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Adrenal glands t sg
- 2. • Outline: • Adrenal gland • Basic anatomy • Embryology • Primary Adrenal Insufficiency
- 4. • Fibromascular capsule Containing artertial plexus • Each adrenal gland, together with the kidney, is enclosed in the renal fascia (of Gerota) and surrounded by fat. • The glands are separated from the kidney by a fibrous tissue but are enclosed by renal fascia,
- 5. Adrenal Blood Supply and Venous Drainage The adrenal blood supply and venous drainage. Copyright © 2022 Decker Medicine LLC. All rights reserved.
- 6. Embryology • The medulla accounts for apx 10% of the mass of the adult adrenal gland and arises from the neuroectoderm; it is thus a modified sympathetic ganglion. • The cortex arises from intermediate Mesoderm. Copyright © 2022 Decker Medicine LLC. All rights reserved.
- 7. Histology
- 8. Hormones Zona Glomerulosa - 15% - Columnar Epithelial cells produces Mineralocorticoids Middle layer Zona fasciculata, 65 to 80% is responsible for the secretion of glucocorticoids zona reticularis - 10% of the cortex. primarily produces weak androgen, such as dehydroepiandrosterone (DHEA), The Medulla parenchyma has chromaffin cells, which are considered modified sympathetic postganglionic neurons due to thier lack axons and dendrites
- 12. Adrenal Insufficiency • Low Plasma cortisol often confirmed by ACTH Stimulation testing • And or mineralocorticoid deficiency (PAI) • Symptoms Consistent
- 15. Synthetic Pathways Figure 3 Synthetic pathways for adrenal steroid synthesis. DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate. Copyright © 2022 Decker Medicine LLC. All rights reserved.
- 16. Copyrights apply
- 17. Causes of Primary AI • Autoimmune adrenalitis • Isolated adrenal insufficiency • Autoimmune polyglandular syndrome 1 • Autoimmune polyglandular syndrome 2 • Infectious Adrenalitis • TB, HIV, CMV, histoplasmosis, paracoccidioidomycosis, syphilis , African trypanosomiasis • Metastatic cancer; due to rich sinusoidal blood supply. • Primarily lung, breast, stomach and colon cancer or lymphoma • Adrenal haemorrhage/infarction • Drugs – inhibit cortisol biosynthesis • azole antifungals, etomidate (even after single dose), rifampin, anticonvulsants • Deposition diseases • hemochromatosis, amyloidosis, sarcoidosis • Others
- 18. Clinical features • Symptoms • Weight loss • Anorexia • Malaise • Weakness • Fever • Depression • Impotence/amenorrhoea • Nausea/vomiting • Diarrhoea • Confusion • Syncope from postural hypotension • Abdominal pain • Constipation • Myalgia Joint or back pain • Pigmentation, especially of new scars and palmar creases • Pigmentation (dull, slaty, grey-brown) is the predominant sign in over 90% of cases. • Buccal pigmentation • Postural hypotension • Loss of weight • General wasting • Dehydration • Loss of body hair (Vitiligo)
- 20. Precipitators of a crisis • In chronic primary adrenal insufficiency-infection or any major stress. • Patients with known 10 or 20 adrenal insufficiency who are under- replaced, • insufficient daily doses of glucocorticoid and/or mineralocorticoid; • failure to take more glucocorticoid during an infection or other major illness; • persistent vomiting or diarrhea caused by viral gastroenteritis or other gastrointestinal disorders, leading to decreased absorption. • bilateral infarction or hemorrhage • pituitary infarction. • Abrupt withdrawal of steroids-for both oral and inhaled steroids
- 21. Chronic Primary adrenal insufficiency • Fatigue; 84-95 %. • Weight loss; 66 -67% • Nausea, vomiting, abdominal pain; 49-62 %. • Muscle and joint pain; 35-40 % • Skin hyperpigmentation 41-74 % (buccal, palmar creases) • Postural hypotension; 55-68 %, due to mineralocorticoid deficiency. • Salt craving (38 to 64 %). • Decreased axillary and pubic hair and loss of libido in women* • Amenorrhea -25%
- 22. • Laboratory findings • Hyponatremia (70 to 80 %) • Hyperkalemia (30 to 40 %) • Anemia (11 to 15 %)
- 23. Diagnosis • Demonstrate inappropriately low cortisol secretion • Determine whether the cortisol deficiency is dependent on or independent of corticotropin (ACTH) deficiency and evaluating mineralocorticoid secretion in patients without ACTH deficiency • Seek a treatable cause of the primary disorder e.g pituitary adenoma
- 24. • Morning serum cortisol (6AM) • 10 to 20 mcg/dL (275 to 555 nmol/L)-Normal • <3 mcg/dL [80 nmol/L] is strongly suggestive of adrenal insufficiency • Morning salivary cortisol concentration • >5.8 ng/mL (16 nmol/L) excludes adrenal insufficiency, • <1.8 ng/mL (5 nmol/L) adrenal insufficiency most likely
- 25. ACTH stimulation test • Standard high-dose test (250 mcg) — • normal = 60-min (or 30-min) post-ACTH cortisol ≥18 μg/dL • abnormal in primary b/c adrenal gland diseased and unable to give adequate output • abnormal in chronic secondary b/c adrenals atrophied and unable to respond • low-dose (1 mcg as an IV bolus) • normal =20 or 30 minutes post ACTH cortsiol: 17 to 22.5 mcg/dL (400 to 620 nmol/L)
- 26. • Plasma ACTH • 10-8AM plasma ACTH is high, as high as 4000pg/ml • 20- low or normal ACTH. Normal value (20-52 pg/mL) • Renin and aldosterone conc. • Imaging studies • Pituitary MRI • Adrenal CT
- 28. Other Lab findings • Hyponatraemia (90%) • Hyperkalaemia (65%) • Hypoglycaemia • Metabolic acidosis • Normocytic normochromic anaemia, • Eosinophilia, lymphocytosis, and neutropenia
- 29. Treatment Adrenal crisis • Hydrocortisone (prefered) • 100-mg IV bolus, • Followed by 200 mg every 24 hours, either as a continuous infusion or as frequent IV/ IM boluses (50 mg) Q6hrly. • Subsequent doses depend on the response. Taper over 1-3 days, then switch to oral • Dexamethasone 4 mg every 24 hours • Methylprednisolone 40 mg every 24 hours • Fluids • 1 to 3 liters of NS or D5 in NS (to correct possible hypoglycemia) within the first 12 to 24 hours based on assessment of volume status and urine output • Follow normal resuscitation protocol • Treat precipitating factors
- 30. Copyrights apply
- 31. CHRONIC ADRENAL INSUFFICIENCY • Hydrocortisone 15–25 mg PO qd (⅔ a.m., ⅓ early p.m.) • Prednisone 5mg od • Dexamethasone 0.5mg od • Fludrocortisone 0.1mg/d. may use 0.05mg/d for those on hydrocortisone. Upto 0.2mg/d for those on Dexa or prednisone. Use only in primary adrenal insufficiency • Monitor BP, Pulse, serum potassium, and plasma renin activity (PRA). Adjust the fludrocortisone dose to lower the PRA to the upper normal range • Androgen replacement (DHEA) - in women with adrenal insufficiency. DHEA 25mg-50mg od for 3- 6 months
- 32. Treatment CNTD
- 33. Treatment CNTD
- 34. Patients with non specific symptoms after cessation of corticosteroids. Have a low threshold for adrenal insufficiency diagnosis Broersen, L. H., Pereira, A. M., Jørgensen, J. O. L., & Dekkers, O. M. (2015). Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism, 100(6), 2171-2180.
- 35. Pause
- 36. Hyperaldosteronism • Physiology Recup • Causes • Presentation • Diagnosis • Treatment
- 38. HYPERALDOSTERONISM • Causes • Primary (Adrenal disorders, Renin Independent) • Bilateral idiopathic hyperaldosteronism (idiopathic hyperplasia, IHA)(60–70%), • Aldosterone-producing adenoma (APA) (Conn’s syndrome, 30–40%), • Unilateral adrenal hyperplasia- 2% • Familial hyperaldosteronism (Types 1,2,3) –1% • Pure aldosterone-producing adrenocortical carcinomas and ectopic aldosterone-secreting tumors (ovary, kidney )
- 39. • Secondary (extra-adrenal disorders, ↑ aldosterone is renin-dependent) • Primary reninism: • renin-secreting tumor (rare) • Secondary reninism: • Renovascular disease: RAS, malignant hypertension • Edematous states w/ ↓ effective arterial volume: CHF, cirrhosis, nephrotic syndrome • Hypovolemia, diuretics, T2DM • Bartter’s syndrome • Gitelman’s syndrome
- 41. Pseudohyperaldosteronism • Have a clinical picture of hyperaldosteronism with suppression of plasma renin activity and aldosterone. • Characterised by hypertension, salt retention , hypokalaemia, low renin and aldosterone concentrations. • Causes; • 11β-HSD defic. • Licorice • Exogeneous mineralocorticoids • Liddles syndrome
- 42. Synthetic Pathways Figure 3 Synthetic pathways for adrenal steroid synthesis. DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate. Copyright © 2022 Decker Medicine LLC. All rights reserved.
- 43. Clinical features • Hypertension (5-10% of pts with HTN) – may have resistant HTN • Headache • Hypokalemia- 9 to 37 % • Muscle weakness, • Polyuria, polydipsia, • Cardiac arrhythmias • Ileus • Hyperglycaemia • Metabolic alkalosis • Mild hypernatraemia • LVH • Metabolic syndrome
- 44. Diagnosis
- 46. Primary hyperaldosteronism • Case detection testing(screening) • Plasma aldosterone conc (PAC) • Plasma renin activity (PRA)/plasma renin conc (PRC) • PAC/PRA ratio (ARR)** • Avoid beta blockers, RAAS blockers for 2/52, diuretics,MRAs for 6/52 before testing. Use alpha blockers, NDP-CCBs for BP ctrl. • Case confirmation; demonstrate inappropriate aldosterone secretion • Oral sodium loading; 5g of Na over 3/7, check 24-h urine thereafter. (+ve if urine aldo >12mcg/dl) (sens 96%, sp-93%) • Saline infusion test; 2L of NS over 4 hrs, +ve if aldo at end of infusion is >10ng/dl • Fludrocortisone suppression test • Captopril test • Subtype classification (APA vs IHA) • Adrenal CT. • Adrenal venous sampling (gold std criterion) 50mcg/hr of ACTH,30mins before sequential sampling of the adrenal veins
- 50. Treatment • Unilateral Adenoma or Hyperplasia • Laparoscopic adrenalectomy • Preop. Control BP with MRAs • Post op- • AM aldosterone • d/c MRAs, • Check for hyperK+- inpt, then once weekly for 4/52. • Bilateral disease • 1st line; MRA • Spironolactone 12.5-25mg OD to a max of 400mg-prefered • Eplerenone 25mg BD to a max of 100mg/d • 2nd line: K+sparing diuretics • Amiloride- 5mg BD • Triamterene • ? Subtotal adrenalectomy
- 51. Pause
- 52. Cushing syndrome • Epidemiology • Incidence; 1-2/100,000 per year • Cushing’s disease; Common in female • Ectopic ACTH syndrome; common in male
- 53. Aetiology : ACTH-dependent Cushing's syndrome Cushing's disease (60-70%) Ectopic ACTH syndrome (5-10%) Ectopic CRH syndrome ACTH-independent Cushing's syndrome (15-25%) Adrenal adenoma Adrenal carcinoma Micronodular hyperplasia Macronodular hyperplasia Pseudo-Cushing's syndrome Major depressive disorder Alcoholism Iatrogenic – Overall, most common cause
- 54. Clinical features • Reproductive • Menstrual irregularities,- oligo/amenorrhea, reduced libido • Dermatological • Easy bruisability, striae, atrophy, hyperpigmentation, cutaneous fungal infections • Metabolic • Glucose intolerance, central obesity, buffalo hump, moon facies • Cardiovascular • Diastolic Hypertension, dyslipidemia, MI, Stroke, VTE • Musculoskeletal • Proximal myopathy, osteoporosis, • Neuro psychological • Emotional lability, Depression, Irritability, anxiety,panic attacks • Immune function • Increased frequency of infection, increased WBC • Opthalmologic • Glaucoma, cataracts
- 55. Diagnosis of hypercortisolism • Exclude exogeneous steroids and physiologic hypercortisolism • Low risk pts: one of the following • Salivary cortisol (two measurements) = >3x ULN • 24-hour urinary free cortisol (two measurements) • Low dose DST(overnight 1mg or 2 day 2mg test ) • High risk pts: • 2 or 3 of the above
- 57. Treatment • Surgical -resection of pituitary adenoma, adrenal tumor or ectopic ACTH-secreting tumor • Medical therapy • Indications • Management of hypercortisolism when surgery is contraindicated • Control of hypercortisolism in preparation for surgery • Persistence or recurrence of hypercortisolism after surgery • Control of hypercortisolism while waiting for the effect of pituitary radiation in patients with Cushing's disease • Treatment of occult ectopic ACTH syndrome
- 58. • Ketoconazole 200 mg BD/TDS - 400 mg TDS • Metyrapone; 250 mg BD/TDS, max 4.5g/d • Mitotane- 0.5 g nocte to a max of 2-3g/d • Pasireotide • Cabergoline- 1-7mg/week • Mifepristone
- 59. Pause
- 60. Disorders of the Adrenal Medulla
- 61. DOPA 1 Dopa decarboxylase Dopamine Dopamine fi- hydr oxyla se MAO ms and signs of phaeochromocytoma Tyrosine Tyrosine hydroxylase dopa Dopa decarboxylase Dopamine Dopamine fi-hydroxylase COMT MAO The synthesis and metabolism of catecholamines. COMT, catechol-O-methyl transferase; MAO, monoamine oxidase.
- 62. Catecholamine Synthesis and Degradation Copyright © 2022 Decker Medicine LLC. All rights reserved.
- 63. Effects of Catecholamines on Various Organs and Tissues Copyright © 2022 Decker Medicine LLC. All rights reserved.
- 64. Pheochromocytoma • Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla • norepinephrine, epinephrine, and dopamine
- 65. Epidemiology • Rare tumours . <0.2% of pts with HTN • most common in the 4th -5th decade. • M:F = 1:1 • Mostly sporadic . 40% with other familial disorder (VHL, MEN 2A/B, NF1)
- 66. Clinical features • Classic triad; • episodic headache • sweating • tachycardia • Sustained or paroxysmal hypertension –maybe absent in 10-15% • Headache -90% • Sweating- 60-70% • Pheochromocytoma crisis-Hyper/HOTN, fever>40°C, mental status changes, and other organ dysfunction
- 67. Other symptoms • Orthostatic hypotension • visual blurring, • Papilledema • weight loss, • Cardiomyopathy – due to catecholamine excess • Paroxysmal elevations in blood pressure
- 68. Rule of 10s •10% are extra-adrenal •~10% are bilateral •~10% are malignant •~10% are found in children •~10% are familial •~10% are not associated with hypertension •~10% contain calcification
- 69. Diagnosis • Indication for testing • The classic triad • Hyperadrenergic spells • HTN @ young age, resistant hypertension • A familial syndrome that predisposes to Pheochromocytoma • A family history of pheochromocytoma. • Adrenal incidentaloma with or without hypertension. • Pressor response during anesthesia, surgery, or angiography. • Idiopathic dilated cardiomyopathy. • A history of gastric stromal tumor or pulmonary chondromas (Carney triad).
- 70. • Approach • Low risk • 24-hour urinary fractionated catecholamines and metanephrines • High risk • plasma fractionated metanephrines.
- 71. • Positive case • 24-hour urine fractionated metanephrines and catecholamines: • Normetanephrine >900 mcg/24 hours or metanephrine >400 mcg/24 hours • Norepinephrine >170 mcg/24 hours • Epinephrine >35 mcg/24 hours • Dopamine >700 mcg/24 hours • Plasma fractionated metanephrines: • For an indwelling cannula, for 20 minutes following an overnight fast before the blood draw, metanephrine <0.3 nmol/L and/or normetanephrine <0.66 nmol/L • For venipuncture in a seated, ambulant, nonfasting patient: metanephrine <0.5 nmol/L and/or normetanephrine <0.9 nmol/ • The above cut offs exclude Pheo
- 72. Imaging • Follows biochemical tests to locate the tumor • CT scan -98-100% sensitive for sporadic cases, 70% specific • Increased attenuation on nonenhanced CT (most are >20 HU • Increased mass vascularity • Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of <50%) • Cystic and hemorrhagic changes • 7% demonstrate areas of calcification
- 73. Other imaging modalities • MRI- sensitivity of 98% • Useful esp for extraadrenal tumors • slightly hypointense on T1 and markedly hyperintense on T2 • I-123 MIBG (metaiodobenzylguanidine • PET scan
- 74. Treatment • Mainly Surgical – Adrenalectomy • Preop treatment • Alpha-adrenergic blockade for minimum 7 days • Phenoxybenzamine • 10 mg OD/BD, Increase by 10 to 20 mg in divided doses every 2-3 days • alpha-1-adrenergic blocking agents (prazosin, terazosin, or doxazosin)- for metastatic disease • Monitor BP BD. Target BP <120/80 • High sodium diet from day 2or 3 • Beta adrenergic blockade • Start 2 to 3 days before Sx after adequate alpha blockade • Propranolol 10mg Q6hrly or Metoprolol 12.5mg BD- day 1 • Increase to a long acting drug on day 2 • Titrate dose to maintain HR between 60 - 80 • Other agents- CCBs, Metyrosine
- 75. Hypertensive crisis • Sodium nitroprusside • infusion at 0.5 to 5.0 mcg/kg/min. Titrate to target BP • Phentolamine • Repeat 5 mg boluses or continuous infusion. • Nicardipine • 5 mg/hour and titrated for blood pressure control
- 76. Metastatic disease • No cure • iobenguane I-131 • Radioactive iodine (I131) attached to the MIBG molecule produces iobenguane I- 131 which functions as a semi-selective agent for malignant pheochromocytoma or paraganglioma.
- 77. REFERENCES • Broersen, L. H., Pereira, A. M., Jørgensen, J. O. L., & Dekkers, O. M. (2015). Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism, 100(6), 2171-2180. • Angelos, P., & Grogan, R. H. (2018). Difficult Decisions in Endocrine Surgery. New York: Springer International Publishing. • Upto date • http://www.endocrinology.org UK Society of Endocrinology • http://www.endo-society.org Endocrine Society • http://www.pituitary.org.uk The Pituitary Foundation (UK charity)
- 78. End
Editor's Notes
- Pair of endocrine glands above the kidney Retroperitoneal Together they weigh apx 8-10g in adults 90% of the weight is cortex
- Gerota Fascia firmly attaches them to the diaphragm.
- The adrenal glands are located 4 to 5 cm apart from each other. Between the two adrenal glands from right to left are the IVC, the right crus of the diaphragm, the right celiac ganglion, the celiac trunk, the superior mesenteric artery, the left celiac ganglion, and the left crus of the diaphragm.
- At Birth 50% drop in adrenal weight, as well as a decrease in the production of adrenal androgens , the definitive zone, possibly together with the transitional zone, develops into the fully differentiated zona glomerulosa and zona fasciculata by the age of 3 years. However, the zona reticularis appears only after 6 years of age and continues to thicken until puberty
- The adrenal cortex produces a complex array of steroid hormones, including glucocorticoids, mineralocorticoids, and androgens The medulla is part of the sympathetic nervous system and produces the catecholamines epinephrine and norepinephrine. Medulla only 10% of the entire gland
- Fasciculata contains long cords of large polyhedral cells, which are filled with lipid droplets and therefore appear vacuolated on a histologic examination. The zona fasciculata Reticularis This zone contains small cells that form a network of irregular cords and typically appears more heavily stained on histologic examination due to the fact that its cells contain fewer lipid droplets and more lipofuscin pigment. The zona reticularis
- Triggers of renin release: Hypotension, Hyponatremia, hypovolemia Zona Fasc. Stress Circadian rythms
- In the mid-1800s, Thomas Addison, an English physician, discovered that the adrenal cortex is essential for survival In 1940, Long and Fry demonstrated that glucocorticoids stimulate gluconeogenesis from amino acids and elicit steroid-induced diabetes
- Thomas Addison: Described it in 1855, note the hyperpigmentation= Vitiligo likely suggests an autoimmune Cause; Fatal in pregnancy Mayo Clinic team Isolated adrenal steroids: treated Rheumatoid arthritis and Addisons disease.
- Variation is about 7 fold, peak in the morning lowest at midnight
- Cholesterol is the substrate for the synthesis of all steroid hormones. The rate-limiting step in the process of steroidogenesis is the transport of free cholesterol through the cytosol into the inner mitochondrial membrane.
- Autoimmune adrenalitis : humoral and cell-mediated immune mechanisms directed at the adrenal cortex, often associated with autoimmune destruction of other endocrine glands (referred to as polyglandular autoimmune syndromes). Antibodies that react with several steroidogenic enzymes (most often 21-hydroxylase) and all three zones of the adrenal cortex are present in the serum of up to 86 percent of patients with autoimmune primary adrenal insufficiency (anti-21-hydroxylase.clinical findings are noted after 90% of the adrenal cortex has been destroyed. APS 1- childhood onset. By early 20s. Associated with adrenal insufficiency, hypoparathyroidism and mucocutaneous candidiasis. Other features primary hypogonadism, malabsorption . DM and autoimmune thyroiditis is uncommon APS 2 II (adult onset) Adrenal insufficiency, autoimmune thyroid disease, diabetes mellitus type 1. more common than type 1. Adrenal insufficiency is the initial manifestation in about 50 percent of patients, occurs simultaneously with autoimmune thyroid disease or diabetes mellitus in about 20 percent, and follows them in about 30 percent Other nonendocrine autoimmune disorders, such as vitiligo, myasthenia gravis, thrombocytopenic purpura, Sjögren's syndrome, rheumatoid arthritis, and primary antiphospholipid syndrome, occur occasionally Azoles inhibit CYP 450
- Three Problems Unanswered by endocrinologists: Delayed diagnosis Persistent presence of adrenal crisis Persistent problem with well being Features of peritoneal inflammation resulting in X Lap
- Symptoms are largely nonspecific the weight loss is primarily due to anorexia, but dehydration may contribute. The amount of weight lost can vary from 2 to as much as 15 kg and may not become evident until adrenal failure is advanced [29]. Skin hyperpigmentation (41 to 74 percent), due to increased production of proopiomelanocortin (POMC), a prohormone that is cleaved into the biologically active hormones corticotropin (ACTH), melanocyte-stimulating hormone (MSH), and others. The elevated MSH results in increased melanin synthesis, causing hyperpigmentation. *These changes are unusual in men, in whom most androgen production occurs in the testes Amenorrhea develops in approximately 25 percent of women. It may be due to the effects of chronic illness, weight loss, or autoimmune-mediated primary ovarian insufficiency
- Secondary and tertiary- present with symptoms of pituitary failure; Hyperpigmentation is not present, because corticotropin (ACTH) secretion is not increased; Dehydration is not present, and hypotension is less prominent; Hyperkalemia is not present, reflecting the presence of aldosterone; Hypoglycemia is more common in secondary adrenal insufficiency;there may be clinical manifestations of a pituitary or hypothalamic tumor, such as symptoms and signs of deficiency of other anterior pituitary hormones, headache, or visual field defects
- we suggest the 1 mcg low-dose ACTH test if new or recent onset ACTH deficiency is suspected (eg, one to two weeks after pituitary surgery). For all other patients, including those who are more than four months post-pituitary surgery, we suggest starting with the high dose ACTH stimulation test Tests should be done in the AM Secondary adrenal insufficiency — The low dose test may have advantages over the standard high dose test in some clinical settings, in particular, for the diagnosis of recent onset ACTH deficiency (secondary adrenal insufficiency) and chronic partial pituitary ACTH deficiency [20]. In patients with recent onset ACTH deficiency (eg, within one to two weeks after pituitary surgery), the adrenal glands have not yet become completely atrophic and are still capable of responding to ACTH stimulation. Only insulin-induced hypoglycemia or the metyrapone test is completely reliable in these patients [38,39]. The practical clinical importance of this limitation is unclea
- Insulin tolerance test Have 50% dextrose on standby. Pt fasts for 8 hrs before test. Must remain supine during procedure. Give 0.15iu/kg of regular insulin. Check glucose, cortisol and serum ACTH before insulin and then every 15 mins thereafter. Obtain last sample when adequate hypo is induced 1.9mmol/l (others 2.2mmol) (5-10 minutes after hypo or when pt starts to perspire). Hypoglycemia usually occurs 30 to 45 minutes after insulin injection. If adequate hypoglycemia is not achieved, a second similar dose of regular insulin should be injected intravenously. a normal serum cortisol response ranges from 18 to approximately 22 mcg/dL (500 to 600 nmol/L)
- eosinophilia, lymphocytosis, and neutropenia due to low cortisol; cortisol normally suppresses levels of eosinophils and lymphocytes normally de-marginates a portion of the neutrophil population which results in measurable neutrophil count
- Hydrocortisone has mineralocorticoid activity
- Excessive Production of aldosterone Adrenal is at the Zona Glomerulosa Part of RAAS: Increase BP Reduce K Increase Na Acts at DCT stimulating Na K Pump at the Chief cells to work harderNet effect is K excreated Na retained Water follows Na by osmosis Stimulate Proton ATPase pump in Alfa intercalated Cells Cause H_ excreation in exchange for HCO3 resulting in raised PH
- Unclear Cause of increased Aldosterone Producing cells in zona Glomerulosa Conns Adenoma causes increased Aldosterone Secreation Familial hyperaldosteronism: Z Glomerulosa Respond to Pituitary ACTH and Rennin The excess aldosterone initially stimulates Na + reabsorption by the renal collecting and distal tubules, causing the extracellular fluid volume to expand and the blood pressure to rise. When the extracellular fl uid expansion reaches a certain point, however, Na + excretion resumes despite the continued action of aldosterone on the renal tubule. This “ escape ” phenomenon is probably due to increased secretion of atrial natriuretic peptide. Because the escape phenomenon causes the excretion of excess salt, affected patients are not edematous. Aldosterone escape is due to; ANP Pressure natriuresis Reduced na-cl channels in the distal tubule hence less sodium reabsorption
- High rennin Levels due to HF, Chronic Decrease in BP Hyperaldosteronism Hypokalemia Hypernatremia HTN Alkalosis
- 11 beta hydroxysteroid dehydrogenaseis responsible for the conversion of cortisol to the inactive cortisone, preventing activation of the mineralocorticoid receptor by cortisol but permitting activation by aldosterone. Normally 11-hydroxysteroid dehydrogenase type 2 converts cortisol into inactive cortisone at the renal parenchyma (In order to prevent cortisol activation of the mineralocorticoid nuclear receptor and subsequent hyperaldosteronism)
- Cholesterol is the substrate for the synthesis of all steroid hormones. The rate-limiting step in the process of steroidogenesis is the transport of free cholesterol through the cytosol into the inner mitochondrial membrane.
- Meatbolic alkalosis -This disorder is largely due to increased urinary hydrogen excretion mediated both by hypokalemia and by the direct stimulatory effect of aldosterone on distal acidification. Aldosterone causes cardiac remodelling- LVH Polyuria , polydipsia- hypokalaemia causes nephrogenic DI Weakness due to hypokalaemia Hyperglycaemia- reduced insulin secretion, insulin seceretion is K dependent
- Obtain sample in the am (8am), in a seated ambulatory pt In primary hyperaldosterone, PRA or PRC is suppressed (PRA <1 ng/mL/hour; PRC less than the lower limit of reference range) and that the PAC is inappropriately high for the PRA (typically >15 ng/dL [416 pmol/L], but as low as 10 ng/dL [277 pmol/L]) ArR; aldosterone, renin ratio. Ratio of >20 is suspicious of primary Secondary hyperaldosteronism. Both PAC and PRA are increased and the ARR<10 Fludrocrtisone. 0.1mg eQ6 for 4 days +KCl. +ve if Aldosterone >6ng/dlon day 4 at 10am; Captopril-25-50mg given, 1 hr later. –ve if aldosterone is suppressed by >30% APA patients have higher aldosterone secretion rates, resulting in more severe hypertension, more profound hypokalemia (<3.2 mEq/L), and higher plasma (>25 ng/dL) and urinary (>30 mcg/24 hour) levels of aldosterone; these patients are also younger (<50 years) than those with IHA
- Plasma renin activity= PRA Plasma renin concentration =PRC Plasma aldosterone con= PAC In normal individuals, when the 24‐h urinary sodium excretion exceeds 200 mEq there is no reason to release renin or secrete aldosterone. Thus, a urinary aldosterone excretion of more than 33.2 nmol day−1 (>12 μg/24 h) in the setting of low PRA (or PRC) is consistent with autonomous aldosterone secretion
- An adrenal carcinoma should be suspected when a unilateral, large (>4 cm) adrenal mass is found on CT in a patient with primary aldosteronism Bilateral adrenal gland thickening or micronodular changes suggests adrenal hyperplasia; however, patients with hyperplasia may also have normal-appearing adrenal glands on CT . When a solitary, hypodense, unilateral macroadenoma (>1 cm) and normal contralateral adrenal morphology are found in a young patient (<35 years of age) with vigorous primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option
- 90% of cushings disease is by pituitary microadenoma . 5-10% pituitary macroadenoma (>1cm) Ectopic ACTh- SCLC, thymus, pancreas Ectopic crh- medullary thyroid cancers, pheochro
- hyperpigmentation occurs most often in patients with the ectopic ACTH syndrome, less often in those with pituitary overproduction of ACTH, and not at all in patients with adrenal tumors in whom ACTH secretion is suppressed. glucocorticoids inhibit the synthesis of almost all cytokines, apparently by inducing the synthesis of I kappa B alpha, a protein that traps and thereby inactivates nuclear factor kappa B. The granulocytosis is partly due to decreased margination and partly to a rise in circulating granulocyte colony-stimulating factor. Amenorrhea due to cortisol mediated inhibition of gonadotrophin release Excesss glucocorticoids suppress gonadotrophs with subsequent hypogonadism and amenorrhea and suppression of HPA axis resulting in reduced TSH secretion Steroids inhibit osteoblasts activity and increase osteoblasts apoptosis. They also inhibit calcium reabsorption in the GI
- Physiological hypercortisolism Pregnancy ●Patients with severe obesity, especially those with visceral obesity or PCOS ●Patients with psychological stress, especially patients with a severe major depressive disorder and melancholic symptoms ●Poorly controlled diabetes mellitus ●Rarely, chronic alcoholism ●Physical stress (illness, hospitalization/surgery, pain) ●Obstructive sleep apnea The low-dose DSTs are standard screening tests to differentiate patients with CS of any cause from patients who do not have CS. The high-dose DSTs are not used to make the diagnosis of CS. They are used after the diagnosis of CS is made to distinguish patients with Cushing's disease (CS caused by pituitary hypersecretion of ACTH) from patients with ectopic ACTH syndrome (CS caused by nonpituitary ACTH-secreting tumors). The overnight test consists of administration of 1 mg of dexamethasone at 11 PM to 12 AM (midnight), and measurement of serum cortisol at 8 AM the next morning. Failure to suppress cortisol level <1.8 mcg/dL (50 nmol/L) is diagnostic of cushing syndrome The two-day 2 mg test, consists of administering 0.5 mg of dexamethasone every six hours for eight doses, and measurement of serum (not urinary) cortisol either two or six hours after the last dose.
- Overnight 8 mg test — Dexamethasone (8 mg) is taken orally between 11 PM and midnight. A single blood sample is drawn at 8:30 and 9 AM the day before and the next day for measurement of serum cortisol and, if one wishes, plasma ACTH and serum dexamethasone. Interpretation — The test is interpreted by calculating the suppression of morning serum cortisol concentration on the day before and after dexamethasone administration, and considering a 50 to 80 percent or greater suppression to indicate Cushing's disease Most patients with Cushing's disease respond with ACTH and cortisol increases within 45 minutes after the intravenous administration of corticotropin-releasing hormone (CRH, Acthrel). Patients with adrenal tumors with increased urinary free cortisol and most with ectopic ACTH-secreting tumors do not respond because pituitary ACTH secretion is suppressed. Vasopressin or desmopressin (dDAVP) also stimulates ACTH release in most patients with Cushing's disease and usually induces a response similar to that of CRH; when given with CRH it can improve sensitivity in Cushing's disease. For CRH- acth increases by >40% at 15-30min while cortisol increases by >20% at 45-60minutes
- Inferior petrosal sinus sampling Used to document a central-to-peripheral ACTH gradient in the blood draining the tumor. The petrosal venous sinus drains the pituitary via the cavernous sinus . catheters are inserted via the jugular or femoral veins into both inferior petrosal veins. ACTH is measured in petrosal and peripheral venous plasma before and within 10 minutes after administration of CRH. Interpretation — A central-to-peripheral plasma ACTH gradient of ≥2.0 before CRH administration, or ≥3.0 after CRH, is diagnostic of a pituitary source of ACTH; Serum cortisol levels would remain unchanged with both low-level and high-level dexamethasone testing due to the lack of glucocorticoid receptors to facilitate negative feedback on the ectopic cells producing the ACTH. Anterior pituitary corticotrophs do have these receptors and, therefore, will be suppressed by any dose of dexamethasone.
- Metyrapone is an 11-beta-hydroxylase (P450c11) inhibitor that blocks the final step in cortisol biosynthesis Mitotane is an adrenocorticolytic drug that is used primarily for the treatment of adrenal carcinoma somatostatin analogue, pasireotide, and the dopamine agonist, cabergoline. Glucocorticoid-receptor antagonists (mifepristone)
- the approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 2 to 3 percent with NF1. 40 percent of patients with multiple endocrine neoplasia type 2A (MEN2A) and in approximately 50 percent of those with type 2B (MEN2B)
- Patients with symptoms related to paroxysmal elevations in blood pressure (hypertension, tachycardia, or arrhythmia) during diagnostic procedures (eg, colonoscopy), induction of anesthesia, surgery, with certain foods or beverages containing tyramine, or with certain drugs (such as beta-adrenergic blockers, tricyclic antidepressants, corticosteroids, metoclopramide or monoamine oxidase inhibitors [MAOIs]) should undergo formal evaluation for pheochromocytoma polyuria, polydipsia, constipation, increased erythrocyte sedimentation rate, insulin resistance, hyperglycemia, leukocytosis, psychiatric disorders, and, rarely, secondary erythrocytosis due to overproduction of erythropoietin he abnormalities in carbohydrate metabolism that occur (insulin resistance, impaired fasting glucose, apparent type 2 diabetes mellitus) are directly related to the increase in catecholamine production
- fractionated catecholamines (dopamine, norepinephrine, and epinephrine) and fractionated metanephrines (metanephrine and normetanephrine) Low risk ; Resistant hypertension Hyperadrenergic spells (eg, self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor) High risk A family history of pheochromocytoma ●A genetic syndrome that predisposes to pheochromocytoma (eg, MEN2) ●A past history of resected pheochromocytoma ●An incidentally discovered adrenal mass that has imaging characteristics consistent with pheochromocytoma (eg, unenhanced CT attenuation [measured in Hounsfield units (HU)] >10 HU, marked enhancement with intravenous [IV] contrast medium on CT with delayed contrast washout [<50 percent at 10 minutes], high signal intensity on T2-weighted magnetic resonance imaging [MRI], or cystic and hemorrhagic changes)
- Approximately 15 percent of the tumors are extra-adrenal, but 95 percent are within the abdomen and pelvis
- on the second or third day of alpha-adrenergic blockade, patients are encouraged to start a diet high in sodium content (>5000 mg daily) because of the catecholamine-induced volume contraction and the orthostasis associated with alpha-adrenergic blockade. This degree of volume expansion may be contraindicated in patients with congestive heart failure or renal insufficiency. the beta-adrenergic blocker should never be started first, because blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure Metyrosine inhibits catecholamine synthesis