Addison s Disease. Disclosures. Ringo 9/8/2016. Consulting, AVL Laboratories, St. Louis, MO. Signalment: 2 ½ year old, MC, Gt Dane History:

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1 Addison s Disease Stanley I. Rubin, DVM, MS Diplomate ACVIM Clinical Professor Department of Veterinary Clinical Medicine Disclosures Consulting, AVL Laboratories, St. Louis, MO Ringo Signalment: 2 ½ year old, MC, Gt Dane History: Listlessness Decreased appetite Wt loss (10 lbs) Diarrhea X24 hrs Pu/PD 1

2 Physical Examination BCS 4/9, Wt 110 lbs (50 kg) Vital signs: HR 132, RR 24, Temp Otherwise NAF Ringo Differential Diagnoses Pu/Pd Kidney dz Hyperadrenocorticism DM/DKA Pyometra Hypercalemia Liver dz Hypoadrenocorticism Hypokalemia Drugs Psychogenic Diarrhea Primary GI Dietary indiscretion/toxins Infectious Obstruction/FB/Intusscep tion Acute pancreatitis IBD Neoplasia Secondary GI/Systemic Uremia Hypoadrenocorticism Hypercalcemia Liver dz Ringo Diagnostic Plan CBC Serum biochemistry Urine analysis 2

3 Ringo Laboratory Na+ 135mEq/L ( ) K+ 5.4 meq/l ( ) Chloride 105 meq/l ( ) BUN 32 mg/dl (6 30) Creatinine 1.4 mg/dl ( ) Cholesterol 101 mg/dl ( ) Glucose 69 mg/dl (68-126) Ringo Laboratory WBC 13.8 ( ) Neutrophils 6.9 (3 11.5) Lymphocytes 5.7 (1-4.8) Hematocrit 56.8 (35 52) Most Significant Abnormalities Hyponatremia/Hypochloremia Abnormal Na/K ratio (25:1) Mild azotemia/non-concentrated urine Non-stress leukogram Hemoconcentration Next steps? 3

4 Ringo Next Steps Resting cortisol < 27.6 nmol/l Cortisol (1 hr post ACTH) < 27.6 nmol/l Ringo Diagnosis: Hypoadrenocorticism Rx: DOCP 110 mg Prednisone 12.5 mg/day (0.25 mg/kg/day) Recheck Wk 4 Doing well at home, appetite is normal Gained 3.6 kg Beau Signalment: 8 month, MC, Labradoodle History: Presented to ER on day 1 5-day history of anorexia Vomiting Rx: IV fluids, ondansetron, doxycycline 4

5 Beau History: Declined after discharge Represented to ER on day 5 Vomited that day Physical Examination QAR BCS 3/9, Wt 42 lbs (19.2 kg) Vital signs: HR 120, RR 40, Temp Otherwise NAF Beau Laboratory (Nova ) Na+ 131mEq/L ( ) K+ 6.7 meq/l ( ) Chloride 105 meq/l ( ) BUN 25 mg/dl (9 24) Creatinine 1.4 mg/dl ( ) Calcium, ionized 1.48 ( ) Received IV fluids 5

6 Beau Laboratory WBC ( ) Neutrophils (3 11.5) Lymphocytes 3.94 (1-4.8) Hematocrit 52.9 (35 52) Beau Hypoadrenocorticism Failure of adrenal glands to secrete normal quantities of corticosteroids to support normal homeostasis Big reserve > 85% of mass must be lost before c/s Most common is primary adrenal failure dt deficiency of both glucocorticoids and mineralocorticoids 6

7 Normal Function Adrenal medulla catecholamines Adrenal cortex mineralocorticoids, androgens and cortisol Synthesis and secretion of cortisol hypothalamic pituitary axis CRF from hypothalamus stimulates secretion of ACTH from pituitary ACTH stimulates secretion of cortisol Cortisol has negative feedback on CRF and ACTH release Normal Function Aldosterone secretion regulated by reninangiotensin axis, plasma [K+] Increased plasma K+ and angiotensin II stimulate aldo release from adrenal Glucocorticoids Stimulate hepatic gluconeogenesis and glycogenolysis Important in maintaining vascular reactivity to catecholamines Maintain normal BP Counteract effects of stress Normal Function Mineralocorticoids Increase absorption of Na+ and secretion of K+ from the kidney, sweat glands, salivary glands and intestinal epithelial cells Conserve Na+ and maintain vascular volume 7

8 Etiopathogenesis Most dogs classified as idiopathic Immune-mediated adrenalitis May be concurrent with other endocrine disorders such as hypothyroidism, dm and hypoparathyroidism Unusual causes Granulomatous destruction Hemorrhagic infarction Necrosis Metastatic neoplasia Lysodren, trilostane Signalment 70% of affected dogs are female Median age of onset for all breeds 4 years (4 months to 14 yrs) Inherited in Standard Poodle, Portuguese Water Dog, Nova Scotia Duck Tolling Retriever, Bearded Collie Increased risk in many breeds, eg. Great Dane Most Commonly Diagnosed Breeds Mixed 24% Toy or miniature poodle 10% Labrador retriever 9% Rottweiler 9% Standard poodle 8% German Shepherd dog 6% Doberman Pinscher 4% Golden Retriever 4% West Highland White Terrier 4% Great Dane 3% 8

9 30-40% of dog population insured in Sweden 534 dogs diagnosed with Addison's 64% female Breeds at highest risk: Standard poodle, Bearded Collie, Portuguese Water Dog, Cairn Terrier and Cocker Spaniel Decreased risk in German Shepherd Dog and Dachshund Female dogs 1.85 X greater risk than males History Acute illness Gradual in onset, waxing/waning c/s Illness may be triggered by stressful event Vague signs Anorexia, vomiting/diarrhea, lethargy, weakness, wt loss Pu/Pd Abdominal pain Dehydration, hypovolemic shock, collapse 9

10 History Vague signs Less common: seizures, episodic muscle cramping, GI hemorrhage Many owners unaware of what constitutes a normal pet Some dogs have been ill much of their lives Periods of good health often followed by nonspecific veterinary care Physical Findings Often vague/nonspecific Poor body condition Lethargy, weakness, hypothermia, Weak pulses, prolonged CRT, signs of shock Laboratory Findings Classic findings Hyponatremia/hyperkalemia Non-regenerative anemia Lymphocytosis 10

11 Hematologic Abnormalities Non-regenerative anemia; may be masked by hemoconcentration Eosinophilia; normal eosinophil count in stressed or ill dog Lymphocytosis; normal or increased counts in ill or stressed dog Above changes only seen in 10-30% of dogs Absence of stress leukogram 90% of cases Upside down CBC Serum Chemistry Hyperkalemia Hyponatremia Mild metabolic acidosis Azotemia with USG < (60% of dogs) Hypercalcemia Hypoglycemia Hypoalbuminemia Na + /K + Ratio A red flag A tool for gaining suspicion of dogs with adrenal insufficiency Normal > 27:1 Values < 27:1 consistent with primary hypoadrenocorticism 11

12 Abnormal Na + /K + Ratio Intestinal parasitism; trichuris/ancylostoma Perforated duodenal ulcers Salmonellosis Diabetes mellitus Pleural effusion Artifact: Akita, hemolysis, marked leukocytosis, thrombocytosis Imaging Microcardia Small cranial lobar pulmonary artery Narrow caudal vena cava Microhepatica Megaesophagus Adrenal glands small or cannot be id d Endocrine Studies Basal/resting cortisol Some normal dogs will have low baseline cortisol yet have normal response to ACTH [cortisol] < 55 nmol/l (2 µg/dl) are suggestive of but not diagnostic for hypoadrenocorticism A baseline [cortisol] > 55 nmol/l (2 µg/dl) does not support diagnosis of hypoadrenocorticism 12

13 Endocrine Studies ACTH stimulation test Gold Standard Need to confirm diagnosis life long treatment Baseline and 1 hr post ACTH Most dogs resting & post-acth < 1 ug/dl (<27.6 nmol/l) Occasionally see borderline results ; post- ACTH [cortisol] between 55 and 110 nmol/l May occur with secondary hypoadrenocorticism or relative adrenal insufficiency Synthetic ACTH - Corsyntropin Endocrine Studies Endogenous [ACTH] If above reference range then confirms diagnosis of primary hypoadrenocorticism If below reference range consistent with secondary hypoadrenocorticism Plasma [Aldosterone] Assays not widely available May be useful in dogs with pure glucocorticoid deficiency Aldosterone-to-renin/Cortisol-to-ACTH hormone ratios Only need one blood sample Assays not readily available Treatment Acute management Treat for shock Run diagnostics concurrently Can t confirm diagnosis once replacement therapy initiated IV catheter Normal (0.9%) saline Collect sample for baseline [cortisol] Give ACTH Collect second sample 1 hour after give ACTH Can give dexamethasone Emergency treatment for hyperkalemia Monitor ECG Can give DOCP or fludrocortisone 13

14 Maintenance Therapy Glucocorticoid replacement DOCP lacks glucocorticoid activity Physiologic dose of prednisone ( mg/kg) Gradually taper to lowest dose that prevents signs of hypoadrenocorticism May only need EOD Maintenance Therapy Glucocorticoid replacement Avoid excess supplementation 50% of dogs given fludrocortisone require glucocorticoid therapy > 90% of dogs given DOCP require glucocorticoid therapy Owner should have prednisone to give to dog in time of stress, mg/kg twice a day DOCP Desoxycorticosterone pivalate Only FDA approved drug Some consider it treatment of choice 2.2 mg/kg every 25 days Interval may be increased to every 30 days or longer 14

15 Recheck at 12 & 25 days after first 2 or 3 DOCP injections Increase dose if dog has hyponatremia or hyperkalemia Shorten interval if day 12 profile is normal but abnormal at day 25 DOCP Fludrocortisone Florinef and generics 0.02 mg/kg PO once daily or divided Initially reassess electrolyte every 1 2 wks Goal is to reestablish normal Na+ and K+ concentrations Some report that dose requirement increases over time Fludrocortisone Wide range in doses required to control electrolyte concentrations Dog may develop Pu/Pd and urinary incontinence 15

16 Recheck Visits Some recommend weekly after first start fludrocortisone Some recommend every 12 and 25 days with DOCP Expectation is that dog feels well Consider amount of glucocorticoid supplementation Aypical Hypoadrenocorticism Signs of glucocorticoid deficiency Serum electrolytes normal Deficiency could adrenocortical (Most common) or pituitary (impaired secretion of ACTH) May be early sign of failure and mineralocorticoid deficiency wks or months later Aypical Hypoadrenocorticism Diagnosis Vague GI c/s: lethargy, anorexia, vomiting, diarrhea, wt loss Normal routine blood tests Abnormal ACTH stimulation test Need to periodically check electrolytes 16

17 Questions? References available on request 17