Endocrinology-Week 4- Adrenal Disorders

What does High dose non-suppression Dexamethasone suppression test indicate

Establishes diagnosis of ectopic ACTH or CRH secretion.

What is Cushing's Syndrome -70% of the time it is the cause of waht?

Excessive synthesis and secretion of cortisol - Cushing's Disease due to a pituitary adenoma. -need to do a biopsy since it can be adenoma, or carcinoma

What causes False non-suppression Dexamethasone suppression test? (2)

False Non-suppression: - non-suppression signals Cushing syndrome but can be seen in healthy subjects on: 1. Estrogens in oral contraceptive pills. -Estrogen increases cortisol-binding globulin leading to an increase in total cortisol. -Women taking oral BC should stop use 6 weeks prior to test 2. Medications that can induce CYP3A4 and increase hepatic clearance of dexamethasone. -does not suppress since dexamethasone is rapidly metabolized so test doesn't work. a. Barbiturates b. Carbamazepine c. Rifampicin.

Familial Glucocorticoid Deficiency 1. how it occurs

Familial Glucocorticoid Deficiency 1. Autosomal recessive ACTH receptor inactivating mutation - ACTH can't control cortisol because problem with the ACH receptor.

How to perform Adrenal vein sampling AVS 1. AC ratios a. R: 14, L: 10, IVC: 2 b. R: 14, L: 3, IVC: 14 c. R: 3, L10, IVC:10

-Place catheter in vein and put it up into inferior vena cava and take sample (this is used as a reference point). Keep going up until you get to level of adrenal level where they drain into inferior vena cava, get sample from right and left renal veins. - Compare aldosterone to cortisol ratio in renal veins with what is in the inferior vena cava. - In normal cases, ratio of aldosterone and cortisol in inferior vena cava should be comparable to that of adrenal veins. - If one of adrenals is putting out aldosterone at crazy rate, ratio will be higher than that in inferior vena cava. a. R: 14, L: 10, IVC: 2 Bilateral hyperplasia b. R: 14, L: 3, IVC: 14 Right adrenal adenoma c. R: 2 L: 10 IVC 10 Left adrenal adenoma

How to evaluate Primary aldosteronism- find the cause Step 1

-Primary hyperaldosteronism is usually due to adenoma or hyperplasia. If adenoma, just remove, if hyperplasia, need to figure out how much of adrenal to remove. Step 1: Do Adrenal CT scan Results: 1. Normal, micronodularity, or bilateral masses - Figure out probability of adenoma. -High probability of adenoma--> Do AVS - Low probability of adenoma-> consider screen for glucocorticoid remediable aldosteronism (GRA). Need to rule out rare stuff like: a. GRA pharmacologic therapy b. idiopathic hyperaldosteronism: pharmacologic therapy. 2. Unilateral hypodense nodule >1 cm. -If less than 40 years of age= Adenoma - if greater then 40 years of age= Need to do Adrenal Vein sampling (AVS). Step 2: Do AVS if indicated -Do if greater than 40 years of age with unilateral hypodense nodule, have normal adrenals, micronodularity, or bilateral masses Results: 1. Lateralization with AVS -adenoma, primary adrenal hyperplasia, or unilateral laparoscopic adrenalectomy 2. No lateralization with AVS -consider screen glucocorticoid remediable aldosteronism.

Congenital Adrenal hyperplasia -3 enzymes we need to know and what their absence/malfunction causes -include percent occurrence

1. 17 alpha Hydroxylase deficiency (rare) - Associated with delayed onset of puberty - only mineralocorticoids are made 2. 11 B Hydroxylase deficiency (5%) - Can't form cortisol or aldosterone - NOT associated with abnormalities of puberty 3. P450c21 (21-Hydroxylase) Deficiency (95%) - Causes Precocious puberty (in boys) and extreme virilization (in girls)

5 causes of primary adrenal insufficiency

1. Addison's Disease 2. Congenital Adrenal hypoplasia 3. Congenital Adrenal hyperplasia 4. Familial glucocorticoid deficiency 5. Allgrove (AAA) Syndrome

Management of Adrenal Incidentalomas 1. What are they 2. Steps in treating

1. Adrenals that are found when you're evaluating for something else. Not causing patient any issues. 2. Steps: Step 1: See if functional or nonfunctional by testing for Cushing's syndrome, Pheochromocytoma, and Hyperaldosteronism a. Cushing's Syndrome - Serum cortisol - urinary cortisol (optional) - ACTH -1 mg dexametasone suppresion test b. Pheochromocytoma - should always be evaluated c. Hyperaldosteronism - Serum Potassium -Serum aldosterone levels -Aldosterone-to-renin ration **If hormones are present=FUNCTIONAL: deal with it like you would with any other excess hormone production **If not producing hormones: NON-functional Step 2: Nonfunctional tumors: a. Leave it alone if less than 4cm b. If greater or equal to 4 cm, possibility of malignancy is high so they must be sent for surgery.

Confirmation tests for Primary Hyperaldosteronism Two types -how are they done

1. Aldosterone Excretion Rate - In a patient with undetectable PRA an aldosterone excretion rate >12 microgram/day in 24 hour urine sample that contain >200 mEq/L of Na establishes the biochemical diagnosis of primary hyperaldosteronism. 2. Saline Loading Test - PAC> 10 ng/dl after an intravenous infusion of 2000mL 0.9% NS over 4 hours in patients with an undetectable PRA establishes the biochemical diagnosis of hyperaldosteronism. -If give NS, aldosterone should decrease because volume of blood has increased. If aldosterone does not decrease, then Primary hyperaldosteronism.

Hypoaldosteronism 1. What is it 2. Two main causes of it

1. Aldosterone deficiency without cortisol deficiency 2. Two main causes: a. Hyporeninemic (RTA IV) b. Hyperreninemic

TTKG 1. What does it evaluate 2. Formula 3. normal TTKG 4. Abnormal values 6. What indicated hypoaldosteronism

1. Assesses renal K secretion at the cortical collecting duct under the influence of aldosterone -estimates the ratio of K in the lumen of the CCD where K is secreted to that in the peritubular capillaries. 2. TTKG = Kurine + Osmserum/Osmurine x Kserum 3. normal TTKG= 6-9 4Abnormal values: - Higher than 9= hyperkalemia when more K is secreted -lower than 6 = in hypokalemia when less K is secreted 5. TTKG <6 in hyperkalemia is indicative of mineralocorticoid deficiency - The formula for TTKG is valid only when urine osmolality is >300 Osm/Kg and the urine sodium is >25.mEq/L

4 causes of Addison's disease -most common cause in US.

1. Autoimmunity (US) 2. Bilateral Adrenal Hemorrhage 3. Granulomatous 4. Infiltrative Disorders.

Cosyntropin (ACTH) Stimulation Test - how is it done

1. Baseline (8:00am) - draw ACTH and cortisol level - High ACTH level >200pg/ml - Low cortisol level <10 microg/dl Values above indicate Addison's 2. Give artificial ACTh (Cosyntropin) injection - Less than 25% rise of cortisol in 45 minutes= Addison's - Cortisol should double if normal

Testicular Adrenal rest tumors (TARTs) 1. What is it? 2. How does it develop? 3. What are they associated with 4. How to treat?

1. Bilateral tumors of the testes 2. Develop from the stimulation of ectopic adrenal tissue in the testes by the high ACTH levels in CAH. (enlarges adrenal tissues) 3. They are associated with impaired spermatogenesis and infertility 4. Respond to suppressive treatment with steroids. - Give steroids to suppress ACTH so they aren't stimulated as much.

1. What modulates the synthesis and secretion or cortisol 2. How does cortisol increase blood pressure 3. What do cortisol levels NOT affect 4. what does NOT affect cortisol levels

1. CRH and ACTH 2. Cortisol increases blood pressure NOT by increasing sodium reabsorption but by enhancing peripheral vascular tone. 3. Cortisol levels a. Cortisol levels do not 4. Cortisol levels DO NOT affect renal Na handling 5. Renal salt wasting and sodium depletion do NOT affect cortisol levels

Example of medications to treat hyperkalemia in hypoaldosteronism

1. Calcium Gluconate 2. Albuterol 3. Patiromer (Veltassa)

Cardiovascular disease causes and hypoalbuminemia causes for 2nd hyperaldosteronism with edematous states ***know

1. Cardiovascular disease. a. SVC obstruction b. Heart failure c. IVC obstruction d. Portal hypertension 2. Hypoalbuminemia a. Protein Losing enteropathy b. Liver cirrhosis c. Alcoholic malnutrition d. Nephrotic syndrome.

Chromaffin Cells 1. What are they 2. What are they innervated by 3. Where else are they found? 4. What do they secrete

1. Chromaffin cells are neuroendocrine cells found mostly in the adrenal medulla - Act as modified sympathetic ganglia cells. 2. They are innervated by preganglionic fibers of the sympathetic nervous system 3. Found along the sympathetic chain behind the liver, in the urinary bladder wall, and along the vagus nerve and carotid arteries. - Largest collection of chromaffin cells outside of the adrenals is in the para-aortic body (organ of Zuckerkandl) -this is why it is hard to locate a pheochromocytoma 4. Secrete catecholamines (Norepinephrine 20% and Epinephrine 80%) directly into the bloodstream

Pheochromocytoma Evaluation: Plasma epinephrine and norepinephrine 3 levels to know and what they indicate

1. Combined levels >200 - diagnostic of pheochromocytoma 2. Combined levels <2000 but >1000 pg/ml - Indicated Clonidine Suppression test for Non-Suppression 3. Combined levels <1000 pg/ml - Indicates Glucagon stimulation test

Laboratory test to order for Addison's disease (2) and results of each (3 and 4)

1. Complete Blood Count a. Neutropenia b. Eosinophilia c. Lymphocytosis 2. Basic Metabolic Panel a. Hypoglycemia - No cortisol to increase glucose b. Hyponatremia - low aldosterone so Na doesn't get reabsorbed c. Hyperkalemia - don't secrete enough due to low aldosterone so K increase d. Hypercalcemia - tubular flow is low so there is too much Ca since not enough Ca is being secreted e. Metabolic acidosis - too much H present in plasma since low aldosterone prevents from it being secreted

2 reasons of primary hypoadrenalism and causes of each

1. Congenital a. Congenital adrenal hypoplasia -small adrenal so can't make as much b. Congenital adrenal hyperplasia -Adrenals overstimulated due to enzyme deficiencies c. Familial glucocorticoid deficiency d. Triple A (Allgrove) Syndrome 2. Acquired Addison's disease

Addison's: Congenital Adrenal Hypoplasia 1. How it occurs 2. What can this lead to

1. Congenital absence of the adrenal cortex 2. Delayed puberty

1. What determines how much cortisol is secreted? (2) 2. How is cortisol inactivated -what can prevent this from occurring and what does this lead to?

1. Cortisol secretion determined by: a. Time of day- Circadian Rhythm - Highest in the early hours of the mornings and lowest in the evenings b. Stress level - High amount released under acute stress 2. 11 Beta-Hydroxysteroid dehydrogenase - it converts active cortisol to inactive cortisol at the steroid receptor sites in a reversible reaction -Glycyrrhetinic acid in licorice prevents this inactivation and can lead to hypertension

How to treat Primary Adrenal insufficiency 1. Crisis 2. Stable 3. Surgery

1. Crisis: a. Give IVFs b. Give IV glucocorticoid replacement (hydrocortisone) c. Treat the precipitating even 2. Stable a. Oral glucocorticoid replacement (hydrocortisone) b. Add mineralocorticoid (Fludrocortisone) c. Monitor BP, blood sugar, and serum electrolytes 3. Reconstructive surgery - congenital adrenal hyperplasia with genitalia ambiguity

10 causes of Hyporeninemic leading to hypoaldosteronism

1. Diabetes 2. Lupus Nephritis 3. Analgesic nephropathy 4. Multiple myeloma 5. IgA Nephropathy 6. Nephrolithiasis 7. Glomerulonephritis 8. Obstructive Uropathy 9. Sickle cell nephropathy 10. Drugs a. Inhibitors of Renin production - beta Blockers -Ca Channel blockers b. Inhibitors of renin release -NSAIDs

How to treat Cushing's syndrome- Cushing's Disease

1. Do Transphenoidal Surgery 2. Incomplete or Recurrence (if returns or unsure if all was removed) - Radiotherapy (to let it shrink) - Anticortisolic Drugs - Bilateral Adrenalectomy

PHA Type 2 1. How does it occur 2. What does it result in

1. Due to activating mutation of the WNK1 and WNK4 genes that regulate the reabsorption of Na and Cl ions in the DCT. This activated mutations creates the condition that makes it possible for the tubules to absorb sodium regardless of aldosterone presence. 2. Results in sodium retention with hypertension, hyperkalemia, metabolic acidosis, and low levels of renin and aldosterone.

What is hyponatremia of primary adrenal insufficiency due

1. Due to renal sodium wasting but that of secondary and tertiary adrenal insufficiency is due to dilution

How to treat Secondary adrenal insufficiency 1. What must be evaluated first 2. How to treat hypopituitiarism

1. Evaluate for hypopituitarism - Insulin tolerance test: assess the response of HPA (GH) and adrenals (cortisol) to insulin-induced hypoglycemia 2. Treat hypopituitarism a. Thyroid hormone b. Antidiuretics hormone c. Growth Hormone d. Gonadotropins

Causes of Hyperkalemia not related to primary adrenal insufficiency 2 and examples for each

1. False 2. True a extracellular shift b. Increased intake c. reduced output

False Dexamethasone Suppression Test 1. 2 causes for false results

1. False Non-suppression and False Suppression

Clinical Manifestations of Pheochromocytoma

1. Headache 2. Palpitations 3. Pallor (vasoconstriction) 4. Nausea 5. Sustained Hypertension. -initially labile but as the vessels get lost, it becomes consistent 6. Orthostatic Hypotension -alpha 1 mediates vasoconstriction. tachycardia mediated by beta 1. Beta 2 work on airway and blood vessels by dilation. When catecholamines are released, both beta 2 and alpha 1 are stimulated. When you stand up, beta 2 suppress alpha 1 resulting in dilation of vessels leading to hypotension. 7. hyperglycemia 8. Psychological symptoms (anxiety, panic) 9. Weight loss

Step three of treating Hyperkalemia in hypoaldosteronism: Excretors 1. What do they do 2. 3 options

1. Help to excrete K out of the body 2. 3 types a. Furosemide -diuretic, makes you urinate a lot b. Sodium bicarbonate -least best c. Sodium Polystyrene Sulfonate (Kayexalate) - causes diarrhea d. Patiromer (veltassa) -Approved alternative to Kayexalate

4 causes for Infiltrative Disorders leading to Addison's disease

1. Hemochromatosis 2. Amyloidosis 3. Malignant Infiltration 4. X-linked Adrenoleukodystrophy (Fatty acid builds up in the adrenal cortices, testes, and nerve tissues)

3 ways to perform Dexamethasone suppression Test (DST) -when you do them

1. High dose DST: 2 mg PO q6 hr x 2 days - Establish Cushing's disease 2. Low dose DST: 1 mg p.o. q6h x 2 days Screen for Cushing Syndrome 3. Overnight DST: 1 mg po qhs x 1 dose. -Screen for Cushing Syndrome. Low dose and overnight are both for screening for cushing syndrome, similar to 24 hr UFC

1. What is hyperaldosteronism? 2. Two categories of hyperaldosteronism and subclasses

1. Hyperaldosteronism: excessive synthesis and secretion of Aldosterone 2. Two types a. Primary Hyperaldosteronism- - Idiopathic Hyperaldosteronism (most common) - Adenoma (second most common) - Glucocorticoid suppressible (hybrid glomerulosa cells responsive to ACTH) b. Secondary Hyperaldosteronism - Volume Depletion -Edematous states

4 clinical manifestations of hypoaldosteronism

1. Hyperkalemia 2. Metabolic acidosis 3. High urine sodium (>20) 4. Low urine K (<40)

Clinical findings for Primary Hyperaldosteronism 6

1. Hypertension 2. No nocturnal dipping (no decrease in BP when sleeping) 3. Hypokalemia 4. Metabolic Alkalosis 5. High urine Na 6. High urine Cl.

Commonalities of Congenital Adrenal hyperplasia (CAH)

1. Hypoglycemia 2. Hyponatremia 3. Hyperkalemia

What 4 things do primary hyperaldosteronism cause

1. Hypokalemia -Due to excretion of K. 2. Hypernatremia -Na is reabsorbed from tubular urine back into blood stream 3. Metabolic Alkalosis -K+ and H+ moves from blood stream into tubule and is excreted. 4. Hypertension. -Reabsorption of Na

How do each of the Primary hyperaldosteronism causes occur

1. Idiopathic hyperaldosteronism -enlargement of zona glomerulosa so increase in release of aldosterone 2. Adenoma - tumor secretes excess aldosterone 3. Glucocorticoid suppressible - Secretion of cortisol is under the control of ACTH. Cells in zona fasciculata are stimulated by ACTH to release cortisol. There is a hybrid- promoter region of cells in zona fasciculata have been fused with promoter region in zona glomerulosa. This hybrid fusion now subjects the synthesis and secretion of aldosterone to ACTH. - When give patient steroids to suppress ACTH, you take out excess production of aldosterone.

Addison's- Allgrove (AAA) Syndrome 1. How it occurs (gene affected) 2. 3 results of this syndrome

1. Inactivating mutation of the AAAS gene for the nuclear pore protein ALADIN responsible for nucleocytoplasmic transportation a. Adrenal insufficiency (because can't make cortisol) b. Achalasia (difficulty swallowing) c. Alacrimia (deficient tear production)

Addison's Disease- Granulomatous 1. Type kinds and examples of each -specify where they are more common

1. Infectious Granulomatous a. Tuberculosis (Worldwide most common) b. Histoplasmosis (Midwest; Ohio) c. Coccidioidomycosis (Southwest) - When someone grows up in an area, aren't affected but will be affected by new bacteria/viruses if they travel somewhere else. **why travel history is important* 2. Non-infectious Granulomatous. - Sarcoidosis

2 causes of secondary (pituitary) hypoadrenalism -which is the most common reason

1. Isolated ACTH deficiency 2. Panhypopituitarism - Panhypopituitarism: affects pituitary resulting in decrease in ATCH

3 reasons for Hyponatremia

1. Isoosmolar (false) 2. Hypoosmolar (volume low) 3. Hyperosomolar (increased solutes)

3 main functions of glucocorticoids (cortisol)

1. Keep blood glucose level normal 2. Immune Modulation 3. Enhance vascular Tone

How does Cortisol do the following 1. Keep blood glucose level normal (4) 2. Immune Modulation (2) 3. Enhance vascular Tone

1. Keep blood glucose level normal a. Promotes new glucose formation in the liver b. Promotes peripheral protein breakdown into amino acids for glucose formation in the liver. c. Inhibits glucose uptake by fate and muscle cells d. promotes fatty acids release from adipose tissue for energy production in the muscle cells 2. Immune Modulation a. Upregulation of anti-inflammatory protein b. Down-regulation of proinflammatory protein 3. Enhance vascular Tone - makes vessels more responsive to Epi and Norepi for vasoconstriction - when cortisol is not present, vessels aren't as responsive.

How to treat Cushing's Syndrome: Ectopic ACTH secretion

1. Localization and Resection 2. Anticortisolic Drugs 3. Bilateral Adrenalectomy - lifelong steroid replacement.

How to treat hyperkalemia

1. Membrane stabilization (protect the hear) 2. Shifters (move the potassium) (protect heart) 3. Excreters ( get rid of K)

1. Can you tell primary and secondary hyperaldosteronism from labs? 2. How can you distinguish the two

1. No. They're both metabolic alkalosis and hypokalemia 2. Primary: hypertension, high urine Na and Cl Secondary: hypotension, low urine Na and Cl.

Clinical findings for Secondary hyperaldosteronism 5

1. Orthostatic hypotension - Narrow PP <30 -SBP <20 - DBP <10 - PR>20 2. Hypokalemia (loss of Ca) 3. Metabolic alkalosis 4. Low urine Na 5. Low urine Cl.

Differential diagnosis for hyperaldosteronism -need to find the driving force for elevated aldosteronism. 1. Two things that are looked at 2. What are the two possibilities

1. Plasma Renin Activity (PRA) and Plasma Aldosterone Concentration (PAC) 2. High PRA and high PAC Low PRA and low PAC

Clinical manifestations of hyperaldosteronism 1 Primary hyperaldosteronism 2. Secondary hyperaldosteronism

1. Primary Hyperaldosteronism: - Initiating event: Increase in aldosterone production (abnormal event) --> increase in Na reabsorption --> Increase in intravascular volume --> decrease in Renin (because have enough BV) 2. Secondary Aldosteronism -Initiating event: decrease in intravascular volume --> increase in Renin release --> increase in aldosterone production --> Increase in Na retention

Low PRA and Low PAC- Differential for hyperaldosteronism 1. RAS-independent Non-Aldosterone-mediated mineralocorticoid excess -Two things that can cause this -two examples of each 2. Activating mutation of the EnaCs (amiloride-sensitive) in the CCD -cause

1. RAS-independent Non-Aldosterone-mediated mineralocorticoid excess a. Deoxycorticosterone-mediated -precursors can do some stuff - 17 alpha hydroxylase deficiency (not aldo but similar enough to simulate kidneys to reabsorb) -11 beta hydroxylase deficiency b. Cortisol mediated - 11 B hydroxysteroid dehydrogenase deficiency (deactivates cortisol but if deficient, then can't so cortisol stays around longer) - 11 Hydroxysteroid dehydrogenase inhibition (glycyrrhetinic acid in the root of licorice) 2. Liddle's Syndrome - Activating mutation -Leads to excess reabsorption of Na.

PGA Type 2 1. Name 2. What it includes 3. Clinical signs (3) 4. Gene defect? 5. Associated with? 6. What must be ruled out 7***Important thing to do when treating PGA type 2*

1. Schmidt's Syndrome (more common) 2. Addison's disease plus: a. Hypoparathyroidism b. Hypothyroidism c. Type 1 diabetes 3. Clinical Clues a. Chronic active hepatitis b. Pernicious anemia c. Alopecia and Vitiligo 4. No linkage to gene defect 5. Associated with HLA 6. Rule out Celiac disease 7. Whenever you have diagnosis of Addison's and hypothyroidism, treat adrenal insufficiency FIRST before Thyroid.

Step two in treating hyperkalemia is hypoaldosteronism: Shifters 1. How do they work? 2. Two ways to do this

1. Shift some of the K from circulation to inside the cells. 2. How to do it: a. Insulin (short acting) - MUST give glucose as well to avoid hypoglycemia -This drives K into the cells b. Albuterol -Easier way to do it. -beta stimulation

Anticortisolic Drugs 1. 4 medications and examples

1. Somatostatin Analogues a. Pasireotide b. Octreotide 2. P450 Inhibitor a. Ketoconazole - inhibits cortisol synthesis 3. Steroidogenic Inhibitors a. 11 beta-hydroxylase inhibitors - Metyrapone -Mitotane 4. Glucocorticoid Receptor Antagonist -Mifepristone.

Steps to controlling blood pressure in Pheochromocytoma

1. Step 1: Initiate alpha Blockage 2. Step 2:(if 1 didn't help) Add calcium challen blocker if necessary 3. Step 3: Beta Blocker MUST BE CARDIOSELECTIVE -can't use one that blocks both beta 1 and beta 2. If you do, then alpha 1 (vasoconstrictor) will take over and result in elevated blood pressure. 4. Step 4: give lots of fluids.

2 causes of Tertiary (hypothalamic) hypoadrenalism

1. Sudden withdrawal of chronic high dose steroid therapy - If you put someone on steroids for more than 1 week, need to tapper off. Steroids put a negative feedback on hypothalamus. If takes time for hypothalamus to wake up and release ATCH. So if patient suddenly stops steroids, they will not be able to make cortisol and could end up ER. Need to tapper off of steroids to slowly escape negative feedback loop 2. Posttransphenoidal surgical cure for Cushing's Disease - surgery affects HPA axis.

Adrenal (Addisonian) Crisis 1. What is it 2. Two causes 3. example

1. Sudden-onset adrenal insufficiency - Medical emergency 2. Causes: a. Acute adrenal failure - adrenal hemorrhage b. Acute stress (Sepsis and trauma) - Preexisting Addison's disease. - can occur acutely with hypotension 3. Woman with history of chronic diarrhea on treatment for IBS got a call from the school that her son fell and was being taken to the hospital. She gets in the car and passes out. At the hospital, she has low BP, low sodium, and high K. Stress from her son put a demand on her body to make more cortisol but it couldn't so lead to crisis

How to treat Cushing's Syndrome- Adrenal Adenocarcinoma

1. Surgical Resection 2. Anticortisolic Drugs 3. Rescue Corticosteroid Therapy.

How to treat Cushing's syndrome- Adrenal adenoma

1. Surgical Resection 2. Short term corticosteroid therapy - B/c normal cells need time to wake up. They haven't been stimulated by ATCH in a while.

Addison's Disease 1. Symptoms (5) 2. Signs (3)

1. Symptoms: a. Abdominal pain b. Vomiting c. Diarrhea d. Weight loss e. Muscle weakness 2. Signs: a. Darkening of skin (POMC) b. Orthostatic Hypotension - cortisol low so can't cause vasoconstriction to increase BP for become hypotensive. c. Loss of secondary sexual hairs

Treatment of Primary Hyperaldosteronism 1. Treat Aldosterone-producing adrenal adenoma (APA) -how is BP improved -% of PHA 2. Bilateral Adrenal hyperplasia (Idiopathic hyperaldosteronism or IHA) - What do you give -% of HPA

1. Treat Aldosterone-producing adrenal adenoma (APA) a. Unilateral adrenalectomy normalizes K levels b. BP control improves in all but HTN is cured only in less than 50%. 2. Bilateral Adrenal hyperplasia (Idiopathic hyperaldosteronism or IHA) - Mineralocorticoid receptor blockade a. Nonspecific-Spirolactone b. Specific: Eplerenone - 60% of PHA

1. What is secondary hyperaldosteronism- why does it occur

1. Trying to correct something that is occurring on in the body so excess aldosterone is released -intervascular volume depletion resulting in. - Amount of blood inside blood vessel that your heart can pump.

Two causes of secondary hyperaldosteronism -and their two sub categories

1. Volume depletion (water in blood is lost to the outside) Amount of blood inside blood vessel that your heart can pump. a. Covert b. Overt 2. Edematous States (volume in blood is lost from inside the blood vessel to outside but still within the body. Goes to interstitial area. a. Cardiovascular disease b. Hypoalbuminemia

When to start hemodialysis

1. When there are EKG changes and you have given membrane stabilization, shifters, and excreters without improvement.

PGA Type 1 1. Name 2. What it includes -signs 3. Cause

1. Whitaker Syndrome (less common) 2. Addison's disease plus hypoparathyroidism - Candidiasis - Hypocalcemia 2. Autosomal recessive genetic defect in the autoimmune regulator gene (AIRE) on chromosome 21 - The AIRE gene product mediates immunological tolerance

False suppression Dexamethasone Suppression test? 1. What does a false suppression test indicate. 2. 2 causes of False suppression

1. suppression excludes Cushing's syndrome. But this false suppression can be seen in patients with Cushing syndrome if they're under certain conditions 2. Causes: a. Low levels of albumin and cortisol-binding globulin - Nephrotic syndrome -Liver cirrhosis b. Medications that inhibit CYP3A and decrease hepatic clearance of dexamethasone. - Itraconazole -Diltiazem -Cimetidine. *because cortisol will last a lot longer in circulation since metabolism is being decreased so cortisol level will be depressed but this is not true.

Pheochromocytoma 1. what is it?

1. tumor of the chromaffin cells in the adrenal medulla

Signs/symptoms of Cushing's Syndrome

1. weight gain 2.slow healing cuts 3.increased infections 4. fatigue 5. glucose intolerance 6. Skin thinning 7. Buffalo hump 8.Weakness 9. Acne 10. Excessive hairiness 11. Straiae 12. Psycholigical 13. new or worsening high BP 14. Increased risk of fractures 15. Reproductive: in females, irregular or absent menstrual periods. In males: erectile dysfunction.

Drugs that cause Hyperreninemic

1.Renin inhibitors (Alliskiren) 2. ACEIs (ace inhibitor) 3. ARBs 4. Aldosterone Antagonist - Spironolactone - Prorenone 5. Epithelial Na Channel (ENaCs) blockers - Triamterne - Amiloride - Trimethoprim - Pentamindine 6. Calcineurin Inhibitors (inhibit T cell activation) - cyclosporin

1. In secondary and tertiary adrenal insufficiency, what glands are affected? 2. In secondary and tertiary adrenal insufficiency hypotension is mediated by what? 3. What does hypotension stimulate in secondary and tertiary adrenal insufficiency? -how does this affect RAS system

1.Secondary (pituitary) Tertiary (hypothalamus 2. reduce vascular tone (due to low cortisol) 3. Hypotension stimulates ADH release and water reabsorption - The intravascular volume expansion associated with ADH secretion (increase water absorption) attenuates the RAS system response a. Low Renin (B/c volume now normal) b. Low potassium c. low aldosterone - RAS remains suppressed in spite of low sodium because renal blood flow is preserved.

Step 1 in treating hyperkalemia in hypoaldosteronism: Membrane Stabilization 1. What does this do? 2. What medication do you give?

1.protects the heart by stabilizing the membrane 2. Calcium gluconate IV

What is released by Adrenal cortex and what is released by adrenal medulla

Adrenal cortex: 1. Cortisol (corticosteroid-glucocorticoid) 2. Aldosterone (corticosteroid-mineralocorticoid) 3. Androgens Adrenal medulla 1. Catecholamines (epi and norepi)

Main site for production of Catecholamines - what is produced produced

Adrenal medulla -Norepinephrine (20%) - Epinephrine (80)

Primary Adrenal insufficiency- Addison's disease Autoimmunity 1. percent in the US as the cause of Addison's disease 2. How it occurs 3. Isolated or not?

Autoimmunity- Addison's 1. 80% in the US 2. Antibodies against 21-Hydroxylase -early enzyme to convert cholesterol. 3. Usually insolated but can be a part of polyglandular autoimmune syndrome. (PGA)-attack multiple glands

High PRA and High PAC 1. What is it dependent on? 2. Two causes for high PRA and high PAC 3. Someone's cause for Primary hyperaldosteronism has anything to do with renin?

High PRA and high PAC 1. RAS-dependent Aldosterone mediated mineralocorticoid excess. 2. Causes a. Secondary hyperaldosteronism b. Salt wasting nephropathy 3. No, primary hyperaldosteronism has nothing to do with RAS.

Addison's disease- Bilateral Adrenal hemorrhage 1. 3 causes 2. What is DIC

Bilateral Adrenal Hemorrhage- Addison's disease (rare) 1. Septicemia with DIC - Fulminant Meningococcemia - Waterhouse-Friderichsen Syndrome Pt is very ill with sepsis and develop DIC. 2. Heparin-induced thrombocytopenia - Can cause DIC 3. Antiphospholipid Syndrome. - Can cause DIC DIC: Disseminated Intravascular Coagulopathy - Blood clots are being broken down and formed at the same time inside of blood vessels. Leads to acute hemorrhaging into the adrenals.

How to treat Pheochromocytoma - 2 things that must be done

Blood pressure control Surgical excision

Primary Adrenal Insufficiency CRH: ACTH: DHEA: Cortisol: Aldosterone: Renin: Na: K:

CRH: high ACTH: high DHEA: high Cortisol: low Aldosterone: low Renin: high Na: low K: high

Secondary Adrenal Insufficiency CRH: ACTH: DHEA: Cortisol: Aldosterone: Renin: Na: K:

CRH: high ACTH: low DHEA: low Cortisol: low Aldosterone: low Renin: low Na: low K: low

Tertiary Adrenal insufficiency: CRH: ACTH: DHEA: Cortisol: Aldosterone: Renin: Na: K:

CRH: low ACTH: low DHEA: low Cortisol: low Aldosterone low: Renin: low Na:low K: low

With Hypoaldosteronism, what is the most important thing to treat

Hyperkalemia

How is glucocorticoid synthesis regulated? - glands and hormones involved

Hypo--CRH--> Ant Pit--ACTH--> Adrenal cortex--> glucocorticoids --> negative feedback on pituitary and hypothalamus -Adrenocorticotropic hormone (ACTH) is released from the anterior pituitary and stimulates cortisol synthesis in adrenals. -Cortisol suppresses the release of ACTH from the anterior pituitary and the release of CRP from the hypothalamus

Hypoadrenalism 1. What is it? 2. 2 other names for it 3. three causes of it

Hypoadrenalism: 1. Deficiency of the adrenal corticosteroids 2. Hypoadrenalism= adrenal insufficiency hypocortisolism 3. Three causes of Hypoadrenalism: a. Primary (adrenal) b. Secondary (pituitary) c. Tertiary (hypothalamic)

Why is Glucagon stimulation test performed in evaluating pheochromocytoma

Combined levels of Epi and Norepi <1000 pg/ml - a 3 fold increase or an absolute rise in plasma catecholamines above 2,000 pg/ml form baseline over 3 minutes in response to IV bolus injection of Glucagon 2 mg - Positive response is diagnostic of small tumors.

When would you do Clonidine Suppression test for non-suppression when evaluation Pheochromocytoma

Combined levels of Epi and Norepi <2000 but >1000 - Give chlonidine to suppress plasma catecholamines by at least 50% or to <5000 pg/ml from baseline over 3 hours - Non-suppression is diagnostic of Pheochromocytoma

Addison's Disease- Congenital Adrenal Hyperplasia 1. How it occurs 2. What it can lead to

Congenital Adrenal Hyperplasia 1. Congenital absence of key enzymes for steroid synthesis - Form excess of certain androgens because missing enzymes to produce other steroids. So get too much of the androgens leading to early puberty. Adrenal gland is overstimulated and making lots of the same enzymes so it grows in size.

Two lab results that must be further evaluated before further evaluating for primary adrenal insufficiency

Hyponatremia and Hyperkalemia

Next step to establish diagnosis of primary adrenal insufficiency after differentials of hyponatremia and hyperkalemia are ruled out

Cosyntropin (ACTH) Stimulation Test

Causes of Convert and Overt volume depletion in 2nd hyperaldosteronism

Covert: 1. Small bowel obstruction 2. Soft tissue injury 3. Pancreatitis 4. Peritonitis Overt 1. vomiting 2. Enterocutaneous fistula 3. Nasogastric aspiration 4. Diarrhea.

What do you give for glucocorticoid remediable hypertension

Dexamethasone.

What innervates the medulla

Innervated directly by the preganglionic fibers of the sympathetic nervous system

Low PRA and Low PAC 1. Two causes low PRA and low PAC

Low PRA and low PAC -Due to congenital issues -Another steroid is causing the hyperaldosteronism if Low PRA and low PAC. need to find out which one. Can be cortisol if in excess since it can do somethings that aldosterone does. 1. Causes a. RAS-independent Non-aldosterone-mediated mineralocorticoid excess b. Activating mutation of the ENaCs (Amiloride-sensitive) in the CCD)

What can lead to elevated levels of catecholamines? - What must you do before saying a test is negative

Many medications can false results. So make sure to check the medication history since some medications may increase measured levels of catecholamines and methanephrines With current assay methodology, antihypertensive medications do not interfere with testing.

What to do after you have confirmed Primary hyperaldosteronism

Must evaluate it

PHA Type 1 . The two subtypes - 4 causes of each

PHA Type : -cannot reabsorb sodium so lose Na in urine. - results in Salt Wasting neuropathy Systemic PHA- inactivating mutaiton of the epitherlial Na channels 1. Autosomal recessive 2. Moderate-Severe Variant 3. Inactivating mutation of the Epithelial Na Channels in CCD - aldosterone modulated and amiloride-sensitive Na Channels 4. Involves both renal and external renal sites (colon, sweat, and salivary glands) Renal PHA-- limited to kidneys, Due to inactivation of mineralocorticoid receptors 1. Autosomal Dominant 2. Mild-Moderate Variant 3. Inactivating mutation of the mineralocorticoid receptors 4. Limited to the kidneys

Steroid hormone synthesis - What does everything start with? -how are they formed

- Cholesterol - Enzymes use cholesterol to form different products and intermediates to make other steroids.

Only disease that causes both sustained hypertension and orthostatic hypotension

Pheochromocytoma

Two diseases that need to ruled out when diagnosing Adrenal insufficiency

Polyglandular Autoimmune (PGA) Syndromes PGA Type 1 (Whitaker Syndrome) PGA Type 2 (Schmidt's Syndrome)

Why is renin level high in primary adrenal insufficiency

Renal sodium wasting attenuates renal response to ADH and compromises renal blood flow.

What has greater control on aldosterone? - HPA axis or Renin-Angiotensin system

Renin-angiotensin system

How to treat tertiary hypoparathyroidism

Restart glucocorticoid at the initial dose and slowly taper off.

Rule associated with Pheochromocytoma

Rule of 10's

Salt Wasting Nephropathy- High PRA and high PAC -Two causes - how they occur -What type of diuretic target is it.

Salt Wasting Nephropathy- High PRA and high PAC 1. Bartter's Syndrome - Inactivating mutation in Na-K-2Cl co-transporter in thick segment of ascending loop of Henle. - Loop diuretic target (block Na reabsorption in loop of henle so looks like they're abusing diuretics) 2. Gitelman's Syndrome - Inactivating mutation of Na-Cl co transporter in distal convoluted tubule - Thiazide diuretic target

PHA type 1 result in what

Salt wasting nephropathy with hypotension, hyperkalemia, and metabolic acidosis but with high levels of renin and aldosterone

What is Hyperpigmentation specific for

Specific for Addison's disease and is secondary to the increased formation of Melanocyte-Stimulating Hormone along with ACTH from the precursor molecule Pro-OpioMelanoCortin

How to evaluate for Cushing's Syndrome Step 1

Step 1: Measure 24 Hour UFC (urine free cortisol) - 24 UFC>100 microg/mL (concerning)-->measure ACTH Step 2: Measure plasma ACTH Results: a. High ACTH level = Cushing's disease - Perform High dose dexamethasone suppression test. (give steroid-should suppress ACTH) *Non-suppression: Work up for an ACTH secreting tumor (ectopic- not coming form pituitary) * Suppression: Head CT CT/MRI for pituitary tumor. b. Normal ACTH level - Means its in early stage. c. Low ACTH level - tells you that cortisol is coming from adrenals in fasciculata, not pituitary. - **Do Abdominal CT/MRI for adrenal hyperplasia/neoplasia.

How to diagnosis Primary hyperaldosteronism (do if its not High PRA/High PAC or Low PRA/Low PAC) Step 1: ? -result is called? Step 2?

Step 1: Measure PRA and PAC - Low PRA and high PAC =What primary is. - RAS-independent Aldosterone-mediated mineralocorticoid excess (Conn's syndrome) Step 2: Check PAC/PRA ratio: - if greater >30 then can establish diagnosis. If not, need to do confirmatory test.

What is the purpose of doing Clonidine Suppression test for Non-suppression and Glucagon Stimulation test?

Sum of catecholamines is a direct coorelate of the size of the tumor - If small, patient will be symptomatic but the level will be less than 1,000 and these small ones respond better to glucagon stimulation test - If sum is over 1000 but less than 2000, do Clonidine Suppression Test for Non-Suppression for larger tumors.

Test to diagnosis hypoaldostronism

Transtubular Potassium gradient (TTKG)

Main site for production of cortisol -what is released

Zona Fasciculata - Cortisol

Main site for production of aldosterone

Zona Glomerulosa

Main site for production of androgens - what is released

Zona Reticularis - Androgens: Dehydroepiandrosterone (DHEA) Androstenedione

Main cause of hyperreninemic leading to hypoaldosteronism

drug induced.

How to evaluate for pheochromocytoma

measure plasma epinephrine and norepinephrine

What must you never do to a patient with pheochromocytoma scheduled for surgery

send them to surgery without controlling blood pressure - If blood pressure is not well controlled, patient can have a stroke during surgery.

Function of androgens

Androstenedione and DHEA have no direct effect on the body but serve as intermediates for the synthesis of testosterone and dihydrotestosterone and Estradiol in the peripheral tissues. -Androgens are not an active product

Disease that can cause hyperreninemic

Aldosterone synthase deficiency - Zona glomerulosa does not have enzyme to make aldosterone.

Function of mineralocorticoid (aldosterone) and two ways it is done

Aldosterone/Mineralocorticoid 1. Regulation of mineral salt reabsorption in response to changes in blood volume and blood pressure a. Aldosterone stimulates the reabsorption of Na in exchange for K and H+ in the cortical collecting duct. - distal colon and sweat glands also retain Na in response to aldosterone stimulation b. Angiotensin II from Renin Angiotensin System and extracellular potassium modulate the synthesis and secretion of aldosterone. -Much more so than the hypothalamo-pituitary-adrenal (HPA) axis. If blood pressure decreases, aldosterone increases to increase blood volume by bringing in Na and releasing K and H.

Surgical outcome of malignant pheochromocytoma

Although surgical excision reduces the symptoms of malignant pheochromocytoma the 5-year survival rate is about 50%. The location of the metastasis predicts patient's survival with bone metastases being the best and the lung and liver metastases being the worse. Chemotherapy is associated with deadly catecholamine release from dead and dying chromaffin cells usually within 24 hours.

Test to confirm Addison's disease in child (for congenital adrenal deficiency)

Congenital Adrenal hyperplasia a. High serum level - LH and FSH (ratio >2) - Testosterone - Higher levels of DHEA than Androstenedione - 17(OH) Progesterone (P450c21 Deficiency)

What is a differential diagnosis for hypoaldosteronism

Pseudohypoaldosteronism (Aldosterone Resistance) - PHA type 1 -PHA type 2

How to localize Pheochromocytoma?

Radiological a. Plain -CT -MRI b. PET with Flurodopamine (FDOPA) - CT -MRI Radioliodinated Scan - MIBG scan (I-MetaIodoBenzylGuanidine scan) - In anterior and posterior view of pheochromocytoma in the left adrenal gland with an undesirable thyroid uptake of radioiodine and the normal renal excretion of radioiodide.