ACTH + Adrenal Physiology
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| 407365299 | HPA Axis | This is the hypothalamic-Pituitary Adrenal axis and control | |
| 407365300 | CRH | Corticotropin Releasing Hormone | |
| 407365301 | ACTH | Adreno-CorticoTropin Hormone | |
| 407365302 | ADH=AVP | Anti-Diuretic Hormone | |
| 407365303 | GC's | Glucocorticoids | |
| 407365304 | Primary Deficiency | This is an issue with the target hormone | |
| 407365305 | Secondary | This is a pituitary issue | |
| 407365306 | Tertiary | This is an issue with the hypothalamus | |
| 407365307 | Secretagogue | This is something that increases the secretion of substance [X] | |
| 407365308 | Key feedback points | Cortisol production normally turns off ACTH and CRH synthesis -Cortisol also turns off ADH synthesis meaning you retain more H2O -The lack of ADH synthesis leads to hyponatremia "hyperwateremia" | |
| 407365309 | GFR | This is the acronym that helps you to remember the three layers of the adrenal cortex G-Glomerulosa (makes Aldoseterone) -RAS acts here F-Fasciculata (Makes Cortisol) -ACTH acts here and does its thing R-Reticularis (Makes sex steroids) The Adrenal Cortex is completely under the control of the sympathetic nervous system | |
| 407365310 | ACTH Secretagogues to watch for | -CRH (BIG ONE), ADH, cholycystokin plays a role to Another critical thing to watch out for is for tanned skin in these individuals | |
| 407365311 | Glucocorticoid Function | -All cells have receptors!! -Monitor many of the critical functions within the cell! -Also manage the metabolism of various biologic compounds -Important in immunity and wounds -Maintains CVS integrity and contractility Type of shock with a lack of glucocorticoids: -Distributive (lack of vasoconstriction) and Hypovolemic (lack of aldosterone + contractility)!! | |
| 407365312 | Clinical Features of Primary AI | -Tanned Skin -Vitilgo (other autoimmune conditions) -Decreased body hair -Hyperkalemia -Salt craving | |
| 407365313 | Clinical Features of Secondary AI | Double Vision, Decreased Acuity, Headaches, Nausea, Vomiting and other pituitary related symptoms | |
| 407365314 | Normal Cortisol Secretion | It is PULSATILE -Circadian Rhythm similar directly opposite to GH secretion -Highest between 4 am to 8 am -Lowest between 11 pm and 4 am -Negative feedback inhibition by glucocorticoids | |
| 407365315 | Severe Stress leading to cortisol release | •Severe Trauma •Burns •Illness •Major surgery •Hypoglycemia •Fever •Hypotension •Exercise •Cold exposure Activation? -It activates the HPA stimulating the release of CRH and AVP -When you get this sort of activation | |
| 407365316 | The "Steroid Fork" | SEE THE CHART THA YOU MADE -Only biochemical pathway to memorize before the exam | |
| 407365317 | Congenital Adrenal Hyperplasia | 21 Hydroxylase deficiency!! -This is the most common enzyme deficiency -Autosomal Recessive condition that you are dealing with Because you aren't making any aldosterone or cortisol you end up with a ton of ACTH -this makes your skin very tanned No ALDO -hypo Na, Hyper K, acidosis, hypotension, circulatory collapse No Cortisol -Failure to thrive, lethargy, hypoglycemia Androgen effect on females -Ambiguous Genitalia (fusion of labial folds, clitoromegaly, penile urethra, urogenital sinus) -most common cause of ambiguous genetalia in XX females Androgen Effect on males: -Normal male anatomy -Precocious puberty (Excess growth, acne, pubic hair) -Easily missed if not presenting with adrenal insufficiency Diagnosis: You want to try and stimulate with ACTH -you won't get an adequate response in these people -You will also get a buildup of side products as you try to stimulate it -Consider making it in females with ambiguous genitalia, cryptochid males, an infant with shock, hypoglycemia, hyper K Treatment: -Acute fluid resuscitation (Isotonic saline) -Acute glucocorticoid/mineralocorticoid replacement (aldosterone and cortisol) -Surgical Therapy (Clitoris reconstruction, vafinoplasty/correction of urogenital sinus) | |
| 407365318 | Primary Adrenal Insufficiency | Disease of the cortex in both glands: Destruction or surgical removal Infiltration Hypoplasia Infarction -Potentially life-threatening deficiency of both glucocorticoids and mineralocorticoids Common Causes: -Autoimmune or addisons disease (Developed world) -Developing world #1 cause is TB (5% of all cases) Rare Causes: Congenital, Infectious, Drugs, Hemorrhage/thrombosis Epidemiology: 1/10000 people -5 cases per 1 million per year -50% of these people present in life threatening crisis even though they have had symptoms up to a year before! Diagnosis: -You can do anti-adrenal antibodies to help you figure out what you are deficient in -Often have low aldosterone and hyponatremia -Also can be hyperkalemia -Mildly elevated TSH | |
| 407365319 | Secondary Adrenal Insufficiency | 1. Suppression of normal hypothalamic-pituitary-adrenal axis with exogenous glucocorticoids -Eg: Prednisone 30 mg daily x 2 years for Crohn's disease 2. Diseases of the hypothalamus/pituitary leading to deficiency of adrenocorticotrophic hormone ACTH -Eg: Pituitary tumour infiltrating the normal gland 3. Adrenal suppression following successful therapy of endogenous Cushing's syndrome -Eg: Post-op day #1 from laparoscopic adrenalectomy Diagnosis: -Steroid History (any type) -Headaches (pituitary issues) -Polyuria, polydypsia, nocturia -Head trauma or other CNS disease -Pituitary surgery/radiation -Pale alabaster skin -No salt craving -Post Partum bleed -Mildly elevated TSH | |
| 407365320 | Tests of Adrenal Function | Random Cortisol -this is a test that is rarely useful -ACTH can only help you to interpret these tests not give you the actual diagnosis Insulin Tolerance test -This is the gold standard and should induce the production of a TON of Cortisol -Contraindicated in seizure disorders/heart disease -Can only be done in major centres ACTH stimulation -this is clinical clerk proof -If you don't get the desired response than you have shown to have cortisol deficiency | |
| 407365321 | Treating of acute deficient patients | ABC's IV access + bolus normal saline IV hydrocortisone 100 mg q8h Look for infectious, cardiac, or metabolic precipitants Close monitoring; may need ICU | |
| 407365322 | Treatment of Chronic Patients | You need to give a physiologic dose that matches what you would expect in a normal person -Too little would give you weight loss and hypotension -Too much gives you cushing, diabetes, htn and osteoporosis In primary cases you need to give salt because you are going to waste a ton of it!! You shouldnt give sex steroids in primary adrenal insufficiency because you can't get compounds containing the correct amount of hormone in it | |
| 407365323 | Hypercortisolemia presentations | Non-Cushings syndromes: 1. Rapid onset of disease -Ex. new high dose of exogenous corticosteroids 2.High serum cortisol does not reflect the action of free cortisol on the receptor -could be just high cortisol binding globulin (birth control pill) -could also be due to resistance syndrome (rare) | |
| 407365324 | Road map to follow | 1. Make a clinical diagnosis 2. Confirm unequivocal hypercortisolism 3. ACTH dependent or independent ? 4. More tests to elicit and image the source 5. Treatment | |
| 407365325 | Epidemiology of HyperC | Endogenous 2-10 cases per million -2-3% = DM -HTN 0.5-1% of all cases -Incidental Adrenal mass 6-9% Exogenous: unknown but much higher -Untreated: mortality 4-5 times increased -Average disease duration before diagnosis | |
| 407365326 | Incidence of causes of Cushings | Cushing disease ->70% Ectopic ACTH ->10% Ectopic CRH <1% Adrenal Adenoma -> 10% Adrenal Carcinoma -> 5% Adrenal (other) -> 4% | |
| 407365327 | Clinical Diagnosis | -Emotional Disturbance -Enlarged Sella turcica -Moon Facies (wide face) -Osteoporosis (fragility fractures) -Cardiac hypertrophy (HTN related) -Buffalo Hump (dorsocervical) -Obesity (Central!!!) -Adrenal turmor or hyperplasia -Think wrinkled skin (bruises easily to) -Abdominal Striae -Amenorrhea (Hirsutism) -Muscle Weakness (proximal) -Purpura -Skin Ulcers Difficulties: -You may have a huge overlap with other conditions -Type II diabetes -Obesity -Polycystic ovarian syndrome Helping ->Take pictures and seek old photos | |
| 407365328 | Unequivocal Hypercortisolism | 3 tests to use in combination 1) 24 hr urine free cortisol -gold standard but patient compliance kind of sucks 2) Late night salivary cortisol -chew, soak at 11pm and then collect -new kid on the block 3) Overnight low dose dexamethasone suppression test -should be suppressed however in people with cushings it will still be elevated | |
| 407365329 | ACTH dependent of Independent?? | Basal plasma ACTH level Suppressed <1.1 pmol/L ACTH-independent cause High or inappropriately normal >3.3 pmol/L ACTH-dependent cause Indeterminate: 1.1-3.3 pmol/L Repeat ACTH; consider CRH stimulation test | |
| 407365330 | Tests to elicit the source | ACTH-Independent -You want to do a CT scan to look for an adrenal tumor -small is an adenoma -large can be an adrenal carcinoma!!! ACTH dependent -Tell between pituitary or ectopic sources -Pituitary: these can often be seen on CT or MRI (6mm or larger is cushings disease) -Ectopic is the ACTH sampling (Central:Peripheral ACTH > 2:1 is cushing's disease) | |
| 407365331 | Ectopic causes | Carcinoid tumors producing ACTH -Bronchial, lung, pancreas -Small cell lung cancer Pheochromocytoma Gastrinoma | |
| 407365332 | Treatment | Cushing's Disease (most common) Trans-sphenoidal pituitary surgery to resect adenoma Cure: post-op hypocortisolemia- steroids until recovers but need lifelong surveillance Post-op persistence or recurrence: -Repeat surgery may need total hypophysectomy -Pituitary radiation -Medical treatment: ketoconazole & others -Bilateral adrenalectomy +/- pituitary radiation -Permanent Adrenal Insuffciency! | |
| 408402322 | Primary Aldosteronism | This was previously believed to be an uncommon condition!! -The sheer number of hypertensive patients out there call into question how much primary aldosteronism there really is -First described as Conn's syndrome Pathogenic Findings: -You have a marked increase in sodium and water and sometimes hypokalemia Symptoms -The only one of real note is Hypertension -Very oligo-symptomatic -Edema is very UNCOMMON (adaptation) Causes: Common (aldosterone secreting adenoma or bilateral adrenal hyperplasia) Uncommon: (Unilateral adrenal hyperplasia, adrenal carcinoma, familial hyperaldosteronism type 1 or 2) When to consider: 1. Hypertension with hypokalemia 2. Resistant HTN: needing 3 or more meds 3. Hypertension onset age 20 or younger or 80 and older 4. Severe Hypertension: > 160/100 5. Incidental Adrenal Mass & hypertension Workup: SCREENING Aldosterone: Renin ratio: -If it is greater than 555 you need to do further testing -Test is very sensitive but not specific!!! CONFIRMATORY Salt Load: -You give them a ton of salt for a couple days and see if their aldosterone goes down at all Fludrocorticone Load: -Adds mineralocorticoid to suppress aldosterone -look to see if you can turn it off Treatment: -Depends on the issue and the individual -You need to image in order to decide CT: -Looking for the associated masses Adrenal Vein Sampling: -Looking to see if you have abnormal secretion on both sides -Very good tests as long as you get the catheters in the right location Surgery -Well tolerated because it is laproscopic!! -HTN gets better in all and about half become normotensive!!! Medical -Spironolactone can mask the effect and make things significantly better ($) -Eplerenon is a much more selective antagonist but you have to pay ($$$$) | |
| 408402323 | Pheochromocytoma | These are life threatening conditions that need to be found!!! -Adrenal 80-85% -Extra-renal 15-20% (paragangliomas) Prevalence -Relatively rare however it can KILL YOU!! Pre-Disposing Genetic conditions: Multiple Endocrine Neoplasia Type 2A & 2B Von Hippel Lindau Syndrome Neurofibromatosis Type 1 Familial Paragangliomas (SDHB/SDHD mostly) New emerging genetic mutations All can be screened for and family members identified pre-clinically as most are Autosomal Dominant mutations Signs and Symptoms: -Headache, Palpitations, Sweating in an episodic manner is the classic one -A ton of symptoms can be there to but are less likely to be related to pheochromocytoma Who to Screen: Paroxysmal spells Resistant Hypertension Hypertensive emergencies Adrenal Incidentalomas Unusual BP response under anesthesia Biochemical testing: 1) 24 hour urine collection of metanephrines and normetanephrines 2) Plasma Free Metanephrines fasting and supine -Both are very good tests although it is important to know that some places won't offer certain tests -> You do have to be careful with false positives (DRUGS ->anti-depressants, anti-hypertensives, beta blockers, CCB's, decongestants, cocaine, amphetamines) Imaging -CT / MRI / Nuclear MIBG Treatment: -You need to take these suckers out -Need to prep the patients by putting the tumor into submission -> catecholamine blockade using alpha adrenergic antagonists then salt intake with beta-blockers Post op: -Watch out for hypotension and hypoglycemia -The recurrence rate is 15-20% so you need to be careful that it isn't going to occur (following up with biochemical tests | |
| 408402324 | What is a metanephrine?? | It is the breakdown product of epinephrine and the associated products | |
| 408402325 | Pheo dynamics | The tumor cells are continually making new materials and storing them -You get really weird stimulation signals that force it out and circulating through the body | |
| 408402326 | Incidental Adrenal Mass Definition | Adrenal Mass >1 cm discovered incidentally during imaging for a "non-adrenal" indication Vast majority >80-90%: Benign & Non-functioning About 5% are pheochromocytomas and 5% are Adrenocortical carcinoma Incidence from autopsy & CT series: 4-6% of all adults Incidence increasing with more & better scans! | |
| 408402327 | Approach to Investigation | 1. Functioning or Non-Functioning -Do a history and physical looking for signs of hormonal secretion irregularities -Everyone gets screened for pheochromocytoma because it can kill you -Do further study of those who have positive results 2. Benign or Malignant -Suspect malignant with (Age, Mass effects, Constitutional Symptoms, History of a known non-adrenal malignancy) -Lung, breast, colon, kidney, melanoma, lymphoma are the most common historical points Other keys of when to treat: 1. Size: -Surgery for all > 6 cm, some suggest > 4 cm -> 4 cm: 90% sensitivity for adrenal Ca but only 24% specificity. Close observation if no surgery 2. Imaging phenotype: -Uses techniques to take advantage of the fact that 70% of adenomas have a high lipid content. -Attenuation or Hounsfield Units (HU) < 10. -HU <10 ~98% sensitivity for benign adenoma -PET scan high sensitivity but non-specific 3. Rapid growth of the tumor Biopsy?? -Don't go there because the histology isn't overly useful and you can spread the malignancy | |
| 408402328 | HU | Hounsfield Units -This is a measure of how many lipids are within a mass -lower than 10 = lipids mostly -Higher than 10 (or 25) is a good chance of malignancy |
