenal crisis if adequate steroids are not on board

What is Adrenal Crisis? How does patient usually presents? What are some causes?

- acute adrenal insufficiency - usually no prior diagnosis of adrenal insufficiency, or known AI in patient who do not increase dosing of needed steroids in crisis situation - causes: adrenal hemorrhage or infarction; pituitary apoplexy; can happen with secondary or tertiary AI, but less frequent

dehydroepiandrosterone (DHEA) secretion

- adrenal sex steroid, released from zona reticularis - regulation not understood, involves ACTH

When should you do an adrenal gland biopsy?

- after you've excluded a pheo- NEVER STICK NEEDLE IN A PHEO - to identify metastatic spread of cancer to the adrenal gland **will not separate out primary adrenal disorders and will not confirm the diagnosis of adrenal carcinoma

Treatment for a pheo?

- alpha blockers (phenoxybenzamines) - THEN beta blockers **never just beta blockers - they precipitate a crisis*

examples of stress

- anxiety, pain, emotional stressors, sleep deprivation - physical trauma/injury, prolonged strenuous exercise - infection - hypoglycaemia - shock, cold - dec. o2 supply

Describe the steroid production pathway

- begins with cholesterol (LDL receptors in the adrenal gland) - precursors are DHEAS and 17 OH progesterone - end products are estradiol, cortisol and aldosterone

What pattern is cortisol released in?

Diurinal Pattern; highest peak in early AM, second peak in late afternoon

increase (increase glucose by promoting gluconeogenesis in the liver and decreased uptake of glucose by cells)

Do Glucocorticoids increase or decrease glucose?

increase

Do glucocorticoids increase or decrease gastric acid production?

norepi

Do pheochromocytomas usually secrete epi, norepi, or both?

So what happens next if you get an abnormal cosyntropin test?

- check ACTH (determine if it's a pituitary (low) or adrenal (hi) problem) - make sure to do this before giving cosynthropin - check plasma renin (should be high in mineralcorticoid deficiency- renin is trying to provoke more aldo production) - look for steroid autoantibodies

What sort of imaging should be done to diagnose secondary adrenal insufficiency

- consider CT of adrenals for primary - MRI of brain for secondary unless the cause is overt (like the patient off of chronic steroids - this is a logical reason for suppressed ACTH and low cortisol)

cushing's syndrome

- cortisol excess - primary cause ACTH independent, e.g. adrenal tumour - secondary cause can be ACTH dependent e.g. excess ACTH secretion from pituitary tumour or ectopic source such as lung carcinoma - more common is prolonged corticosteroid treatment

How is 2° adrenal insufficiency SX different? (from low ACTH)

- decreased cortisol - decreased adrenal sex hormone - NORMAL** aldosterone secretion (from RAAS)***** Less severe sx NO HYPER-pigmentation No HYPER-kalemia

What is Congenital Adrenal Hyperplasia

- defect in *21 alpha hydroxylase enzyme* leading to increased androgen over cortisol - results in ambiguous genitalia in infant girls - in male infants, *presents as crisis of adrenal insufficiency*; must screen for 17-OH progesterone - variations: incomplete blockage of enzyme ---late onset CAH- adult women with hirsutism ---early puberty

What are some screening tests for Cushings?

- dexamethasone suppression test (normal is decreased cortisol) -24 hour urine free cortisol

How is primary aldosteronism diagnosed in the lab?

- elevated 24 hour urine aldosterone on high sodium diet and off diuretics (BP should be up and potassium should be gone, no need for aldosterone), or saline infusion

age & DHEA secretion

- fetal adrenal secretes large amounts of DHEA, falls after birth - DHEA production resumes ~7-8 years: adrenarche. Converted to active androgens, may initiate pubic and axillary hair before onset of gonadal steroidogenesis at puberty - DHEA declines with age

fetal adrenal gland development

- fetal zone involutes rapidly after birth - definitive cortex differentiates into 3 layers

cortisol secretion

- glucocorticoid, from zona fasciculata - pulsatile secretion - follows ACTH - diurnal rhythm- highest in the morning - mostly bound to cortisol binding globulin (CBG)

What is the usual history of someone with secondary adrenal insufficiency? *What is the MC etiology?*

- history of longterm steroid use - sudden stopping of steroids - presents with cough, fever and lung infiltrate - steroid dependence is the most common etiology!

cortisol- immune function

- immunosuppressive effects - anti-inflammatory effects

cortisol- anabolic actions

- inc. gluconeogenesis - dec. glucose and amino acids utilisation - inc. hepatic glycogen synthesis

What is late onset CAH?

- incomplete block of steroidogenesis pathway - diagnosis not made at birth because the genitalia is not ambiguous - presents with hirsutism in adult female - overt, critical adrenal insufficiency is not usually seen at presentation

cortisol- CV system

- increases blood pressure - maintains fluid volume - maintains vascular integrity & reactivity - maintains responsiveness to catecholamines

How is CAH tested for in infants?

- look for excess 17-OH-progesterone

What are the lab values in someone with secondary adrenal insufficiency?

- low sodium - normal potassium (suggests normal aldosterone production with the pituitary as the only source of the problem) - low ACTH - low cortisol

Hirsutism is a symptom- what are diseases that present with hirsutism?

- malignant neoplasms *(esp. if demonstrating virilization, instead of looking like a female with hair) * - late onset CAH - Cushing syndrome - virilizing tumors - PCOS

medulla hyperfunction

- may be due to tumour of chromaffin tissue (pheochromocytoma) - symptoms reflect actions of catecholamines = hypertension, tachycardia, tremor, sweating, weight loss, anxiety, glucose intolerance - measure plasma catecholamines or metabolites in urine and visualise tumour by scanning

actions of cortisol

- metabolism (prepare for starvation) - inc. plasma glucose - 'anti-insulin' - catabolic & anabolic (next)

How does an adrenal carcinoma present?

- metastatic at diagnosis - may present with weightloss - rapid in onset - cannot be proven with adrenal biopsy

aldosterone secretion

- mineralocorticoid, released from zona glomerulosa - preserves circulatory homeostasis in response to loss of water or salt - e.g. prolonged sweating, vomiting, diarrhoea, blood loss - acts in distal convoluted tubule of kidney to promote sodium reabsorption ( increasing water retention & restoring blood volume)

What are the clinical symptoms of primary adrenal insufficiency?

- nausea and vomiting, weakness, fatigue, confusion or coma, hypoglycemia, hyperpigmentation, electrolyte imbalance, weight loss

When should you consider pheochromocytoma as a diagnosis?

- patient with poorly controlled BP, diaphoresis, headache - when it seems unusual for patient to have HTN (no family history, lean, young patient)

How is hyperaldosteronism different from a pheo?

- primary hyperaldosteronism rarely becomes super critical

features of addison's disease

- progressive weakness, weight loss - low plasma glucose & sodium - high plasma potassium - dehydration, hypotension, low blood volume - pigmentation of skin (inc. MSH)

How does estrogen affect cortisol binding globulin?

- raises CBG (which means high cortisol) - cannot effectively test serum cortisol in patients on estrogen

fetal adrenal gland

- relatively large - large inner 'fetal zone', no 3βHSD so can't make glucocorticoids or mineralocorticoids directly from pregnenolone- makes DHEA instead, used as precursor for oestrogens by placenta -definitive cortex - converts progesterone to cortisol, particularly late gestation

What are some etiologies of secondary hyperaldosteronism?

- sodium restriction - renal disease - high potassium intake - pregnancy - diuretics

*Why are people with secondary adrenal insufficiency less likely to enter adrenal crisis?*

- they have adequate aldosterone to handle the hypotension that brings it on (their adrenals are working fine)

How do exogenous steroids affect the axis?

- they suppress it - ACTH is suppressed and may be persistently suppressed (unless patient was noncompliant with their treatment) - consider weaning steroids slowly if given for more than 4 weeks

Cause of hyperaldo?

- unilateral adrenal adenoma - idiopathic hyperaldo with bilateral dz

How does Cushing's present?

- weight gain, hirsutism, diabetes, osteoporosis - centripetal obesity, striae, acne, hypertension, capillary fragility and amenorrhea

What is bitemporal hemianopsia?

- you can see midline but nothing in the temporal fields

*How is adrenal insufficiency diagnosed?*

-* cosyntropin (synthetic ACTH) stimulation test * - take a baseline serum cortisol, give cosyntropin and check at 30 and 60 minutes later - goal is for *cortisol to be 20 mcg/dl or greater* (if not, adrenal insufficiency is diagnosed)

How to diagnose Pheochromocytoma?

-24 hr urine Catecholamine Levels -METANEPHRINE IS THE BEST INDICATOR! -Clondine suppression, Glucose Stimulation to check for HTN -CT/MRI: I313 Scan

What are some symptoms of addison's disease?

-BRONZING OF THE SKIN -Lack of aldosterone, Lack of androgens (loss of axillary, pubic hair, low libido, amenorrhea, etc.) - hyperkalemia - systemic symptoms

Man with episodic headaches - palpitations - diaphoresis - HTN What labs?

Pheochromocytoma LABS - plasma catecholamines/metanephrines (VMA)

>250 mg.day

Pheochromocytoma can be diagnosed when the total urine catecholamines are what?

Pheochromocytoma: rare, catecholamine-secreting tumor that may precipitate life-threatening hypertension. -- The tumor is malignant in 10% of cases and can be cured completely by surgical removal. -- Classic tetrad of symptoms: Headache, palpitations, VERY high BP, and diaphoresis

Pheochromocytoma of the Adrenal Medulla

From a prolonged exogenous use of a steroid, secondary adrenocortical insufficiency can look like what?

Physical exam findings of Cushings

Causes of Cushing Syndrome - ACTH dependent (HIGH ACTH)

Pituitary Adenoma (2°) - (Cushing Disease) Ectopic ACTH tumor (small cell lung tumor)

How do you treat cushing syndrome?

Pituitary: surgery, radiation, anti-adrenal drugs Ectopic: surgery, drugs Adrenal: surgery, drugs

Investigations of cause of CS

Plasma ACTH: usually shows diurnal variation. Undetectable level indicates ACTH-independent cause. Consider chest/abdo CT/MRI to look for tumour. Elevated level indicates ACTH-dependent cause. High-dose dexamethasone suppression test: causes suppression of cortisol production from pituitary causes (e.g. Cushing's disease), less so from ectopic causes. Pituitary MRI. Inferior petrosal sinus sampling to determine the source of excess ACTH production.

suppressed (remember the problems is only with aldosterone), elevated

Plasma Renin activity is typically _____ in primary hyperaldosteronism and is _____ in secondary hyperaldosteronism.

Investigations in Cushing's syndrome

Plasma cortisol (not useful, levels vary throughout day) Overnight dexamethasone test or 24hr urine free cortisol - confirms Cushing's syndrome if serum cortisol >50nmol/L morning following tablets Localisation tests 9am and midnight ACTH - if suppressed, non ACTH dependant cause (e.g. adrenal adenoma) likely High dose dexamethasone test CRH stimulation test Petrosal sampling

In Secondary Hyperaldosteronism is the renal level always low or high? Why?

Plasma renin high; because there is an appropriate release of aldosterone for pathologic reasons (i.e. pt in edematous state) so you have low flow through the JGA-if chronic low flow through the JGA, the renin is elevated all the time-which means the aldosterone is always up

Diagnosis of phaeochromocytoma

Plasma/urinary catecholamines/vanillyllmandelic acid/metanephrines. Then various imaging techniques to locate it.

Signs of Cushing's syndrome

Plethoric moon face Buffalo hump Purple abdominal striae Proximal myopathy Hirsuitism Thin skin Easy bruising HTN

Adrenal insufficiency, Autoimmune thyroid dx, Type 1 DM, primary hypogonadism, vitiligo, rheumatoid arthritis myasthenia gravis

Polyglandular (DM + gonads, skin, joints/connective tissue) Autoimmune Syndrome type 2 (Schmidt's) HINT: Look for sx of DM plus other autoimmune disorders

Adrenal insufficiency + hypoparathyroidism + chronic mucocutaneous candidiasis + primary, hypogonadism + malabsorption

Polyglandular (adrenals, parathyroids, skin, gonads, GI tract) Autoimmune syndrome type 1

Should be started at a low dose and the patient should be euvolemic. Watch for angioedema. Raise K† (Why?) Caution in bilateral renal artery stenosis; can raise creatinine (why?) Dose should be gradually increased; diuretic such as HCTZ is a rational add-on Contraindicated during pregnancy (tetratogenic)

Precautions To Take When Prescribing "prils"

What is DHEAS?

Precursor to testosterone and androstenedione (which is the precursor to estrogen) Development of secondary sex characteristics

Precursors to Aldosterone

Pregnenolone -> 11-Deoxycorticosterone -> aldosterone

Precurosrs to Estrogen and Testosterone

Pregnenolone -> DHEA -> test/estrogen

Precursors to Cortisol

Pregnenolone -> cortisol

Options for diagnostic tests for CS

Raised 24 hour urinary free cortisol levels. Overnight low-dose dexamethasone suppression test: CS results in failure to suppress serum cortisol. Midnight cortisol levels: demonstrate loss of normal diurnal variation of reduced cortisol production in the evening compared to the morning. Dexamethasone suppressed CRH test: dexamethasone is given, followed by CRH. CS results in failure of the dexamethasone to result in suppression of the action of CRH to raise serum cortisol.

Other abnormal investigations in phaeochromocytoma

Raised blood glucose Raised calcium Raised haemoglobin due to reduced circulating volume.

Diagnosis of CAH

Raised serum 17-hydroxyprogesterone. Builds up to due negative feedback and can't be metabolised onto the next step.

Management of adrenal carcinoma

Rare - poor prognosis, 30% 5 yr survival Rx - open surgery c complete tumour resection if possible If metastatic disease - chemo + radio + mitotane (adrenal specific cytotoxic agent)

What is pheochromocytoma?

Rare catecholamine producing adrenal tumors cause a "panic attack" like episode

What is a phaeochromocytoma

Rare tumour, formed from chromaffin tissue which secretes catecholamines. Usually in the adrenal medulla but can also be pretty much anywhere else in the body.

Causes of secondary hyperaldosteronism due to increased renin

Renal artery stenosis (renin released in response to reduced renal arterial pressure). Coarctation of the aorta (as above). Renin-secreting tumours. Low-output heart failure/liver failure (reduced renal perfusion). Nephrotic syndrome (loss of plasma volume to ECF). Gitelman's/Bartter's syndrome/diuretic use (renin released in response to reduced Na).

Renin: made in juxtaglomerular cells of kidneys in response to HYPOPERFUSION -- hypotension -- volume depletion -- obstruction of arterial bloodflow Renin (catalyst) + angiotensinogen-->angiotensin I Angiotensin I + angiotensin converting enzyme (ACE) --> Angiotensin II (this last step takes place in vascular endothelium of the lung and kidney)

Renin-Angiotensin-Aldosterone System

Gene affected in MEN- 2a

Ret proto-oncogene

Features of ectopic ACTH secretion

SCLC, carcinoid tumours Pigmentation (increased ACTH), hypokalaemic metabolic alkalosis (increased cortisol --> mineralocorticoid activity) Classic features of Cushing's are often absent

Adrenal Insufficiency: 5 S's of Management

Salt - IV Normal saline Sugar - IV Glucose (5% Dextrose) Steroids - IV Hydrocortisone Supportive Care Search - for underlying cause If chronic: Also give Mineralocorticoids

Barterr's syndrome

Salt wasting disease PC - childhood, failure to thrive, polyuria + polydipsia BP normal Na+ loss --> volume depletion --> RAAs activation --> K+ excretion --> metabolic alkalosis Rx - K+, NSAIDs, ACEi

Appropriate increased aldosterone production d/t RAAS

Secondary Hyperaldosteronism

What is Secondary Hyperaldosteronism? Common causes?

Secondary Hyperaldosteronism involves the Renin Angiotensin system. Common causes include: 1. Renal Artery Stenosis: Blood flow to kidney is obstructed, kidney goes into state of "shock", thinks entire body is in state of shock, and begins to release Renin, which then releases angiotensin I -- angiotensin II and then Aldosterone 2. Renin producing tumor

What is a difference of symptoms between primary adrenocortical insufficiency/Addison's disease and secondary adrenocortical insufficiency?

Secondary has NO hyperpigmentation

angiotensin 2

Secondary hyperaldosteronism is caused by what?

Tumours involving zona reticularis

Secrete excess sex steroids --> converted in periphery to androgens and/or oestrogens --> virilisation in women (deepened voice, cliteromegaly) --> feminization in men (e.g. gynaecomastia) Ix: - check cortisol - incr. serum DHEA + sex steroids - if cortisol normal, adrenal vs gonadal cause investigated using CT/MRI and adrenal/ ovarian vein sampling Rx: surgery

S/S Cushings

See muscle wasting, thin skin, hursitum, purple striae, buffalo hump, central obesity, hyperglycemia, poor healing.

Cough Angioedema Proteinuria* (↑,↓) Taste changes Orthostatic hypotension (or hypotension) Pregnancy problems Rash Increased renin & lower angiotensin II Lytes (for the electrolyte disturbance of hyperkalemia) **Captopril: first ever ACE inhibitor; high doses led to membranous glomerulopathy In general, ACE inhibitors & ARBs, in the doses currently used, reduce proteinuria significantly in type 2 diabetic patients.

Side Effects of ACE Inhibitors

Factors suggesting malignancy in adrenal incidentaloma

Size main determinant - adrenalectomy indicated if >4cm regardless of hormonal status Impossible to distinguish adenoma from carcinoma on biopsy Size also determines likelihood of hormone hypersecretion (except aldosterone producing andeoma, small <1cm)

Common locations of ectopic ACTH secreting tumours

Small cell lung cancer. Phaeochromocytoma Pancreatic neuroendocrine tumours Medullary thyroid cancer Gut carcinoids

What is aldosterone suppression test?

Sodium load or saline solution is given in order to suppress Aldosterone. Normally, aldosterone levels should be low. In Hyperaldosteronism, levels remain high.

Treatment of bilateral adrenal hyperplasia

Spironolactone (aldosterone antagonist). A new aldosterone antagonist called eplerenone is being developed which doesn't have the testosterone antagonist SEs of spironolactone. It has not been fully evaluated however.

What other treatment is required in the post operative period following adrenalectomy for adenoma?

Steroid cover - hydrocortisone or prednisolone Post op hyPOadrenalism b/o contralateral adrenal suppression from previously high circulating levels of cortisol Can take severe months

Steroid induced hypoadrenalism

Steroids suppress HPA axis Cessation of long-term Rx --> adrenal crisis - pts taking long-term steroids advised NOT to stop steroids abruptly Pts should carry steroid card and be educated about steroid supplementation at times of illness

increases

Stress _______________ ACTH release

Primary hyperaldosteronism - unilateral R adrenal mass on imaging (CT) 1st line TX:?

Surgery (removal of adrenal adenoma)

Treatment for pheochromocytoma?

Surgical Resection: 1. Laparoscopic if <8cm preferred

How to treat CAH?

Surgical correction, cortisol supplement

Treatment for Primary Hyperadlosteronism if it is an adenoma causing it

Surgical excision

MEN 1 treatment

Surgical resection (often multiple required) 1. Transphenoidal approach w/ pituitary tumors (often difficult b/c multicentric) 2. Parathyroidectomy + thyroidectomy 3. Subtotal or total pancreatectomy Medical management 1. Dopamine agonists (bromocriptine/cabergoline) for prolactinoma 2.H2 receptor antagonist, PPI for ZES (Zollinger Ellison Syndrome)

Treatment of Pheochromocytoma?

Surgical resection of tumor w/ alpha and beta blockers

Cushing's Treatment

Surgical resection-Culprit Tumor is resected-typically transphenoidal resection of pituitary mass

Treatment of phaeochromocytoma

Surgical resection. Pre-operative treatment with alpha-blockers and beta-blockers is required to control blood pressure and prevent intraoperative hypertensive crises.

How to treat Unilateral Adenoma

Surgically remove the tumor

45 yo M - with weakness and cramps*** - Recent-onset HTN******* - HYPER-natremia (MILD) - HYPO-kalemia******* - Metabolic acidosis ******* Q: What is the next step (best screening test)?

Suspected: Primary hyperaldosteronism (Conn's Syndrome) NEXT: Plasma Aldosterone:Renin - ratio > 20 = Diagnostic

Cushings Syndrome vs Disease

Syndrome = excess corticosteroids Disease = ACTH hypersecretion

What is the most common EXTRA ADRENAL SITE OF Pheochromocytoma?

THE ORGAN OF ZUCKERLANDL (At Aortic Bifurcation)

How to treat Cushing's Disease?

TRANSSPHENOIDAL MICROSURGERY

What is the first step in the diagnosis of Hyperaldosteronism?

Take PT off of Hypertensive drug or diuretic! Diuretics can cause "Aldosterone Escape", leading to false results

What heart problem is associated with phaeochromocytoma

Takotsubo's cardiomyopathy (temporary condition where your heart muscle becomes suddenly weakened or 'stunned' - the LV changes shape and enlarges). Due to stress. AKA "Broken heart syndrome".

How to treat Cushing's Syndrome?

Taper Steroid

Tertiary vs Secondary Vs Primary Adrenal effects

Tertiary - at the level of the hypothalamus as it releases CRH Secondary - at the level of the pituitary as it secretes ACTH Primary - at the level of the adrenal cortex as it releases DHEA, aldosterone, and Cortisol

exercise, excessive ingestion of tyrosine rich foods, caffeine, and general anesthesia

The acute sx of pheochromocytoma can be triggered by what?

hyperpigmentation (Remember: This is caused by the excess of ACTH, here there is no ACTH, so you would not have this)

The clinical presentation of secondary hypocortisoliem is similar to Addison's disease, except secondary does not have what?

altered mental status, difficulty learning, poor memory, mild euphoria, lack of fatigue, depression, and schizophrenia (Remember: Cortisol has neurologic suppressing effects and is involved in emotional behavior)

The cortisol activity in Cushing can have an affect on the hippocampal neurons. What might a patient present with if it has affected this?

virilization (frontal balding, muscularity, and deep voice)

The increase in androgens in congenital adrenal hyperplasia cause what?

When is free cortisol measured?

To detect excess cortisol- not done if sus for low cortisol

Treatment of Cushing's disease

Transphenoidal surgery to remove pituitary tumour Bilateral adrenalectomy if source unlocatable or recurrence post op

Treat the primary lesion if possible (pituitary or adrenal adenoma). Gluco- and mineralocorticoid replacement as needed with supplemental stress doses as needed Hydrocortisone (20 mg/d BID-TID), prednisone (5 mg/d) or dexamethasone (0.5 mg/d) commonly used for glucocorticoid replacement. Fludrocortisone (Florinef) 0.1-0.3 mg/d usually used for mineralocorticoid replacement.

Treatment of Adrenal Insuffciency

W/o treatment, ~50% of affected individuals die within 5 years of onset as a result of overwhelming infection, complications from generalized arteriosclerosis, or suicide. Treatment: specific for the cause and includes medication, radiation, and surgery.

Treatment of Cushing's Syndrome

Primary: If aldosterone-secreting tumor is found, treatment is surgery Can block effects of aldosterone with spironolactone Secondary: Optimize the underlying condition Addition of spironolactone is often helpful. Be sure to watch K+

Treatment of Hyeraldosteronism

True

True or False: All the hormones secreted by the adrenal glands are secreted in an unbound state and bind to proteins for transport.

True

True or False: Cortisol is necessary for life?

True (remember: cortisol promotes gluconeogenesis in the liver leading to an increase in glucose)

True or False: Cushing patients can have glucose intolerance and have a DM presentation.

True

True or False: Death can occur from untreated MTCH?

True

True or False: Glucocorticoids are essential to survival.

True (Remember: Cushing is a manifestation of hypercortisolism.)

True or False: In Cushing, ACTH stimulates production of cortisol with a loss of the normal feedback mechanism.

True

True or False: In Cushing, there is a loss of the diurnal or circadian secretion patterns of ACTH and cortisol.

True

True or False: In the late evening salivary cortisol level test, the cortisol level can be normal amd the patient can still have Cushing.

True

True or False: Pheochromocytomas are extremely vascular and can rupture leading to fatal hemorrhaging.

True

True or False: The 24 hour urine free cortisol test establishes the hypersecretion of cortisol in 75% of patients.

True

True or False: The adrenal androgens have little effect on normal sexual function, however DHEA do contribute to pubertal growth and supply hormones for the fetal-placental unit.

False (there is NO edema) (because of ANP causing the aldosterone escape?)

True or False: There is edema in primary hyperaldosteronism.

True (Cortisol is catabolic and causes this)

True or False: There is protein wastingign Cushing.

What is the MC location of tumor formation in pheochromocytoma?

Tumor arises from the chromaffin cells of the adrenal medulla. Adrenal medulla MC location

What is an Adrenal Tumor?

Tumor of the adrenal gland that can cause production of cortisol independently of ACTH. HIGH CORTISOL, LOW ACTH, NO HYPERPIGMENTATION!

Gene affected in MEN-1

Tumour suppressor gene

Symptoms of Hyperaldosteronism?

Two major symptoms: Hypertension and Hypokalemia Hypokalemia: Muscle weakness, cramping NO EDEMA IN HYPERALDOSTERONISM!

Investigations for hyperaldosteronism

U&Es as above. ECG in case electrolyte abnormalities have caused arrhythmias. Renin and aldosterone levels: Raised aldosterone. Low renin (if primary cause). CT/MRI can show adenomas and hyperplasia. Adrenal vein blood sampling can determine whether it is unilateral production (more likely to be an adenoma than hyperplasia). Aldosterone levels are usually increased following upright posture. This continues to happen with hyperplasia but there is no variation with adenomas. Genetic testing for familial cases.

What is an Ectopic Tumor?

Usually a small cell lung carcinoma that produces high levels of cortisol and ACTH. HIGH CORTISOL, HIGH ACTH, HYPERPIGMENTATION!

What is Cushing's Disease?

Usually caused by a small pituitary adenoma, PITUITARY GLAND releases excess cortisol as well as excess ACTH. HIGH CORTISOL, HIGH ACTH, HYPERPIGMENTATION!

Presentation of congenital adrenal hyperplasia

Varies in severity due to degree of deficiency. Androgen excess: ambiguous external genitalia in girls, early virilisation in boys. Addison's-like symptoms from deficiencies.

Increased androgens in males?

Virulization, quick maturation, small testes

10 yo kid - fever and vomiting - nuchal rigidity and petechial rash THEN he develops: - HYPO-tension and tachycardia - HYPO-natremia - HYPER-kalemia - HYPO-glycema

Waterhouse-Friderichsen syndrome - N.menigitidis septicemia - causes adrenal hemorrhage

Action of DHEA

Weak androgen which is converted to more potent androgens e.g. testosterone/oestrodiol by peripheral tissues.

sodium and water depletion

What activates the RAAS system, thereby increasing the amount of aldosterone present?

autoimmune, infections (TB, fungal, HIV, and CMV), Infiltrative disease (amyloidosis, metastatic cancer), or bilateral adrenal hemorrhage

What are some common etiologies for Addison's?

idiopathic, familial, PCOS, steroidogenic enzyme defects, or neoplastic disorders (ovaries or adrenals)

What are some possible etiologies for hirsutism?

Chromaffin cells (AKA pheochromocytes)

What are the cells of the adrenal medulla?

hypervolemia and HTN

What are the clinical manifestations of primary hyperaldosteronism?

hypoglycemia, hypercalcemia, and hyperkalemia

What are the findings on a CMP of a person in adrenal crisis?

24 hour urine free cortisol, late evening salivary cortisol levels, and low dose dexamethasone suppression test

What are the first line tests to test for Cushing?

MTC, pheochromocytoma, mucosal neuroma, intestinal ganglioneuroma, and marfanoid features

What are the manifestations of MEN 2B?

mucosal neuromas (tip of tongue, under eyelids, throughout GI tract) and marfan habitus

What are the most distinctive features of MEN 2B?

manage HTN and hypokalemia and surgical removal of the adenoma

What are the non-drug treatments for hyperaldosteronism?

AM ACTH levels, MRI of pituitary, CT of adrenals, CT of lungs, and inferior petrosal sinus sampling

What are the second line tests to test for Cushing?

crave salt, decrease ECF, decreased CO, hypotension, weakness, dehydration, fatigue, and eventually vascular collapse

What are the symptoms associated with decreased aldosterone in Addison's disease?

poor stress tolerance, hypoglycemia (no gluconeogenesis), lethargy, weakness, fever, anorexia, N/V/D, and weight loss

What are the symptoms associated with decreased cortisol in Addison's disease?

bronzed skin (because of the increase in MSH caused by ACTH), darkened creases and pressure points, and black/blue gums and oral mucosa

What are the symptoms associated with the increased ACTH in Addison's disease?

HTN, sweating, tachycardia, palpitations, HA, very warm, heat intolerance, weight loss, and constipation

What are the symptoms generally associated with pheochromocytoma?

Cushing disease (secondary hypercortisolism), Cushing syndrome (primary hypercortisolism), and Ectopic Cushing syndrome

What are the three forms of Cushing?

cortex and medulla

What are the two portions of the adrenal glands?

fmailial MTC or MEN 2A with cutaneous lichen amyloidosis or MEN 2A with Hirschsprung disease

What are the variants or MEN 2A (Sipple syndrome)?

meningococcal septicemia (Waterhouse-Friderichsen syndrome), open heart surgery, childbirth, HIT, removal of one adrenal gland, or adrenal metastases

What can cause adrenal hemorrhage?

pheochromocytoma (Remember: The pheochromocytes are the cells of the adrenal medulla)

What can cause adrenal medulla hyperfunction?

insufficient cortisol

What causes adrenal crisis to be an emergency?

decreased blood volume or decreased blood flow to kidneys (Remember: Aldosterone increases sodium and water reabs in the kidney, so to "compensate" for the loss this (angiotensin II stimulating the adrenals) is activated)

What causes compensatory secondary hyperaldosteronism to occur?

renin secreting tumor of the kidney (Renin in the first step in RAAS), Bartter syndrome (genetic renal tubular defect), or diuretic use

What causes non-compensatory secondary hyperaldosteronism to occur?

liver

What deactivates cortisol?

Addison's (primary), secondary Hyp0cortisolism, and acute adrenal crisis

What diseases are caused by hypofunction of the adrenals?

MEN 1 (Wermer's syndrome)

What do does this describe: Familial multiglandular endocrine tumor syndrome that is caused by inactivating mutations of the tumor suppressor gene MEN1.

suppresses it (Remember: Cortisol suppresses the immune response by reducing humoral and cell-mediated immunity)

What does the increased cortisol levels do to the immune system?

catecholamines

What does the medulla of the adrenal gland secrete?

Secondary hyperaldosteronism

What does this describe: Angiotesin II exclusively stimulating the adrenals causing an increase in aldosterone.

Primary hyperaldosteronism

What does this describe: Excessive aldosterone secretion by the adrenal cortex.

Hypercortisolism

What does this describe: Inadequate stimulation of adrenal glands by ACTH.

MEN 2B

What does this describe: MTC, pheochromocytoma, mucosal neuroma, intestinal ganglioneuroma, and marfanoid features.

Incidentaloma

What does this describe: Mass or lesion found in an adrenal gland by imaging procedure done for other reasons.

pheochromocytoma

What does this describe: Medulla tumor that secretes catecholamines.

MEN 2A (Sipple syndrome)

What does this describe: Medullary thyroid cancer (MTC), pheochromocytoma, and hyperparathyroidism.

Secondary hypocortisolism

What does this describe: Suppressed ACTH that is usually due to prolonged administration of glucocorticoids.

Hypercortisolism

What dos theis describe: A primary inability of adrenals to produce and secrete adrenocortical hormones.

Fludrocortison

What drug can be added to hydrocortisone to treat Addison's?

spironolactone or Eplerenone (aldosterone receptor antagonists)

What drugs are used to treat hyperaldosteronism?

stress, withdraw of adrenocortical hormone, bilateral adrenalectomy, hemorrhage, or trauma, sudden destruction of the pituitary, giving thyroid hormone to a patient with hypoadrenalism, or after etomidate administration (give this for rapid sequence intubation)

What factors might precipitate acute adrenocortical insufficiency (adrenal crisis)?

Cushing syndrome (primary hypercortisolism)

What form of Cushing does this describe: Cortisol secreting adrenal tumor.

Ectopic Cushing syndrome

What form of Cushing does this describe: Non-pituitary, non-adrenal ACTH or CRH secreting tumor.

Cushing disease (secondary hypercrotisolism)

What form of Cushing does this describe: Overproduction of pituitary ACTH by a pituitary adenoma.

decreased ("potassium wasting" it is excreted; hypokalemia)

What happens to the potassium level in primary hyperaldosteronism?

glucocorticoids, mineralocorticoids, and adrenal androgens

What hormones (class) does the adrenal gland secrete?

epinephrine and norepinephrine

What hormones does the adrenal medulla secrete?

Adrenal androgens

What hormones does this describe: A steroid hormone that is supplemental to gonadal androgens.

total and free testosterone, androstenedione, DHEA, and FSH/LH

What hormones should a patient have check by labs if you suspect hirsutism?

autosomal dominant

What inheritance pattern does MEN 1 have?

autosomal dominant

What inheritance pattern does familial MEN 2A (Sipple syndrome) have?

*Angiotensinogen is an α-2-globulin produced and released into the circulation mainly by the liver.

What is Angiotensinogen?

Conn disease or primary aldosteronism

What is another name for primary hyperaldosteronism?

MTC, pheochromocytoma, and hyperparathyroidism

What is associated with MEN 2A (Sipple syndrome)?

ACTH (due to no cortisol (feedback loops)) and androgens

What is increased in congenital adrenal hyperplasia

ACTH increases MSH production

What is it about Cushing that causes a patient to get a brownish pigmentation of the skin, mucous membranes, and hair.

hypercalcemia with intact parathyroid hormone

What is seen in hyperparathyroidism in MEN 1?

eosinophilia and lymphocytosis

What is seen on a CBC in a person with Addison's disease?

elevated BUN (if dehydrates), elevated potassium, low sodium, and low glucose

What is seen on a CMP in a person with Addison's disease?

eosinophilia (Remember: Addison's has this and lymphocytosis)

What is seen on the CBC of a patient with adrenal crisis?

autoimmune

What is the MCC of Addison's?

hyperaldosteronism

What is the MCC of secondary HTN?

HA, muscle weakness, N/V, abdominal pain, fever (>105.1), hypotension, dehydration and vascular collapse, hypoglycemia in patients with T1DM

What is the clinical presentation of adrenal crisis?

hydrocortisone

What is the drug of choice for the treatment of Addison's?

90 minutes

What is the half life of cortisol?

Small cell carcinoma of the lung

What is the most common ACTH or CRH secreting tumor that causes Ectopic Cushing Syndrome?

hyperparathyroidism

What is the most common manifestation of MEN 1?

GI related (intermittent colic, pseudoobstruction, and diarrhea)

What is the most common presentation of MEN 2B?

cortisol

What is the most potent glucocorticoid?

aldosterone

What is the most potent mineralocorticoid?

angiotensin 2

What is the primary stimulant for aldosterone production?

insulin resistance, inflammation, endothelial dysfunction, cardiovascular remodeling, and adipose tissue differentiation

What is the result of the activation of the aldosterone receptor in primary hyperaldosteronism?

twice and in different labs

What is the testing criteria when testing family members for MED?

lifetime glucocorticoid and mineralocorticoid replacement

What is the treatment for Addison's?

remove if functional

What is the treatment for a pancreatic islet cell tumor caused by MEN 1?

Dopamine agonists (Bromocriptine)

What is the treatment for a pituitary tumor caused by MEN 1?

IV high dose hydrocortisone, then give q 6 hours for the frist day and q 8 hours on the second day

What is the treatment for adrenal crisis in the acute phase?

glucocorticoid replacement

What is the treatment for congenital adrenal hyperplasia?

oophorectomy

What is the treatment for hirsutism in a postmenopausal women with severe hirsutism and normal adrenal CT?

observe

What is the treatment for hyperparathyroidism in MEN 1?

alpha and beta adrenergic blockers (prevents HTN and emergency) laproscopic surgery

What is the treatment for pheochromocytoma?

oral hydrocortisone and may need to add fludrocortisone

What is the treatment of adrenal crisis in the convalescent phase?

Congenital adrenal hyperplasia

What is this: An autosomal recessive disorder that causes a deficiency of enzymes critical to cortisol synthesis?

Hirsutism

What is this: Cosmetically unacceptable hair growth that appears in women in a male pattern.

Addison's disease

What is this: Inadequate corticosteroid (cortisol) and mineralocorticosteroid (aldosterone) synthesis with elevated serum ACTH.

Addison's disease

What is this: Primary adrenal insufficiency or chronic adrenal insufficiency.

electrolytes, serum and urine aldosterone levels, and plasma aldosterone to renin ratio

What labs should be done to test for hyperaldosteronism?

Eflornithine

What medication is used to slow hair growth in women with hirsutism?

spironolactone

What medication is used to treat hirsutism if the women is still having her period?

Clomiphene

What medication is used to treat hirsutism, PCOS, and infertility?

Spironolactone, Finasteride, Flutamide, OCP, Metformin, simvastatin, Clomiphene, and Eflornithine

What medications can be uesd for hirsutism?

50%

What percentage of patients with MEN 1 have endopancreatic tumors?

>90%

What percentage of patients with MEN 2A (Sipple syndrome) have MTC?

50%

What percentage of patients with MEN 2A (Sipple syndrome) have a pheochromocytoma?

15-20%

What percentage of patients with MEN 2A (Sipple syndrome)have hyperparathyroidism?

>50%

What percentage of patients with MEN 2B have pheochromocytomas?

5%

What percentage of pheochromocytomas appear non-functioning (no sx)?

50-70%

What percentage of those with Addison's disease have autoantibodies and autoreactive T cells?

weight gain from adipose tissue accumulation (in face (moon facies), trunk and cervical areas (buffalo hump)), thin limbs

What physical clinical findings are seen in Cushing?

ACTH (NOTE: almost all other androgens are regulated by the gonadotropins)

What regulates the adrenal androgens?

CRH (in the hypothalamus) and ACTH (in the anterior pituitary)

What regulates the secretion of cortisol?

RAAS

What regulates the synthesis and secretion of aldosterone?

ACTH

What stimulates the cortex of the adrenal gland?

aldosterone escape

What term describes this: In primary hyperaldosteronism, the body is able to maintain sodium and water loss due to atrial natriuretic factor release and spontaneous diuresis.

Cosyntropin (ACTH) stimulation test

What test confirms the diagnosis of adrenal crisis?

aldosterone, glucocorticoids, and adrenal androgens

What there hormones does the cortex of the medulla secrete?

high levels of cortisol and synthetic glucocorticoids, diurnal rhythms, and stress

What three factors regulate the secretion of ACTH?

nervous

What tissue organs does the adrenal medulla have?

physiologic stress

What triggers the release of adrenal catecholamines through acetylcholine which depolarizes the chromatin cells?

Cushing like syndrome or iatrogenic Cushing syndrome (not a true cushing. resolves when roids taken away)

What type of Cushing does this describe: Increased exogenous glucocorticoids.

MEN 1 (Wermer's syndrome)

What type of MEN does this describe: Tumors of the parathyroid, endocrine pancreas, duodenum, and anterior pituitary

RET protooncogene analysis

What type of analysis is done on proven MEN 2A patient to establish a specific germ line mutation?

glucocorticoids

What type of hormone does this describe: A steroid hormone that has a direct effect on carbohydrate metabolism.

mineralocorticoids

What type of hormone does this describe: Steroid hormones that directly affect ion transport by epithelial cells.

autosomal recessive

What type of inheritance pattern does congenital adrenal hyperplasia have?

Tumors of the parathyroid, endocrine pancreas, duodenum, and anterior pituitary

What type of tumors occur in MEN 1 (Wermer's syndrome)?

treatment of Addison's

When can acute adrenocortical insufficiency (Adrenal Crisis) occur?

childhood

When do patients who have MEN 2A (Sipple syndrome) develop the MTC?

small cell carcinoma of the lung

When doing a CT/MRI of the lungs in a patient you suspect has Cushing, what are you looking for?

0800

When is cortisol at its highest?

nighttime

When is cortisol at its lowest

compensatory or non-compensatory

When looking at the cause of secondary hyperaldosteronism, what two mechanisms need to be looked at?

What is polyglandular autoimmune syndrome

When patients have a number of co-existing autoimmune disorders affecting endocrine glands (and other things) e.g. Addison's. Thyroid disease. T1DM. Coeliac. Pernicious anaemia. Hypoparathyroidism. Premature ovarian deficiency. Alopecia. Vitiligo. Chronic atopic dermatitis. Hypogonadism. Hepatitis.

>1.8 mcg/dL

When test for Cushing and doing the dexamethasone suppression test, what cortisol level includes Cushing?

>0.25 mcg/dL (ALTHOUGH the number can be normal (<0.15) and the patient still have Cushing)

When testing for Cushing, the late evening salivary cortisol level would need to be greater than what to imply Cushing?

>50 mcg in 24 hours

When testing for Cushing, what would the cortisol level be in the 24 hour urine free cortisol test to diagnose Cushing?

ovarian or adrenal neoplasm

When testing for hirsutism, elevated androsteredione points to what?

>700 mcd/dL

When testing for hirsutism, if the DHEA comes back greater than what, does this suggest an adrenal source (hyperplasia) as the cause?

<24, >67

When testing for hyperaldosteronism, a plasma [aldosterone] to plasma renin ratio of _____ excludes hyperaldosteronism and _____ is very suggestive.

everything else is normal and ACTH secreting tumor suspected (ACTH would be VERY high)

When would you do an inferior petrosal sinus sampling in a patient you suspect has Cushing?

on top of each kidney

Where are the adrenal glands located?

periphery

Where does the conversion of the adrenal androgens to testosterone take place?

DHEA

Which adrenal androgen supplies hormones for the fetal-placental unit and contributes to pubertal growth?

ACEI's have an aldosterone blocking effect Normally aldosterone tells body to get rid of K+ and hold onto Na+; inhibition of aldosterone leads to the opposite effect

Why is K+ Raised While Taking "prils"?

CRH (CRH decreases due to negative feedback from all the cortisol)

With an ACTH-dependent tumor (Cushing disease, secondary hypercortisolism, non-adrenal), what hormone(s) does ACTH stimulate a decrease of?

cortisol and androgens (Remember the tumor is a pituitary adenoma making too much ACTH)

With an ACTH-dependent tumor (Cushing disease, secondary hypercortisolism, non-adrenal), what hormone(s) does ACTH stimulate an excess of?

ACTH and CRH (They both decrease since the problem is caused by cortisol. This is negative feedback)

With an ACTH-independent tumor (Cushing syndrome, primary hypercortisolism), what hormone(s) does ACTH stimulate an decrease of?

cortisol (Remember this is ONLY a cortisol secreting tumor, not ACTH. ONLY affects cortisol.)

With an ACTH-independent tumor (Cushing syndrome, primary hypercortisolism), what hormone(s) does ACTH stimulate an excess of?

high

Would you expect the ACTH level in Addison's disease (primary adrenal insufficiency) to be low, normal, or high?

no (because RAAS is intact)

Yes or NO: Are the aldosterone and potassium levels affected in secondary hypercortisolism?

Indications for screening for primary hyperaldosteronism

Young onset HTN Refractory HTN (>3 anti-hypertensives) HTN + hypokalaemia Hypertensive pts found incidentally to have adrenal adenoma

Zones of the adrenal cortex

Zona glomerulosa - aldosterone Zona fasciculate - glucocorticoids Zona reticularis - adrenal androgens ALL adrenal hormones are steroids derived from cholesterol

3 layers of adrenal cortex from superficial to deep and what they produce

Zona glomerulosa: mineralocorticoids (mainly aldosterone). Zone fasciculata: glucocorticoids (mainly cortisol). Zona reticularis: glucocorticoids and androgens (mainly DHEA).

*What is pituitary apoplexy? symptoms?*

a rare neurological emergency - person has a known, non-compressive pituitary neoplasm that changes in size due to vascular change (hemorrhage) Sx: - pituitary function is compromised, causing secondary adrenal insufficiency (thyroid, gn, GH insufficiency as well, but not as significant) - frontal headache, vision problems (blurring of vision, tunnel vision, decreased peripheral vision, bitemporal hemianopsia)

what is stress?

a threat to homeostasis

what does cortisol bind to (receptors)

active form binds both glucocorticoid and mineralocorticoid receptors more action at G receptor

A non-compliant patient with a history of Addison's presents with a headache, N/V, fever, hypotension, hypoglycemia, and purpura. What do you suspect?

acute adrenal crisis (in this case due to undertreated adrenal insufficiency) (can also present in cases of acute stress, adrenal hemorrhage or infection, or undiagnosed adrenal insufficiency)

What is another cause of adrenal crisis?

acute hemorrhagic destruction of bilateral adrenal glands

What is rapid/severe adrenal collapse?

adrenal insufficiency

hyper

adrenal insufficiency leads to _______________kalemia

hypo

adrenal insufficiency leads to _______________natremia

What is the gold standard for imaging to diagnose primary hyperaldosteronism?

adrenal venous sampling

Diabetes is the MCC of three major complications

adult blindness non-traumatic amputations dialysis

How is primary hyperaldosteronism treated?

aldosterone secreting adenoma: surgery (may take 6 months for appropriate results) bilateral adrenal disease: restrict sodium, use spironolactones

Before surgical resection of pheochromocytoma, what should you administer? What is the purpose of this?

alpha-adrenergic blockade 10-14 days and Beta-adrenergic blockade 2 days prior to surgical resection 1. Phenoxybenzamine HCl (Dibenzyline)-alpha-adrenergic antagonist 2. Propranalol or Nadolol-non-selective beta blocker to prevent intra- operative HTN crisis

liver

angiotensinogen comes from what organ?

arterial supply to 'suprarenal' glands

aorta renal arteries phrenic arteries

cortisol half life

around 70-90 mins

Interaction between cortex and medulla

arterial blood drains inwards from cortex to medulla steroid hormones modify enzymes involved in catecholamine synthesis

Is adrenal crisis due to primary or secondary adrenal insufficiency?

both

action of catecholamines on airways

bronchodilation inc. brain breathing centres

cortisol inactivation

by 11β-hydroxysteroid dehydrogenase 2 (HSD) to cortisone - 11β-HSD 2 prevents flooding of mineralocorticoid receptors by cortisol - present in aldosterone sensitive tissues eg. kidney, placenta

catecholamine release inactivation

by reuptake and by catechol-0-methyltransferase and monoamine oxidase, mostly in liver (half life ~1 - 3 min)

what is released from the medulla to prepare for fight or flight

catecholamines

chromaffin cells

cells in the adrenal medulla, make up the specialised sympathetic ganglion specialised postganglionic neurons (without axons) filled with storage granules containing either NA or Adr

features of cushing's syndrome

characteristic appearance - muscle wasting (protein mobilisation) - fat deposition in abdomen & face - thin skin, easily bruised altered metabolism- hyperglycaemia hypertension

Presentation of benign adrenal adenomas/incedentallomas?

coexisting HTN, hypokalemia and hirsutism

If adrenal crisis is left untreated, what can happen?

coma/death

glucocorticoids

common method of incidentally causing secondary adrenal insufficiency in a patient:

treatment of addison's disease

corticosteroid replacement

Hydrocortisone is the RX of what?

cortisol

Released at diurnal basal rate with bursts d/t stress response regulated by Anterior pituitary & ACTH via negative feedback loop

cortisol

decreases

cortisol _______________ ACTH release

Panhypoadrenalism

cortisol and aldosterone deficiency

ACTH stimulates the release of _______ from the adrenal cortex, causing the greatest peak in the (morning / afternoon / evening)

cortisol; morning (with smaller peak in mid-afternoon)

cholesterol desmolase deficiency

death in utero

Following a positive screening test for Cushing's syndrome, a(n) (elevated / decreased) ACTH level indicates adrenal cortisol excess

decreased

embryological origin of the medulla

ectodermal cells of embryonic neural crest

Following a positive screening test for Cushing's syndrome, a(n) (elevated / decreased) ACTH level indicates pituitary disease or ectopic ACTH production

elevated

Would you diagnose pheochromocytoma if the urine results are elevated or low?

elevated; low is normal

Multiple Endocrine Neoplasias (MEN syndorme) is an autosomal dominant syndromes manifested by a predisposition to the development of multiple tumors, particularly of __________ _______

endocrine glands

What is adrenal crisis typically due to? what is another thing that is less common?

exacerbation of chronic adrenal insufficiency; acute hemorrhagic destruction of the bilateral adrenal glands

11β-hydroxylase deficiency (2nd most common)

excess 11-deoxycortisol, 11-deoxycorticosterone these have mineralocorticoid activity --> salt/water retention --> hypertension

cushing's disease

excess cortisol due to a pituitary tumour

Cushing's

excess cortisol, often from a hypothal or pituitary tumor creating excess CRH/ACTH. Can also be from ectopic ACTH or an adrenal tumor.

WHat is Cushing Syndrome? *Sources?*

excessive cortisol ACTH dependent: too much ACTH produced; MC -- endogenous source- MC, pituitary neoplasm -- ectopic source: neoplasm like small cell carcinoma of the lung ACTH independent: adrenal gland excess cortisol

What is the most common cause of Cushing's?

exogenous exposure and HPA suppression can last a year s/p discontinuation of steroids

secondary adrenal insufficiency

exogenous glucocorticoids can cause what pathology in reference to hormone levels?

T/F Aldosterone is a potent anti-inflammatory agent

false (minimal anti-inflammatory properties)

embryological origin of the cortex

from embryonic mesoderm

what is released from the cortex to 'raise the alarm'

glucocorticoids mineralocorticoids

primary regulation of stress response

glucocorticoids- prep for starvation mineralocorticoids- prep for dehydration

renin:angiotensin ratio (>20:1); (PLUS ANY ONE OF THE FOLLOWING:) oral sodium loading test; saline infusion; fludrocortisone suppression test

how do you diagnose primary hyperaldosteronism?

2nd year notes on steroid hormones (don't need to know all of it but useful reference)

https://docs.google.com/document/d/16i1ztrkl88NjvRfEh8iCNh0R71cFYEdAkR_XeCwIgVU/edit?usp=sharing

What is the most common manifestation of MEN1?

hyerparathyroid

consequences of aldosterone excess

hypertension (high plasma volume due to Na+ retention) hypokalaemia (continued K+ excretion)

(probably) primary adrenal insufficiency (secondary AI does not show hyperpigmentation)

if a patient has adrenal insufficiency and hyperpigmentation, what does this indicate?

action of catecholamines on cardiovascular system

inc. HR inc. contractility of cardiac muscle dec. arteriolar tone in skeletal muscle inc. arteriolar tone in non-muscle beds

action of catecholamines on metabolism

inc. gluconeogenesis inc. glycogenolysis inc. lipolysis

other actions of catecholamines

inc. sweating pupil dilation inc. alertness

How are benign adrenal adenomas usually found?

incidentally - always do biochemical workup first before imaging - evaluation is important with coexisting HTN, hypokalemia and hirsutism

what are the effects of stress on the cardiovascular system

increase heart rate blood flow to skeletal muscle increases inc. blood pressure

Anabolic effects of androgens?

increase muscle mass, increase protein synthesis

Corticosteroids are administered in adrenal (hypersecretion / insufficiency)

insufficiency (only time when corticosteorids are used to TREAT a disease, vs. used for it's anti-inflammatory properties)

venous drainage of 'suprarenal' glands

left --> left renal vein right --> inferior vena cava

In Primary Hyperaldosteronism is the renin level always low or high? Why?

low; because the aldosterone is always high causing an increase in Blood Pressure so renin will be LOW

DHEA

major adrenal androgen, weak and not important in males, but if important source of androgens in females for GROWTH SPURT, 2ndary sex chars, libido, and some conversion to estrogen.

Aldosterone

major adrenal mineralocorticoid. Increases Na reabdorption by kidneys causing water to follow. Stimulated by RAAS system from low BP, low Na, or high K. ACTH has minor role.

Cortisol

major glucocorticoid, bound to transcortin in circulation. Directly affects CHO, protein,a nd lipid metabolism by stimulating protein breakdown into AAs, lipid breakdown to FA and glycerol, gluconeogenesis in the liver, and making glucose available FOR THE BRAIN.

What do these do?

mediated by alpha/beta adrenergic receptors which have opposite effects. Ex. alpha - vasoconstriction, beta - vasodilation.

90% of pheochromocytomas are tumors of the chromaffin cells of the adrenal (cortex / medulla)

medulla (secretes epinephrine and norepinephrine) (the other 10% are abdominal or thoracic) (overall, pheos are rare)

How would you tx chronic adrenal insufficiency with a minor illness? How would you tx an adrenal insufficiency pt if they also had hypoparathyroidism?

minor illness: pt take 3X*** the usual maintenance dose of glucocorticoid dose for 3 days (THE 3X3 RULE) You use glucocorticoids for adrenal fix, and levothyroxine for hypoparathyroidism. USE THE GLUCOCORTICOIDS FIRST! always fix adrenal insufficiency first.

cortisol- CNS

modulates perception & emotion

The adrenal Cortex produces what?

more than two dozen steroid hormones, collectively called corticosteroids all synthesized from cholesterol: 1. Glucocorticoids (cortisol) 2. Mineralcorticoids (aldosterone-sodium retention into serum with H20 and K+ secretion into renal tubule (blood pressure) 3. Androgens: DHEA, Androstenedione (precursor to testoseterone

Can you delay treating adrenal insufficiency?

no! obtain a baseline cortisol and then initiate treatment

the 'cost' of the stress response

non-essential functions are shut down (e.g. reproductive function & growth)

A rare adrenal medulla tumor that produce, store, secrete catecholamines; massive pathologic release of catecholamines

pheochromocytoma

what are the effects of stress on arousal

piloerection sweating pupils dilate breathing rate increases intestinal muscles relax

You have administered a cosyntropin (ACTH stimulation) test to a patient with suspected adrenal insufficiency. Cortisol levels rise <10mcg/dL. This is consistent with (primary / secondary) adrenal insufficiency

primary (Addison's)

What is a major pathology difference between primary and secondary/tertiary adrenal disorders?

primary - dysfunction of adrenal glands secondary - pituitary tertiary - hypothalamus Difference secondary/tertiary --> doesn't produce ACTH so no increase of POMC/MSH so no hyper pigmentation

Addisons disease

primary adrenal insufficiency, see panhypoadrenalism. Usually d/t atrophy or destruction of adrenal cortex.

aldosterone excess- causes

primary cause - adrenal tumour autonomously secretes aldosterone (Conn's syndrome) secondary causes - persistent stimulation of aldosterone secretion by low blood volume e.g. with severe heart failure, cirrhosis of liver, nephrotic syndrome

Conn's Syndrome

primary hyperaldosteronism, usually d/t hypersecreting tumor of Zona glomerulosa or high RAAS.

*primary hyperaldosteronism vs. secondary?*

primary: low renin, high aldosterone secondary: high renin, high aldosterone

Hyperpigmentation and salt cravings are only seen in (primary / secondary) adrenal (excess / insufficiency)

primary; insufficiency (stimulation of melanocytes by ACTH causes bronzed skin; salt cravings due to loss of salt with low aldosterone levels)

What is Cushing disease?

problem with pituitary, producing ACTH dependent Cushing Syndrome - MC due to neoplasm

If the surgical resection for Cushing's fails, what should you consider instead?

radiation of anterior pituitary

Adrenal enzyme deficiencies- 21-hydroxylase deficiency

reduces mineralocorticods & glucocorticoids loss of M causes loss of sodium and therefore hypotension and dehydration loss of G causes hypoglycaemia dec cortisol --> inc ACTH --> inc steroidogenesis to a point excess androgens --> ambiguous genitalia at birth, virilisation (boy-like features)

kidneys

renin comes from what organ?

angiotensinogen; angiotensin I

renin increases conversion of _______________ to _______________

what should you tell a pt with pituitary neoplasm?

risk for pituitary apoplexy; go to ED if abrupt vision changes with HA

Overnight dexamethasone suppression tests, 24 hour urine cortisol tests, and 11pm salivary cortisol tests are (screening / diagnostic) tools for Cushing's syndrome

screening (if one of these is positive, check a serum ACTH level and refer to endocrinology)

You have administered a cosyntropin (ACTH stimulation) test to a patient with suspected adrenal insufficiency. Cortisol levels rise rapidly. This is consistent with (primary / secondary) adrenal insufficiency

secondary (low ACTH)

Chronic glucocorticoid use would be a (primary / secondary) cause of adrenal insufficiency

secondary (the 9 I's are also secondary causes)

In what condition do you have panhypopituitarism?

secondary adrenocortical insufficiency

Adrenal medulla catecholamines

see production of epinephrine and norepinephrine. Cell bodies make epinephrine and peripheral neurons secrete norepinephrine. Norepinephrine is converted by enzyome in adrenal gland to epinephrine.

Permissive action of cortisol

small amount is needed for metabolisms that is constantly circulating and works on circadian rhythms.

what causes catecholamine release

stimulation by the splanchnic nerve acetylcholine released from preganglionic sympathetic nerve terminals, binds to cholinergic receptors --> exocytosis of secretory granules from chromaffin cells into circulation

When someone is sick and is on Hydrocortisone, what should you do?

stress their own steroids

what are the effects of stress on metabolism

substrate mobilisation increased blood glucose free fatty acids

What is the adrenal medulla under the control of in the CNS?

sympathetic control, BUT it has cholinergic receptors. Parasymp has no control over AM.

autoimmune adrenalitis

the most common cause of Addison's disease in the U.S. is _______________

TB

the most common cause of Addison's disease in the world is _______________

POMC (pro-opiomelanocortin)

the precursor to ACTH is _______________

MEN 2 treatment of Medullary Thyroid Carcinoma

thyroidectomy

role of the adrenals

to protect against acute and chronic stress

T/F Steroids should be given only for short periods of time and tapered to prevent adrenal insufficiency

true (Adrenal suppression may occur with 2 weeks or more of therapy - Steroid use for prolonged period of time inactivates the pituitary - immediate stop can cause acute adrenal crisis)

rate limite in catecholamine synthesis

tyrosine hydroxylase

MEN 2 treatment for pheochromocytoma

unilateral vs. bilateral resection?

Cortisol deficiency

usually in a secondary adrenal insufficiency d/t insufficiency ACTH from hypoth/pit failure.

lungs

what organ converts angiotensin I to angiotensin II?

when tx diabetic ketoacidosis what should you do when about administering IV insulin, and glucose reaches normal?

you need to keep administering insulin, ***bc the hyperglycemia is not the deadly problem you need to correct the anion gap from the acidosis

How would you dx Adrenal Insufficiency?

you would use a ACTH administration test. At 8 am take serum ACTH and Cortisol. (at 8 am bc that is when it is highest during the day**) then administer ACTH 250 mg IV and recheck serum cortisol at 30 min and 60 min

Commonly prescribed ACE Inhibitors: Benazepril (Lotensin) Captopril (Capoten) Enalapril (Vasotec) Fosinopril (Monopril) Lisinopril (Prinivil, Zestril) Quinopril (Accupril) Ramipril (Altace)

Angiotensin Conversion Enzyme Inhibitors ("prils")

Congenital adrenal hyperplasia

Androgen excess, from genetic deficiency, see inappropriate masculinization, pseudohermaphroditism and virilization in females, pseudopuberty in boys.

What are DHEA and Androstenedione?

Androgens

This hormone causes Na+ retention into serum w/ H20 and K+ secretion into Renal Tubule (blood pressure)

Aldosterone

Mineralocorticoids

Aldosterone NOT controlled by ACTH - synthesis regulated by RAS in response to low circulating blood volume, hyponatraemia or hyperkalaemia Acts mainly on distal nephron --> Na+ and water retention

This hormone - acts on distal renal tubules - increases Sodium reabsorption - in exchange for Potassium and Hydrogen

Aldosterone - if deficient (Addison's) - Non-anion gap metabolic acidosis - HYPER-kalemia - HYPO-natremia - HYPO-tension

Mineralocorticoids and potency

Aldosterone and deoxycorticosterone. Aldosterone is MUCH more potent.

Primary hyperaldosteronism - B/L adrenal hyperplasia on imaging (CT) 1st line TX:? - also if unilateral + refuses/poor candidate for surgery

Aldosterone antagonists - Spironolactone*** (preferred #1) - Eplerenone (less risk of gynecomastia)

Why do you not see clinically significant HYPER-natremia or edema in Primary hyperaldosteronism?

Aldosterone escape

What is the main function of Aldosterone?

Aldosterone saves sodium (and water) by inc reabsorption, and wastes potassium

What hormone(s) does the Adrenal Cortex release?

Aldosterone, Cortisol, Androgens, Catecholamines

annually

All patients with MEN mutations should be screened _____ for pheochromocytomas.

Treatment of hypertensive crisis due to a phaeochromocytoma

Alpha and beta blockade. But must do alpha furst as unopposed beta blockade can make it worse. Elective surgery a few weeks later.

>2.0

An FSH/LH ratio of what suggests PCOS?

Cortex: Zona glomerulosa: mineralocorticoids (aldosterone) Zona fasciculata: glucocorticoids (cortisol) Zona reticularis: androgens (cholesterol → DHEA, DHEA-SO4, and androstenedione → bloodstream → ovary/testis → estrogen/testosterone) Medulla: epinephrine/adrenalin

Anatomy of Adrenal Gland

Most common cause of adrenal insufficiency in children

Congenital adrenal hyperplasia.

Other causes of hypertension especially in younger patients

Conn syndrome Phaeochromocytoma Renal artery stenosis Coarctation of aorta

Primary Hyperaldosteronism is also called what?

Conn's Syndrome

Primary hyperaldosteronism is also known as...

Conn's Syndrome

Adrenal androgens

Controlled by ACTH Minor importance in adult men - testicular Leydig cells produce majority of circulating androgen More important role in adult women and in both sexes pre-pubertally Examples - DHEA and androstenedione Converted to more potent androgens testosterone and dihydrotestosterone (via 5 alapha reductase enzyme)

Two main parts of the adrenal gland

Cortex: production of glucocorticoids, mineralocorticoids and androgens in response to pituitary hormones. Medulla: produces catecholamines (adrenaline and noradrenaline).

The hypothalamus releases _______ releasing hormone, causing the release of ACTH from the (anterior / posterior) pituitary which acts on the adrenal (cortex / medulla) to secrete cortisol

Corticotropin; anterior; cortex

Glucocorticoids and potency

Cortisol and corticosterone. Cortisol is more potent and secreted more.

Why do patients with chronic primary adrenal insufficiency also get hyperpigmentation?

Cortisol deficiency --> pituitary secretes large amounts of ACTH to try and raise those levels (Precursor molecule for ACTH is POMC, also cleaved from this molecule is MSH) --> MSH: melanocyte stimulating hormone --> melanocyte --> skin darkens

Glucocorticoids

Cortisol major human glucocorticoid Regulates metabolic, immune and cardiovascular responses Synthesised from cholesterol; regulated by ACTH - exerts -ve feedback on hypothalamus --> decr. vasopressin and CRH production and on anterior pituitary --> decr. ACTH

early morning

Cortisol peaks at what time of day?

Dexamethasone suppression test RESULTS - Low ACTH (cortisol suppressed ACTH) - Low Cortisol

Cortisol should cause (-) FDBK on ACTH - shows that problem is not pituitary adenoma - (-) FDBK loop intact (central + peripheral)

Excess Cortisol = Cushing's Syndrome (often accompanied by high aldosterone and androgens ) 4 main causes: -- iatrogenic [steroid use; prednisone] -- adrenal gland tumor [primary] -- pituitary tumor (Cushing's Disease; secondary hypercortisolism) [secondary] -- ectopic ACTH production [NOT Cushing's Dz]

Cortisol: Zona Fasciculata

S/S Addisons relating to cortisol vs aldosterone

Cortisol: poor response to stress, hypoglycemia, low metabolism Aldosterone: hyperkalemia, hyponatremia, hypotension

Adrenocortical insufficiency d/t destruction or dysfunction of the adrenal cortex

Primary Adrenocorticol Deficiency/Addison's Disease

What is Primary Hyperaldosteronism? Most common cause?

Primary Hyperaldosteronism occurs independently of the Renin - Angiotensin system. MCC of primary hyperaldosteronism is CONN'S SYNDROME: Unilateral adrenal aldosterone producing carcinoma. IN PRIMARY HYPERALDOSTERONE, ALDOSTERONE GOES UP, RENIN GOES DOWN!

Primary adrenal insufficiency

Primary adrenal failure or Addison's disease Destruction of adrenal gland or genetic defect in steroid synthesis ALL 3 zones of adrenal cortex affected

What is Schmidt Syndrome?

Primary adrenal insufficiency: 1. Adrenal insufficiency 2. DM type 1 3. Thyroid dysfunction

Most common curable cause of secondary hypertension

Primary hyperaldosteronism.

2 main types of adrenal insufficiency

Primary insufficiency = Addison's disease Secondary insufficiency - inadequate pituitary or hypothalamic stimulation of the adrenals.

2 main categories of hyperaldosteronism

Primary: independent of renin-angiotensin axis. Secondary: due to high renin levels.

What is Cushing's syndrome (CS)

Prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids.

Investigation and management of CAH

Raised 17-OHP value either at baseline or in response to synthetic ACTH (synacthen) Rx: replacement c glucocorticoids + mineralocorticoids (if salt wasting)