1	Canine Cushing's Syndrome: HAC Review & New Jonathan M. Fradkin, DVM, MS, DACVIM (SAIM) San Antonio Veterinary Referral Specialists Adjunct Lecturer, TAMU Department of Small Animal Medicine & Surgery Presented to Bexar County VMA, January 13 2004.
2	HAC: Goal Review, Update, Stimulate Thought Common Disease But Still Controversial Knowledge of Pathophysiology Developing Variable Diagnostic Criteria, Test Interpretation Best of Current Tests v.s. New Tests Best of Current Drugs v.s. New Drugs Experts Often Don’t “Do It” the Same Way They Teach It No One Answer Fits All Cases
3	Canine Cushing's: HAC Review & New Basic Pathophysiology and Forms Iatrogenic Pituitary Dependent Adrenal Dependent/Tumor Classic Signs and Complaints Diagnostic Tests Screening Tests: Is it Cushing's Differentiation Tests: PD vs. AD Treatment Options
4	HAC Physiology: Normal HPA Axis Hypothalmus = CRH, Dopamine Anterior Pituitary Gland = Adenohypophysis Pars Distalis = ACTH (major portion) Pars Intermedia = ACTH (minor portion) Sometimes listed as Intermediate Lobe Adrenals Zona Reticulosa and Fasicula = Cortisol Glomerulosa = Aldosterone Medulla = Catacholamines
5	HAC: Normal HPA Axis
6	HAC: Normal HPA Axis Not That Simple Hypothalmus CRH* GHRH* TRH Dopamine * ADH* (via Post Pit) Anterior Pituitary ACTH* GH* FSH LH TSH Posterior Pituitary Prolactin ADH Adrenal Cortex Aldosterone* = ZG Cortisol* = ZF (ZR) Androgens = ZR 17-Hyroxyprogesterone* Testosterone Estradiol* Others* Adrenal Medulla Epinephrine Norepinephrine
7	HAC: Normal HPA Axis Not That Simple
8	HAC: Abnormal HPA Axis & Forms of Cushing’s Syndrome Cushing’s Syndrome = Collection of Signs Due To Excessive Glucocorticoids From Any Source Iatrogenic Pituitary Dependent (PDH) ~ 85% of NonIatrogenic º Cushing’s Disease = PDH Cushing’s Syndrome Adrenal Tumor (AT) ~15% of NonIatrogenic Mixed – Rare But Reported Multiple Pituitary Tumors Bilateral Adrenal Tumors Concurrent Pituitary and Adrenal Tumors Spontaneous Disease Masked by Iatrogenic
9	HAC: Iatrogenic Cushing’s Syndrome Due to External Supplementation of Glucocorticoids Prescribed or Over-the-Counter Route, Dose, and Duration Impact Syndrome Parenteral Oral Topical - Cutaneous, Ophthalmic, Otic Glucocorticoids Suppress Cortisol Production Direct Effect on Adrenal Glands Indirect Effect due to Suppression of ACTH Production Easy Form to Overlook or Forget
10	HAC: Iatrogenic Cushing’s Syndrome
11	HAC: Pituitary Dependent (PDH) Cushing’s Disease 80-85% of Spontaneous Canine Cushing's Due to Excessive Production of ACTH Pars distalis (70-88% PDH, 60-75% HAC) Microadenoma (or Hyperplasia) Production of ACTH Normal Size Anterior Pituitary = 50-90% Macroadenoma Production of ACTH Enlarged Size Anterior Pituitary = ~ 10-50% Pars intermedia (12-30% PDH, 10-25% HAC) Increased ACTH Due to Decreased Dopamine Suppression or Increased ACTH due to Production by Adenoma (Hyperplasia) Increased ACTH leads to Increased Cortisol from both Adrenal Glands Response of Pituitary Tumors to CRH Stimulation and Cortisol Negative Feedback is Variable.
12	HAC: PDH (Classic) Cushing’s Disease
13	HAC: PDH (Alternate) Cushing’s Disease
14	HAC: Adrenal Tumor (AT) Cushing’s Syndrome 15-20% of Spontaneous Canine Cushing’s Due to Excessive Production of Cortisol from Adrenal Tumors ~50% Malignant (~7.5% of HAC) ~ 50% Benign (~7.5% of HAC) Usually Unilateral Excessive Cortisol from AT Suppresses CRH, ACTH, & Cortisol (Opposite Adrenal) Production Most AT are NOT Sensitive to ACTH or Feedback Suppression from Dexamethasone or Cortisol
15	HAC: AT Cushing’s Syndrome
16	HAC Physiology Review
17	HAC: Clinical Texts & References The “Bible” – Feldman & Nelson, “Canine & Feline Endocrinology & Reproduction,” W.B. Saunders, 1996 Most common clinical text, easy quick review Recent Publications & Discussions – last 5 years (VIN Search) 49 Papers in Major Veterinary Journals 50 Presentations at Major Meetings
18	HAC: Diagnostic Keys NEVER Undervalue Clinical History & Findings of Routine PE & Clinical Pathology Screening Test = Used to Rule-In a Disease. Highly Sensitive & Followed by a Confirmatory Test Sensitivity = A Measure of False Negative Rate , High Sensitivity Prevents MISSED Diagnosis (70% Sensitive Means 30 of 100 With Disease are Missed) Specificity = A Measure of False Positive Rate, High Specificity Prevents MIS-Diagnosis (70% Specific Means 30 of 100 Diagnosed Don’t Have It)
19	HAC: Diagnostic Keys In HAC We Discuss Screening Tests and Differentiation Tests We Actually Use the “Screening Test” to Confirm Diagnosis by Combining Test Result With: History Physical Examination Findings Routine Clinical Pathologic Findings Clinical Experience & Intuition Then use Differentiation Test to Diagnose Type Dx Can Be Tough – If Signs Suggestive & First Test is Negative, Try Another Test. Series of Tests May Be Needed.
20	HAC: Signalment Age: Any Age for Iatrogenic Middle-age to Older, Similar for PDH vs. AT PDH Mean 10 yo AT Mean 11.3 yo Gender: 55-65% Female (50:50 in Some Studies) Breeds: PDH = GSD, Beagle, Dachshund, Boston Terrier, Boxer AT = GSD, Poodles, Dachshunds, Labradors, Terriers Size: IAW Breed, Trend for PDH in Smaller Dogs PDH = 75% under 20 kg AT = 45-50% over 20 kg
21	HAC: History/Chief Complaints N&F = “…a clinical disorder, animals with this disease have some associated clinical signs.” PU/PD/PP (80-90%) Lethargy/Weakness (75-85%) “Pot Belly”/Muscle Atrophy (90-95%) Panting Hair Coat Changes, Alopecias (80-100%) Skin Infections/Pyodermas (50-60%)
22	HAC: Physical Examination Hyperpigmentation, Bilateral Symmetric Alopecia Hepatomegaly Testicular Atrophy/ Clitoral Hypertrophy Ectopic Calcification Calcinosis Cutis (Pathognomonic) Bronchial Calcification – On Thoracic Radiographs Bruising As Per History
23	HAC: Routine Clin.Path. Stress Leukogram ~80% Lymphopenia, Eosinopenia ~ 20% Leukocytosis Biochemistries ALP - mod increase in ~95% of HAC ALT – mild increase Other = Variable Urinalysis Usually dilute (<1.013 USG) UTI ~40-50% (May have “Quiet” Sediment)
24	HAC: Secondary & Concurrent Diagnoses & Complications Neurologic Macroadenoma Confusion/Altered Mentation Seizures Blindness Pacing Anorexia Infections-Sepsis Immune Suppression “Resistant” Diabetes mellitus Thromboembolism/ Hypercoagulation Hypertension Pulmonary Mineralizaton Hypoxemia
25	HAC: “Screening” Tests Answers Does the Dog Have HAC? Yes or No = Used for Diagnosis Not Just Screening Elevated ALP Resting Cortisol Urine Cortisol Creatinine Ratio (UCCR) Corticotropin (ACTH) Stimulation Low Dose Dexamethasone Suppression (LDDS) Combined ACTH Stimulation High Dose Dexamethasone Suppression
26	HAC Screening: Increased ALP Protocol = Simple Evaluation of ALP from a Routine Serum Chemistry Panel Basis = Steroid Induction of ALP Should Result in Increased ALP in Most HAC Highly Sensitive - ³ 95% Very Low Specificity Normal ALP often used to “Rule-out” HAC but elevated ALP not helpful to “Rule in’ HAC
27	HAC Screening: Resting Cortisol Protocol = Measure Serum Cortisol at a “Random” Time (Time of Clinic Visit) Basis = Cortisol is Secreted in Cyclic or Pulsatile Manner But Expect Trend Toward Higher Concentrations with HAC No Reported Sensitivity/Specificity Found Thought to be Highly Sensitive = Normal Resting Cortisol makes HAC unlikely but not impossible. Thought to be Low Specificity = Many Normal or NonAdrenal Diseased Dogs will have High Resting Cortisol Stress of Clinic Visit and Blood Draw?
28	HAC Screening: Resting Cortisol Expectation = HAC Will Have High Cortisol IDEXX Normal = 2-6 mg/dl No Diagnostic Guideline Antech Normal = 1-4.5 mg/dl No Diagnostic Guideline Cost: ~1/2 as much as LDDS, 1/4-1/3 of ACTH Stim (but is the inexpensive information really useful??) Comments: Indeterminate Sensitivity & Specificity Makes This Questionable For Ruling In or Ruling Out HAC.
29	HAC Screening: UCCR Protocol = Evaluate Ratio of Urine Cortisol to Creatinine at a “Random” Time & Compare to the Ratio Defined as “Normal” Some Recommend Use of Supernatant Basis = a Point Estimate of Total Urine Cortisol Excretion. If Have High Serum Cortisol There Should be Increased Urine Cortisol Loss Highly Sensitive = 75-100% Depending on Cutoff Not Very Specific = 20-25% Increased Specificity With Home Collection
30	HAC Screening: UCCR Expectation: HAC Will Have High UCCR IDEXX Normal < 13.5x10^-6 Diagnostic Guidelines, “> 13.5x10^-6 Indicate Elevated Cortisol But May Be Adrenal or Nonadrenal Disease” Antech Normal <20x10^-6 Diagnostic Guidelines, “Increased Ratio Suggests HAC, But Can Also Be Induced By Stress.” Cost: ~1/2 of LDDS, 1/3 of ACTH Stim (but is the inexpensive information useful??)
31	HAC Screening: UCCR Comments Fits the True Definition of a Screening Test Is Not Useful as a Canine Diagnostic Test Normal UCCR Makes HAC Unlikely, Helps Rule out HAC Abnormal UCCR Must be Followed with Another “Screening” Test Some Reports of Higher (Diagnostic) Specificity Used a Higher “Normal” Ratio & Therefore Had Lower Sensitivity
32	HAC Screening: ACTH Stimulation Protocol = Measure Serum or Plasma Cortisol Before & After ACTH Injection Natural ACTH Gel (Acthar) = Questionable Effect in Some Dogs with Some Drug, Limited Availability. 2.2 IU/kg IM with Post-Sample at + 1 or + 2 Hours Synthetic Aqueous ACTH (Cosyntropin or Cortrosyn) = Expensive, Sometimes Difficult to Obtain, Post-Sample at +1 Hour Widely Accepted N&F: 250mg/dog (one bottle) IM 5 mg/kg IV = Allows Two Tests per Bottle for Average 20kg Dog, Reduced Cost Can Store Frozen In Plastic Syringes Up To 6 Months
33	HAC Screening: ACTH Stimulation Basis = Only Test Useful for Iatrogenic HAC With Iatrogenic Disease Adrenals Should be Too Suppressed to Respond to ACTH so No Cortisol Increase Both AT and PDH Should Respond to SupraPhysiologic ACTH so Cortisol Should Start High & Increase With PDH There Should be Adrenal Hyperplasia With Increased Capability to Produce Cortisol. With AT the Tumor Should Have Increased Capability to Produce Cortisol.
34	HAC Screening: ACTH Stimulation Sensitivity = ~ 80% Overall For HAC 85-90% for PDH 50% -60% for AT (e.g. Some Tumors Not Responsive to ACTH so no Post-ACTH Increase in Cortisol) Specificity = 82-91% Highest Specificity Test Available Low False Positive Rate Often Recommended as Best Test for HAC in Dogs with Possible NonAdrenal Disease
35	HAC Screening: ACTH Stimulation Expectation: HAC Cortisol Concentration Starts High With Big Increase IDEXX Normal: Pre 2-6 mg/dl, Post 6-18 Diagnostic Guidelines, “Post 18-22 Equivocal, Post >22 Consistent with HAC.” Antech Normal: Pre 1-4.5 mg/dl, Post 5.5-20 Diagnostic Guidelines, “Post >20 Suggests HAC. Iatrogenic HAC Resting Usually 1-5 With Little Increase” Cost: Generally Similar or more expensive than LDDS depending on Patient Size and ACTH dosage
36	HAC Screening: ACTH Stimulation Comments Always Remember This Is Only Useful Test if Recent History Of Steroid Treatment Easy & Fast for Staff & Client Combines Highest Specificity with Good Sensitivity Overall Good as a Diagnostic Test Some Papers Report Sensitivity Similar to LDDS
37	HAC Screening: LDDS Protocol = Measure Serum or Plasma Cortisol Before & After (+4 and +8 Hours) After Administration of 0.01-0.015 mg/kg Dexamethasone ONLY the Eight Hour Sample is Interpreted During Screening (Diagnosis) of Canine HAC Evaluation of the Four Hour Sample MAY Be Useful for Differentiation
38	HAC Screening: LDDS Basis = The Normal Adrenal Gland Should Be Suppressed, e.g. Not Produce Cortisol, After Administration of Dexamethasone. The Diseased HPA Should Not Be Suppressed by Dexamethasone Sensitivity = 85-100% For Detection of HAC Yes or No Specificity = 44-73% For Detection of HAC Yes or No
39	HAC Screening: LDDS Expectation = No Suppression at Eight Hour Sample For HAC IDEXX Normal: Pre = 2-6 mg/dl, Post <1.5 Guidelines: 8 hour Post-Dex > 1.5 likely have HAC Antech Normal: Pre = 1-4.5 mg/dl, Post <1.4 Guidelines: “ PDH or AT Cortisol level > 1.4 at 8 hrs Post-Dex. ~5% of PDH have normal result. Alternatively False Positive May Occur from Stress or Nonadrenal Disease.” Cost: Generally Less than ACTH Stimulation
40	HAC Screening: LDDS Comments Cheaper than ACTH Stimulation and Does Not Require Special Medications. Slightly More Labor and Tech Time Particularly Useful when Rule Out of NonAdrenal Disease or Iatrogenic HAC is Less of a Concern May Allow Single Test to Screen (Diagnose) and Differentiate Generally ACTH Stimulation is recommended Prior to Treatment & For Treatment Monitoring
41	HAC Screening: Combination Test Less Commonly Used: ACTH Stimulation & HDDS Test Done At the Same Time Variable Interpretation Guidelines Really a Combination of a Screening and Differentiation Test Sensitivity based on ACTH Stimulation Portion No Diagnostic Advantage over Staged Screening and later Differentiation (if needed) Increased Intellectual and Financial Cost Not Recommended
42	HAC Screening: What’s New - Modified ACTH Stimulation Protocol = As Previous but Measure Serum 17-Hydroxy-Progesterone Not Cortisol Basis = The Hyperplastic or Neoplastic Adrenal May Respond to ACTH with Exaggerated Release of Hormones Other Than Cortisol NONCushing’s HAC Mixed May Aide Dx When Other Tests Negative
43	HAC Screening: What’s New - Modified ACTH Stimulation Sensitivity and Specificity = Not Fully Evaluated Elevated Androgens Seen with ACTH Stimulation, 6 of 11 with 17-OHP (Chastain, et al, SACE 2001) HAC Dogs With (11) or Without (13) Exaggerated Cortisol Response on ACTH Stimulation Had Exaggerated 17-HydroxyProgesterone Concentrations (Ristic et al, JVIM 2002) Should Have Increased Sensitivity (Less False Negatives) But Not Proven or a First Line Test Yet Testing Other or All Androgens May Be Even Better
44	HAC Screening: What’s New - Modified ACTH Stimulation Assay Availability (Cost excludes ACTH) IDEXX = Ships to U Tennessee, Guidelines from UTenn Antech = No Guidelines Provided, Call for Assistance Panel of 4 Androgens plus Cortisol Available from UTenn. http://www.vet.utk.edu/diagnostic/endocrinology/general.shtml Comments = Useful When Classic Clinical Cushing’s Signs But Normal or Dichotomous ACTH Stimulation (Cortisol) & LDDS. Expensive & Not a First-Line Test. Time Will Tell = More Research Needed
45	HAC: Differentiation Tests Answers What Form of HAC the Dog Has Low Dose Dexamethasone Suppression (+4 hour sample) High Dose Dexamethasone Suppression Resting Endogenous ACTH Concentration Imaging (Metyrapone Suppression Test) (CRH Stimulation Test) Differentiate Iatrogenic Based on History ± ACTH Stimulation Test
46	HAC: Differentiation Tests Why Bother? Playing the Odds Most Dogs Have Microadenoma PDH and I Treat All My HAC With Drugs Anyway? Medical Management is Not the Only Option for Treating Some Forms of HAC Some Medications Not Appropriate For All Forms of HAC Surgery? Prognosis is Not as Good for Adrenal Tumors Professionalism and Liability Concerns Most Modern Clients Want to “Know the Options” Even If They Will Likely Choose Medication
47	HAC Differentiation: LDDS Protocol: As Previous, Do Not Evaluate +4 hour Sample for Differentiation Unless +8 hour Sample Was NOT Suppressed (No Additional Tech Time/Cost) Basis: Most PDH will Suppress After Dex. Injection. Most of AT Will Not Sensitivity & Specificity = Not As Good as HDDS 61% Sensitive for PDH, 33% for AT 33% Specific for PDH, 61% for AT (calculated from Feldman, JAVMA ‘96)
48	HAC Differentiation: LDDS Expectation: AT Will Not Suppress At All, PDH will Suppress at +4 hour & “escape” by +8 hour IDEXX Normal: Pre = 2-6 mg/dl, Post <1.5 Guidelines: If Suppressed (<1.5) at +4 hour and rebounds, likely has PDH Antech Normal: Pre = 1-4.5 mg/dl, Post <1.4 Guidelines: PDH only. Cortisol levels <1.0 at 2-6 hours post-dex supports PDH Cost: “free” since you get this “extra” information from the screening test (but is the inexpensive information really useful?)
49	HAC Differentiation: LDDS Comments Interpretation is Controversial Some Sources Evaluate Not Only Suppression at +4 hours (Yes or No) But Also Degree of Suppression compared to the Pre-Dex. Sample e.g. to Consider It Suppressed Must Be <50% of Resting Level AND < a Cutoff Value The More Detailed the Assessment Criteria the Better the Test, but Harder to Actually Use Useful Indicator But Further Testing Warranted for More Definite Differentiation
50	HAC Differentiation: HDDS Protocol = Measure Cortisol Before & After (4 & 8 Hours) Administration of 0.1-0.15 mg/kg Dexamethasone Basis = PDH Should Suppress Due to Steroid Negative Feedback on Pituitary. AT Should Not have Negative Feedback & Should Not Suppress At All
51	HAC Differentiation: HDDS Sensitivity & Specificity = Better Than LDDS 75-98% Sensitive for PDH, ³43% Sensitive for AT (From Feldman, JAVMA 96) ³ 43% Specific for PDH (From Feldman, JAVMA 96) 75-98% Specific for AT Expectation: If Suppress Then PDH, If Does Not Suppress AT
52	HAC Differentiation: HDDS IDEXX Normal: Pre = 2-6 mg/dl, Post <1.5 Diagnostic Guidelines: “PDH will generally suppress at 4 & 8 hours. A Few PDH will Suppress at 4 & Escape at 8, Up to 25% PDH Will Not Suppress At All” Antech Normal: Pre = 1-4.5 mg/dl, Post <1.4 Diagnostic Guidelines: AT All levels >1.4, PDH levels < 1.4 at 4-8 Hours. A Small % of PDH Will Not Suppress Following High Dose Dexamethasone
53	HAC Differentiation: HDDS Comments “The Old Stand By” Available For Years, Easy & Readily Available Some Dogs May Become Ill Due to Dose Like LDDS, Different Interpretation Guides Exist, e.g. Decreased Related to Pre-level Not Just Cut-Off If Suppresses Strongly Can Conclude PDH & Treat Can Not Definitively Diagnose AT If Test Consistent with AT, Need Imaging Follow-up to Stage Disease, Further R/O PDH (Non-Suppressors ~50% AT, 50% PDH) Imaging & Newer Tests Likely Better & Easier If Done Carefully & Well
54	HAC Differentiation: Imaging Radiographs Ultrasound CT MR
55	HAC Differentiation: Radiology Adrenal Tumors May See Mass Effect May See Calcification NOT Pathognomonic Pituitary Dependent May Rarely See Adrenal Calcification Comment: Not Very Useful for Differentiation Limited Use To Assess Complications
56	HAC Differentiation: Ultrasound Adrenal Tumor Should See Asymmetric Adrenals Atrophied Adrenal May Be Hard to Find Tumorous Adrenal May Have Irregular Shape, Echogenicity or Architecture Needed Prior to Surgical Treatment Pituitary Dependent Should See Bilaterally Symmetric Enlargement Not Always Symmetric or Greatly Enlarged Normal Adrenal Size Not Defined Well NonAdrenal Disease May Cause Adrenal Enlargement (Concurrent or Independent of HAC)
57	HAC Differentiation: Ultrasound Sensitivity & Specificity Very Operator Dependent: Likely Very Good With Experienced Ultrasonagrapher Good Equipment Good Examination Quality (No Gas, Movement, etc) 100% & 95% for AT in RESEARCH environment (JSAP, 2001) Comment: Test of Choice With Experienced Operator Grey Areas Exist Regardless of Operator Skill Bigger Grey Area with Less Skilled Operator Cost: ~1 ½ - 2 times HDDS
58	HAC Differentiation: CT & MR Abdominal CT May Aid Differentiation of AT and PDH Helps Stage AT for Invasion or Metastasis Comment: Not Likely Much Better & More Expensive Than High Quality U/S. Requires Anesthesia Pituitary CT or MR: Microadenoma v.s. Macroadenoma not PDH v.s. AT MR Likely “Better” But Main Concern is Availability Required for Radiotherapy (or Hypophysectomy) Definite Recommendation if Any CNS Signs, Consider for other PDH
59	HAC Differentiation: What’s New -Endogenous ACTH Test Has Been Available for Several Years But Only Recently Popular & Practical Limited Use Due to Lability Of ACTH Protocol: Collect and Measure Plasma ACTH Concentration. Special Handling. Prompt Separation with Freezing or Preservative Added Basis: PDH Should Have High ACTH Due to Tumor Production or Low Dopamine. AT Should Have Low ACTH Due to Cortisol Suppression of Pituitary Gland
60	HAC Differentiation:What’s New - Endogenous ACTH Sensitivity & Specificity Considered One of Most Accurate Methods ~75% of Tests Reported as Diagnostic in Several Papers Sensitivity & Specificity for AT 100% & 95% reported from a RESEARCH setting (JSAP, 2001) Not Specifically Reported for PDH Due to Lability of ACTH Handling Affects Results Expectation: If ACTH High PDH If ACTH Low AT
61	HAC Differentiation: What’s New - Endogenous ACTH IDEXX Normal: 20-80 pg/ml Diagnostic Guidelines: >80 Diagnostic for PDH, Normal Range Inconclusive, <20 Likely AT Antech Normal: 15-45 pg/ml Diagnostic Guidelines: >45 in approximately 90% of PDH & <15 in approximately 60% of AT. Normal Range Nondiagnostic ** Special Tube & Aprotinin Preservative provided if you call ahead of time! Cost: ~1½ - 2 times cost of HDDS (similar to U/S)
62	HAC Differentiation: What’s New - Endogenous ACTH Comments Careful Handling of Samples is KEY to Accuracy of This Test. The Physiologic Gold-Standard Use of Aprotinin Preservative is Recommended to Improve Reliability Likely Choice Differentiation Test of the Future – Maybe Not There Yet IF ACTH Is High, Definitely PDH IF ACTH Is Low or Normal Þ More Tests
63	HAC Differentiation: The Future? Metyrapone Suppression Test: Basis: Metyrapone Interferes With Cortisol Production. If ACTH is Present an Intermediate Product 11-DOC Accumulates Protocol: Pre-Drug Serum Sample, 4-Doses of Metyrapone Over 24 Hours, Post-Sample Measure Cortisol & 11-DOC in Both Samples Expect Increase 11-DOC & Decrease Cortisol with PDH Comment: Not Practical To Many Drug Doses Two Day Duration
64	HAC Differentiation: The Future? CRH Stimulation Test Basis: Cortisol From AT Suppresses ACTH Release From Normal Pituitary. CRH Stimulates ACTH Release from PDH or Normal Pituitary. Protocol: Pre-CRH Serum Sample. + 15 & + 30 Minute Post-CRH Samples. Measure ACTH and Cortisol in Each Sample Expect Increase ACTH & Cortisol With PDH Comment: Not Practical CRH Not Available Still Have Special Handling Concerns for ACTH Assay
65	HAC Differentiation: Trial Tx Start On PDH Dose of Medication If it Works, Assume it is PDH If it Does Not Work Assume it is AT OR Do More Differentiation Tests Comment: OK Approach From Medical Standpoint Unlikely to Harm Patient - Macroadenoma? Adrenal ACA? May Waste Time and Money Client Must Know This Is What You Are Doing
66	HAC Screening Test Summary Resting Cortisol or ALP or UCCR: Normal Makes HAC Less Likely – cheapest but won’t give definitive diagnosis ACTH Stimulation Test: High Sensitivity & Specificity, May MissMore than LDDS but Less False Positive – Generally slightly more expensive than LDDS LDDS Test: Highest Sensitivity, More False Positive with NonAdrenal Disease – Generally less expensive than ACTH Stimulation but if choose to treat medically an ACTH Stim. Is Still Recommended Pre-Induction ACTH Stim for bOHP/Androgens: Follow-up If Routine Tests Are NonDiagnostic and the Patient Really Looks Cushingoid - MultiHormone Recommended but Expensive
67	HAC Differentiation Test Summary LDDS: Moderate S&S, HDDS or Other Are Better HDDS: If Suppresses Can Safely Conclude PDH, AT Less Likely to Suppress But Imaging Needed to Confirm (Remember PDH More Common)and Stage Disease Abdominal U/S: Operator Dependent But Best Sensitivity & Specificity Available for AT, Plus Can Stage AT – Costs more than HDDS and Operator and Equipment affect Accuracy – Referral may be needed, More expensive than HDDS Endogenous ACTH: High ACTH Confirms PDH, Low Strongly Suggests AT but Imaging Needed to Confirm & Stage, Grey Zones? Great if Handled Carefully.- More expensive and labor intensive than HDDS
68	HAC Treatment Options Withdraw Exogenous Steroids (Iatrogenic?) Medical Management o,p’-DDD/Mitotane (Lysodren) Ketoconazole (Nizeral) Selegiline/L-Deprenyl (Anipryl) Trilostane (New) Surgical Management Adrenalectomy Hypophysectomy Radiologic Management
69	HAC Treatment: Iatrogenic Withdraw (Taper) Exogenous Steroids Be Aware of Potential HyPOadrenal Phase (Addison’s) During Recovery = Rare or Uncommon But Does Happen Clinical Improvement Takes >6-12 Weeks PU/PD/PP – First Sign to Recede, ~6 weeks Weight Loss, Improved Abdominal Tone, Normalization of Liver Size and Enzymes Skin/Coat Improvement – 12-30 Weeks With Coat Color Change Frequent, Faster (~5 weeks) with Topical Administration Cases
70	HAC Treatment: Medical Management General Prognosis = Good. Average Lifespan ~2 Years Not As Good For Adrenal Tumors as PDH Remember Average Age at Diagnosis ~10-11 yo Choice for Most Cases “Best” Choice For Majority of Cases = PDH Microadenoma Owner Reluctance to Pursue Definitive Treatment Risk of Morbidity or Mortality Cost Variety of Medications Available – Check Texts For Specific Dose Regimes
71	HAC Med Management: PDH Lysodren^® Most Common Treatment for PDH O,P-DDD , Mitotane Not Approved MOA: Selective Cytotoxicity affecting Adrenal Cortex (Zona fasiculata & Z. Reticularis > Z. glomerulosa) Affects Cortisol & Other Hormone Synthesis
72	HAC Med Management: PDH Lysodren^® Induction = 30-50 mg/kg/d (with food) 7-10 Day Duration OR Until Reduction in Signs Should Be Followed By Recheck ACTH Stim. Some Clinicians Recommend Pre-Induction ACTH Stim. Concurrent Physiologic Prednisone Available D/C 1 Day Prior to ACTH Stim Test If Administered ~10-15% Need Longer Induction ( up to 2 Months) Should Run ACTH Stim weekly to biweekly Goal Is Low Normal Cortisol Pre/Post ACTH
73	HAC Med Management: PDH Lysodren^® Maintenance: 25-50 mg/kg/week (with food) Monitor Signs & ACTH Stimulation (q3-6 months) ~50% Relapse Within a Year Reload Then Maintain on 25-50% Increased Dose Physiologic Prednisone Should Be Available Expectation: Most Reliable Medication, ³ 80% Adverse Effects: Usually Due To HOAC, ³ 60% Anorexia, Vomit, Lethargy, Weakness, Ataxia Should Rapidly Resolve with Prednisone May Take 2-6 Weeks To Resolve (1/2 Dose or None) ~5% Permanent
74	HAC Med Management: PDH Lysodren^® Adverse Effects – NonAddisonian Drug Intolerence Esp. Gastroenteritis Soon After Administration Usually Improves with Divided Dosing Hepatotoxicity Clinical Significance = Uncommon May See Enzyme Changes Cost: Has Historically been least expensive but Cost is rising
75	HAC Med Management: AT Lysodren MOA = Same as PDH, AT Tend to be Resistant Induction = Same as for PDH with Increased Dose and Duration 50-75 mg/kg/d (with food) 10-14 Day Duration OR Until Reduction in Signs Maintenance = Same as PDH with Increased Dose >100 mg/kg/week often needed Relapse & Dose Increases Needed Frequently May Be Used Palliatively Prior to Surgery Medical Treatment of AT ~2 times cost of PDH Management
76	HAC Med Management: Lysodren Comments Accidental HOAC Usually Goes Away Can Take a Long Time Requires More Monitoring HOAC Treatable if Occurs Permanently Availability a Concern Some Advocate Induced HOAC
77	HAC Med Management: Ketoconazole MOA: Reduction of Cortisol and Androgen Synthesis by Reversible Inhibition of Cytochrome P450cA4 needed for Synthesis Negligible Effect on Aldosterone Synthesis Less HOAC Risk Not Approved
78	HAC Med Management: PDH Ketoconazole Induction = 5 mg/kg BID (with food) for 7-10 Days, If No Adverse Effects Increase to 10-mg/kg BID for 14 days. Check ACTH Stimulation (Want Low Normal) Some Clinicians Start Even Lower Dose & “Taper Up” Slower If Not Suppressed, Increase to 15 mg/kg BID Maintenance = Suppressive Dose Long Term Expectation = ~50% of Patients Respond
79	HAC Med Management: PDH Ketoconazole Adverse Effects: Usually Drug Related & Mild Gastroenteritis, Vomit, Anorexia, Diarrhea (common) Hepatic Enzyme Induction (common) Hepatic Toxicity: Monitor Liver Function Regularly Coat Color Change (lightening) Thrombocytopenia HOAC Uncommon Cost: Historically cost a lot more than Lysodren, but Currently Similar to Slightly more Expensive
80	HAC Med Management: AT Ketoconazole Induction: As for PDH Maintenance: Palliative Prior to Surgery May Maintain on High Dose Long Term Lysodren Generally Preferred
81	HAC Med Management: Ketoconazole Comments Risk Intolerant Clients – Concerned with HOAC, noncompliant with Prednisone Administration Guidelines. Client Willing to give BID vs Twice weekly Client that can remember to treat BID but forgets if frequency of 1-2 times weekly Sick Patient with Unclear HAC, e.g. Dm ± HAC Lysodren Intolerant Patient
82	HAC Med Management : L-Deprenyl (Selegiline, Anipryl^®) MOA = Inhibits Monamine Oxidase to Increase Dopamine & Increase Suppression/ Decrease Production of Pars Intermedia ACTH Approved for Cushing’s Disease (PDH) Not Cushing’s Syndrome Implies Differentiation
83	HAC Treatment: PDH L-Deprenyl Induction & Maintenance: 1 mg/kg Daily for 2 Months Continue if Clinically Improved 2 mg/kg Daily for 2 Additional Months Continue if Clinically Approved Switch Drugs if not Clinically Improved Expectation: 10-25% With P.i. HAC Should Improve Studies Vary: 20-70% Effect Monitoring: Clinical Signs, ACTH Stimulation Not Expected to Change, LDDS May or May Not
84	HAC Treatment: PDH L-Deprenyl Adverse Effects: Limited Reports, Probably Uncommon, End With Drug Withdrawal Overstimulation: Restless, Repetitive Movement GI: Vomit, Diarrhea, Anorexia, Hypersalivation Other: Pruritis, Licking, Deafness Drug Interactions [Antidepressants – SSRI(Prozac), TCA (Amitriptyline), Dormitor, Amitraz, Ephedrine] Human Abuse Potential Drug (Amphetamine Effect) Cost: 1/3-1/2 more than Lydsodren. Generic Available at Discount but may not be as good as name brand
85	HAC Treatment: PDH L-Deprenyl Good For “Healthy” PDH Confirmed Cases Not Acceptable for Multi-Endocrine Cases, AT Some Clinical Effect May Be Due to Reduction of PDH Amphetamine Stimulant Effect Bromocriptine (Dopamine Analog) Has Similar Clinical Effect To Many Adverse Reactions for Use Generic Cheaper – Efficacy?
86	HAC Treatment: Trilostane – What’s New MOA: Competitive Inhibition of 3b-HSD at Multiple Steps in Steroid Synthesis to Decrease Cortisol Synthesis Approved in England US Available by FDA New Drug Permit
87	HAC Treatment: Trilostane – What’s New Dose: 5-10 mg/kg per Day or 30 mg Daily or EOD for Dog < 5kg, 60 mg Daily for Dog 5-20kg, 120 mg Daily for Dog >20kg Monitoring: Signs & ACTH Stimulation Tests Goal & Post-Pill Timing Unclear for ACTH Stim Expectation: ³ 80% Response Expected with Few Adverse Effects (HOAC Related)
88	HAC Treatment: Trilostane – What’s New Advantages: Similar Efficacy as Lysodren But Reversible Effect Like Ketoconazole Lower Relapse Rate Than Lysodren Faster Improvement If HOAC Induced Disadvantages Not Readily Available (90 supply on Individual Patient Basis, Twooten@cvm.fda.gov) Dose & Monitoring Protocols May Change Cost: Expensive due to transport and actual cost of medication. Likely 1 ½ - 2 times cost of Lysodren
89	HAC Treatment: Surgery Principle: Go At The Source Pituitary Tumor for PDH Adrenal Tumor for AT Intuitive Treatment of Choice Most Common Treatment in Human HAC Less Utilized in Dogs
90	HAC Treatment: Adrenolectomy Indications Adrenal Tumor = Treatment of Choice Unilateral or Bilateral PDH = For Resistant or Intolerant Patients Bilateral Exclusion Criteria? = Known Metastasis of Adrenal ACA Some Do Well Even If Entire Tumor Not Removed
91	HAC Treatment: Adrenalectomy Outcomes Intra or Post-operative Mortality = ~20-60% Study with 60% = Euth. Known Metastasis Cases Others Did Not Operate Them or Did Not Euthanize Post-op. Morbidity = 100% Transient HOAC Permanent HOAC (with Bilateral Surgery) “Routine” Surgical/Tumor Complications – Bleeding, Thromboembolism, Pancreatitis, Pain, etc. Incomplete Excision or Metastasis Noted: May Need Ongoing Medical Management
92	HAC Treatment: Adrenalectomy Survival: 1.5-2 Years, Clinically Similar to PDH Medical Management Remember Mean Age at Diagnosis ~11 yo Comments: Consider For All AT Full Medical & Imaging Workup Pre-op Use Experienced Surgeons! Cost: ~ same as 1 year medical management with Lysodren
93	HAC Treatment: Hypophysectomy Indication: Physiologically Ideal PDH Treatment Total Hypophysectomy Investigated in Dogs Attempt to Remove Entire Pituitary Gland VERY Limited Availability (Utrecht) Outcomes Creates Secondary Endocrinopathy Hypothyroidism (usually permanent) Diabetes insipidus & HOAC (usually temporary) ~80% Remission of HAC (similar to Lysodren) ~15% Recurrence Rate at 1 year (Better than Lysodren) Mortality = 7% (6/84 from Utrech case series)
94	HAC Treatment: Hypophysectomy Selective Hypophysectomy is Choice in Hu. Attempt to Remove Only the Adenoma Still Create Secondary Endocrinopathies Still Have Significant Relapse Rate, ~75% Comments: Maybe the Future of Treatment? Intense Imaging and Surgical Requirements Will be Very Expensive Trades One Endocrinopathy for One or More
95	HAC Treatment: Radiotherapy Indication: PDH Macroadenomas Primary Reason is Resolve or Prevent CNS Signs Outcome; Px for Resolution of Neurologic signs is Proportional to Severity of Signs & Tumor Size Mean Survival ~ 2 years for Dogs with Mild to Moderate Neurologic Signs ~50% Still Need Medical Management of PDH Comments Consider for All Macroadenoma Expensive but only treatment option available for clinical macroadenoma signs.
96	HAC Diagnosis: Controversy or Consensus Survey of 501 (206 Responses) ACVIM & ACVD Diplomates (JAVMA, June 2002) Would Screen if Had No Clinical Signs, But Has Suggestive Clin Path: Yes=26%, Maybe = 43% Will Rule Out HAC if SAP is Normal: 14% Preferred Screening Test: LDDS 55%, ACTH Stimulation 30%, Other or Depends 15% Will ReRun Screening Test Prior to Treatment if No Classic Signs & First Screening Test is Positive: 69% Will ReRun Screening Tests Prior to Treatment if No Diagnosis on First Test: 89% Preferred Differentiation Test: HDDS 28%, ACTH Concentration 20%, Combination of ³Tests 20%, Ultrasound 9%, Other 14%
97	HAC Treatment: Controversy or Consensus Survey of 501 (206 Responses) ACVIM & ACVD Diplomates (JAVMA, October 1999) Will Treat Based on Screening Test Diagnosis Without Signs: Always 31%, Sometimes 12% Favorite Treatment for PDH: Lysodren 96%, Ketoconazole 2% Favored Adrenalectomy for AT: Always 7%, Always If No Mets. 58%, Sometimes (Multifactorial) 27%, Never 8% Favorite Medical Therapy When Used: Lysodren 89%, Ketoconazole 11% Run an ACTH Stimulation Prior to Induction If Not Already Run: 43% Administer Prednisone During PDH Induction: Always 21%, Sometimes 23% During AT Induction: Always 30%, Sometimes 18% Endpoint for Induction: Multifactorial - Set Number of Days= Most Common Criteria, Decreased Polydipsia = Next Most Common
98	HAC: My Approach Pursue Diagnosis if Clinical Signs Present ACTH Stimulation My Favorite Cortrosyn Cost May Change That Do Not Forget to Rule Out Iatrogenic HAC Differentiation Tests Definitely Valuable Ultrasound (ACVR) &/or Endogenous ACTH (with Aprotinin) Preferred Pituitary CT Discussed if PDH Strongly Recommended if Even Vague CNS Signs Adrenal U/S Recommended if AT (U/S not done yet)
99	HAC: My Approach Treatment All Options Discussed to Educate Client rDVM Preferences Customized Recommendations “Special” Clients PDH: Lysodren>Ketoconazole>Anipryl Looking Forward to Trilostane Pred. Provided Not Routinely Administered End Induction at ¯ PD/PP or 10 Days Without Improvement AT: Surgery>Lysodren>Ketoconazole
100	Canine Cushing's: HAC Review & New Questions?