DISEASES OF THE ADRENAL GLANDS CUSHING’S DISEASE (Hyperadrenocorticism) ADDISON’S DISEASE (Hypoadrenocorticism)

Adrenal Glands Adrenal gland: 2 layers - Medullary (center): responsible for Epinephrine & Norepinephrine - Cortical/Cortex (outer): Glucocorticoids, Mineralocorticoids, & Androgenic/Androgen hormone

ADRENAL GLANDS mineralocorticoids Glucocorticoids Androgens epinephrine Produced by Adrenal cortex (outer): Glucocorticoids promote gluconeogenesis, suppress immune response which decreases inflammation, and inhibit cartilage growth and development. Aldosterone is a mineralocorticoid: it regulates electrolytes and has an effect on water metabolism within the body. Androgens: identical to those produced by the testicles. SEX HORMONE.

Physiology Anterior Pituitary Gland releases Adrenocorticotropic hormone (ACTH) ACTH acts on the ADRENAL CORTEX Glucocorticoid hormone Mineralocorticoid hormone Sex hormones (Androgens) Sympathetic Nervous System stimulates the Adrenal medulla > Epinephrine and norepinephrine FIGHT OR FLIGHT RESPONSE ACTIVATED Increase HR, Inc. BP, Dilated air passages, GI function, vasoconstriction Norepinephrine: It's released into the blood as a stress hormone when the brain perceives that a stressful event has occurred (blood vessels) Epinephrine, more commonly known as adrenaline. Strong emotions such as fear or anger cause epinephrine to be released into the bloodstream, which causes an increase in heart rate, muscle strength, blood pressure (more on the heart)

Hormone Functions *** Regulates electrolyte and H2O balance Associated with Hypoadrenocorticism/ Addison’s Primarily dogs A decrease is life threatening Mineralocorticoids – Aldosterone Promote gluconeogenesis Suppress inflammation Suppress immune system Inhibit cartilage growth and development Associated with Hyperadrenocorticism / Cushing’s Glucocorticoids Glucocorticoids naturally produced by the adrenal gland stop the immune response, thus preventing inflammation from occurring.

Hyperadrenocorticism (Cushing’s Disease) Definition: Disorder caused by harmful effects of high circulating cortisol concentrations on multiple organ systems Systems affected: Renal Skin Cardiovascular Respiratory Endocrine/metabolic Musculoskeletal Nervous Reproductive Cushing’s disease occurs when excess Glucocorticoids are produced by the adrenal gland (in this case cortisol) Cortisol (a class of glucocorticoid) is a steroid hormone that is produced by the adrenal glands. When released into the bloodstream, cortisol can act on many different parts of the body and also increase the body's metabolism of glucose. Renal: cause high blood pressure which can result in kidney damage and kidney failure. Cushing's disease not only raises blood pressure, it also suppresses his immune system, which can result in bladder and kidney infections. Heart: Elevated HR (high BP) Reproduction: disrupt hormones important to reproduce (causes females to go into anestrus) Neurology: dull, behavior changes, weakness

Cushing’s Disease Causes: Anterior pituitary lesion (pituitary-dependent disease) – 85% of cases Adrenal tumor (excess cortisol secretion independent of pituitary control) – 15-20% of cases Overmedication with glucocorticoids - Iatrogenic Anterior pituitary lesion: Tumor sending ACTH to the adrenal gland causing it to produce excessive amounts of Glucocorticoid steroids. Adrenal tumor: Tumor on adrenal gland causing an excessive amount of Glucocorticoid steroids to be produced. Either too much ATCH is being produced or too much Cortisol is being produced (depends where the lesion is located) Iatrogenic: relating to illness caused by medical examination or treatment

Cushing’s Disease

Cushing’s Disease Bilaterally symmetrical alopecia: alopecia on both sides Bilaterally symmetrical alopecia, pot-belly, pyoderma

Cushing’s Disease Clinical Signs: Some are similar to hypothyroidism signs are slow to develop and usually go unnoticed by owner Clinical Signs: Some are similar to hypothyroidism PU/PD/PP Pot bellied; obese Muscle atrophy and weakness, lethargy, excess panting Bilateral symmetric alopecia; pruritis; pyoderma (↓ immune response) Calcinosis cutis (firm plaques of Ca++ under skin) Abnormal gonadal function (lack of estrus; soft, small testicles) -Immune response is suppressed to much. -The potbellied appearance is a result of the shifting of fat to the abdominal area and a weakening and wasting of muscle mass in the abdomen -Calcinosis cutis occurs when calcium crystals are abnormally deposited in the skin. The back, underarms and groin area are most commonly affected, but the lesions often start in one area and spread if the underlying cause is not controlled. Many animals with calcinosis cutis are itchy and uncomfortable.

Cushing’s Disease: Dx Chemistry Panel Urinalysis ↑ ALP, ALT, blood glucose Urinalysis Low USG < 1.015 due to PU/PD Urine cortisol/creatinine ratios Normal ratio=no Cushing’s Elevated ratio=may be Cushing’s (high levels of cortisol in the urine) Cortisol stimulate Gluconeogenesis: production of glucose (remember glycogen is glucose in the liver before it is secreted). This results in elevated liver enzymes and high glucose levels. Cortisol is produced so much it goes into the urine. This increased blood cortisol concentration results in increased loss of cortisol into the urine. Therefore, the urinary cortisol/creatinine ratio is usually increased in animals with Cushing's disease. Creatinine is a chemical waste product in the blood that passes through the kidneys to be filtered and eliminated in urine (in this case kidneys are not working correctly)

ACTH Stimulation for Hyperadrenocorticism ACTH Stimulation test Normal patients show an increase of plasma cortisol Pituitary dependent disease (excess ACTH release) and Adrenal tumors: 60- 85% show EXAGGERATED cortisol response Does not differentiate between Pituitary tumor and Adrenal tumor ACTH Stimulation Test Procedure Take a baseline blood sample to detect cortisol levels Inject ACTH stimulation gel or liquid Wait two hours and take a post sample to look for a rise in cortisol ACTH stimulation test will not show the difference between pituitary or adrenal tumor because either way the cortisol will be elevated with either type of tumor. The Cortisol will be elevated because the ACTH will stimulate more production of Cortisol on top of the excess amount that is already being produced. NOT THE BEST TEST TO DIAGNOSE THIS CONDITION

Cushing’s Disease: Dx Low-Dose Dexamethasone Suppression Test Draw a blood sample to determine baseline cortisol levels Inject low dose of steroid (goal is to suppress ant. pit [ACTH]) Measure plasma cortisol at 4 & 8 hr later Interpretation: Normal dogs will show decrease in plasma cortisol A Cushingoid animal will not show any decrease of cortisol at 8 hr In a normal patient, cortisol will decrease because the Dexamethasone will decrease the production of ATCH If the dog has cushing’s the cortisol will not show any decrease because production is increased even with the suppression of ATCH

Cushing’s Disease: Dx High-Dose Dexamethasone Suppression Test (used to differentiate between Pit Dis and Adrenal tumor) Collect plasma cortisol at 0, 4, and 8 h Interpretation: Pituitary dependent disease—70-75% will show decrease of cortisol at 4 or 8 h Adrenal tumor—no decrease in plasma cortisol level because tumor is autonomous If a pituitary tumor, ATCH will be decreased, thus resulting in a decrease in Cortisol, if it is an adrenal tumor, the cortisol will still be high because decreasing the ATCH will not affect the production of Cortisol if the problem is within the adrenal gland. Autonomous: self controlled (this case, controlled by a adrenal gland tumor)

Cushing’s Disease: Rx Surgical removal Medical treatment Adrenal tumor - Specialized surgery; most vets would refer surgery Pituitary tumors are not surgically removed Medical treatment Lysodren (mitotane)—necrosis of zona fasiculata, zona reticularis repeat ACTH stimulation q 7-10 d until cortisol normal excess dose affects zona glomerulosa (Addison’s Dis) Pituitary tumor: difficult, better to try radiation for this type of tumor zona fasiculata/zona reticularis: portion of the cortex that produces Cortisol zona glomerulosa: secretes mineralcorticoids -excessive dose could damage this part, causing Addison’s disease (decrease in Mineralcorticoids)

Cushing’s Disease: Rx Medical management Vetoryl®(trilostane): less side-effects than mitotane interferes with cortisol production (doesn’t kill cells) Works by blocking the enzymes within the adrenal gland that produce Cortisol (life long, but less dangerous)

Cushing’s Disease: Client info Serious disease; life-long treatment Periodic monitoring required Addison’s disease may result from treatment Prognosis: average life expectancy is 20-30 mo on therapy with frequent recurrence of clinical symptoms

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Addison’s Disease (Hypoadrenocorticism) Definition: Disorder caused by deficient production of glucocorticoids (cortisol) or mineralocorticoids (aldosterone) or both Iatrogenic disease caused by chronic administration of corticosteroids followed by sudden cessation MOST Idiopathic if not caused by steroid administration/neoplasm/hereditary RARE DISEASE IN DOGS, RARER IN CATS Iatrogenic: caused by treatment (excess steroid use in this case) Once steroids are stopped, it can take a long time for the brain to resume sending this signal, which causes adrenal insufficiency (that’s why you taper patients off steroids)

Addison’s Disease (Hypoadrenocorticism) Clinical Signs: lethargy, weakness, anorexia, wt. loss Vomiting/Diarrhea PU/PD, dehydration Bradycardia

Addison’s Disease Pathophysiology Decreased aldosterone => decreased retention of Na=> decreased blood volume =>hypotension, dehydration, azotemia Hyperkalemia affects the heart => bradycardia Glucocorticoid deficiency => vomiting, diarrhea, melena, lethargy, wt. loss, hypoglycemia Sodium keeps normal balance of fluids Mineralcorticoid: Aldosterone causes sodium retention and Potassium secretion. With Addison’s the patient has decreased sodium retention which results in decreased blood volume (hypotension), dehydration (which results in azotemia) – due to decreased blood flow to kidneys. Normally, Aldosterone increases potassium secretions within the kidneys, in this case potassium is not being secreted due to decreased Aldosterone, resulting in hyperkalemia, resulting in bradycardia Overall: Low sodium/high potassium

Addison’s Disease: Dx Chemistry Panel Na:K ratio <25:1!(normal=27:1 to 40:1) ACTH Stimulation test (definitive test) normal dog= ↑ cortisol hypoadrenocorticism dog= low, unchanged cortisol level Test Endogenous ACTH - will be increased due to lack of neg. feedback Give ACTH to see if this causes an increase in Cortisol, if it does not work and Cortisol stays low, the patient has Addison’s Test Endogenous ACTH: This will be high because negative feed back will not be decreasing ATCH production like it should because the Aldosterone/Cortisol will not be high enough to tell the ACTH to decrease (ACTH still doing its job, but Aldosterone/Cortisol will not be increasing)

Addison’s Disease Example Chem Panel (What is not normal?) Parameter Value Normal value BUN 81 mg/dl 7-27 mg/dl Creatinine 2.1 mg/dl 0.4-1.8 mg/dl Sodium 131 meq/L 141-156 meq/L Potassium 6.5 meq/L 4.0-5.6 meq/L Na:K ratio 20 27-40 Kidney values will be elevated because kidneys are not functioning appropriately. Potassium is high because Aldosterone is decreased resulting in high levels of potassium because it is not being secreted like it should. Sodium potassium ratio is decreased. The Na:K ratio is calculated from the patients blood sodium level divided by its blood potassium level

Addison’s Disease ACTH Stimulation Test Results Value Normal Plasma Cortisol Pre-ACTH 0.2 2-6 Post-ACTH 0.3 6-18 Rare case if it caused by an issue with the Anterior Pituitary gland, then the ACTH will be decreased before and after. This means it is not stimulating the Adrenal gland to produce Cortisol or Adoesterone.

Addison’s Disease: Rx Acute Crisis may be life-threatening situation Normal saline IV low Na+ is hallmark finding of Addison’s Glucocorticoid replacement cortisol will also be low Dexamethasone or Prednisone IV or IM Mineralocorcorticoid replacement Florinef® (fludrocortisone acetate) - PO Percortin-V (desoxycorticosterone pivalate) injection Florinef: It works by reducing salt loss, increasing potassium loss, and increasing blood pressure Percortin-V: Corticoid steroid

Addison’s disease: Rx Chronic Management Glucocorticoid replacement Prednisone Mineralocorcorticoid replacement Florinef® (fludrocortisone acetate) - PO daily Percortin-V (desoxycorticosterone pivalate) – inj. given ~monthly Monitor electrolytes, BUN/Creatinine, clinical signs Percortin-V: Given IM, but can be given SQ

Addison’s disease: Client info Mineralocorticoid deficiency is life-threatening Animal requires periodic blood tests Always remind attending vet of pet’s condition Hormone replacement therapy continued for life of pet Prognosis: Good to excellent after stabilization and treatment