---start---- medsurg2 9/18/98 today we're going to talk about Cushing's dz. Hyperadrenocorticism: Excessive amount of cortisol slide: Mac - some sort of long thin dog with thin white curly hair. Hyperadrenocorticism (excess cortisol)- can be exogenous (iatrogenic) or endogenous - if endogenous, can be pituitary dependent (overstimulated adrenal, adrenal is innocent bystander) or autonomous (adrenal is acting on its own, usually tumor, causing excess secretion independent of instructions from pituitary). Pituitary dependent is by far most common. this is a common disease in the dog. this is seen in cats sometimes, but is uncommon. this is also seen in horses - it's very uncommon, and usually seen in older horses who get a long and curly haircoat; almost all of these horses have pituitary tumors. also seen in ferrets, who present completely bald... PU/PD - major sign. You know why this happens - remember cortisol interferes with ADH, creating nephrogenic diabetes insipidus. More urination occurs, so animl has to drink more. THis can be really severe. The urine can have lower osmolality than plasma (hyposthenuria). The other thing about the PU/PD is sometimes it is the only clinical sign. B/c cushing's is common, and DI is rare, always screen for Cushing's prior to modified water deprivation test. In cats, most of them get diabetes secondary to hyperglycemia, and that's why they get PU/PD, not b/c of a DI syndrome. dog: potbellied appearance - due to muscle atrophy. remember cortisol is catabolic, it breaks things down. only in the liver is it anabolic. We see a large liver due to increased glycogen and fat deposition, adding to the potbellied look. There is also a redistribution of fat, from peripheral stores to central stores- central obesity - thin legs, head, neck, but body is obese. "tick like" appearance. We also see alopecia - thinning of haircoat, or bald patches. Hair is easily epilated. Dog will often be panting in inappropriate situations. Also, the skin is papery thin. It can wrinkle in a distinctive way. Also you can see a vein through it. We see a slide of a cat with Cushings, that has skin tears - skin is so thin it has torn - makes it hard to fix b/c you can't suture it b/c suture won't hold. when you see this thin skin in older cat you should consider cat to have cushings until proven otherwise. the alopecia we see is usually bilateral and symmetrical, often truncal, but also may be seen on limbs or elsewhere. it is a nonpruritic alopecia. There is also a loss of hair on the tail - "rat tail" appearance. this effect of hairloss is also seen with hypothyroidism. Iatrogenic cushings in a boxer - the inside of his upper leg has some kind of pyoderma, a very erythematous dermatitis. Glucocorticoids are anti-inflammatory so why does he have this redness? well, it is also very pruritic. It could be demodex (it isn't) b/c we see that with immunosuppression...but, this this is actually hard to the touch, it is calcinosis cutis - calcium gets deposited - dystrophic mineralization occurs as a result of protein breakdown under influence of steroids. This dog has this red, itchy stuff - gets treated with steroids-- gets worse, b/c more mineral is deposited -- gets more steroids --- you see the problem. Trying to control this symptomatically with steroids is not going to work. We also see calcium deposition under the tongue, and in many other tissues of the body. slide of dog belly with blackheads aka comedomes, a prominent vein, some wrinkling of the skin, some alopecia. slide of same dog with very large bruise on her neck. These animals with excess glucocorticoids have increased capillary fragility - capillaries will burst with minimal trauma. This bruise can be the result of one venipuncture. Owners may think you beat up the dog. You shoudl advise the owner that if you are right about the dx, the dog will have a bruising tendency and that taking blood may cause a large, nonpainful bruise. You look a whole lot better if you say this in advance. slide of more abdominal skin, there isa round, slightly red area, with central pigmentation, some scaling - looks like ringworm. This is the classic appearance of ringworm. Cushing's patients are immunosuppressed, so this is also pretty common. Here we see a black dog who looks motheaten - he has a pyoderma. infections are common esp in skin, lungs, and bladder. these animals are very severely immunocompromised. there are some things that are not common, but that do sometimes occur. slide: lab who came in for removal of chronically infected, draining toe. abx and antiinflammatories didn't help. long, draining fistulous tract was present. surgeon noticed high alkaline phosphatase. he was worried it might be cushingoid. dog did have cushings. now, if you didn't treat the cushings first, and took the toe off, it wouldn't have healed. with appropriate medical tx, toe did heal without removal. slide: pus in mouth, severe osteomyelitis of mandible - hole going right into bone - this dog ultimately died even with mandibulectomy. sslide: dog with lots of signs of cushings - central obesity, abdominal alopecia, skin lesions on abdomen, depressed and lethargic, weak muscles. this dog has iatrogenic Cushings. slide: dog brain with very large pituitary - macroadenoma. if you have this, you might go blind from it pushing on the optic chiasm, you might be ataxic, you might have impaired thermoregulation as it presses on hypothalamus. in people these grow down but in dogs they grow up into brain. you might see seizures. this dog was head pressing and acting really depressed. you might also see coma and death. good news: we can help you with cobalt irradiation. but we certainly see problems when it is untreated. The five P's: PU (polyuria) PD (polydipsia) PP (polyphagia) potbellied panting when we give steroids, one or more of these five things is going to happen. other findings: mature leukocytosis - in about 1/3 of dogs eosinopenia - the most common clinical abnormality erythrocytosis - not as common lymphopenia - not as common. prednisone is lympholytic, though. you need to know not only the clinical signs, but also why they occur. know why eosinopenia occurs. (why does it occur??) increased alk phos is very common, most common biochemical abnormality. it exists as an isoenzyme which steroids induce in the dog. this isn't true in cat or ferret, so excess cortisol in those animals do not increase alk phos. increased ALT also pretty common hyperglycemia is also pretty commonly seen. it's important b/c cortisol interferes with insulin and causes a relative insulin resistance, eventually leading to diabetes. it's sure easier to manage the patient before diabetes occurs. if you see hyperglycemia, you are in a race against time, to control cortisol level before diabetes sets in. you may also see hypophosphatemia and an increased total CO2. Dilute urine (low SG) cortisol causes nephrogenic DI so urine isn't concentrated and is often hyposthenuric. a few things about the ferret and the cat - cats get very thin skin as do dogs, but tends to be more fragile and to tear more - we don't see the tearing in the dogs. but cats do not tend to get alopecia, although may be easily epilated. cats do not have corticosteroid inducible alk phos isoenzyme so no increased SAP occurs, most cats with cushings also have diabetes, and the good news is we usually reverse that with successful tx. Lysodren, the tx of choice for the avg cushing's dog, isn't as useful in cats. in ferret - hyperadrenocorticism is a misnomer. plasma cortisol levels are normal, and ACTH stim is normal. but, they have a tumor or two - the tumors are hypersecreting sex steroids. no particular sex steroid. sometimes an androgen like testosterone or DHT or estradiol. they do get alopecia and they get bald - but this usually starts out as seasonal - lose hair, it comes back, then goes away - so it may take a while to realize there is aproblem. often these animals are females- commonly see an enlarged vulva. tx of choice is adrenalectomy. Thanks Dr. Holt for the slide of the bald ferret. Ok, you think you have a hyperadrenocortical dog: indirect assessment: gross appearance, clinical signs, CBC, biochemical tests, U/A direct assessment: ask two questions 1. does the dog have cushings dz? do screening tests 2. is it pituiatary dependent or is there an adrenal tumor? do differentiating tests. CRH is released by hypothalamus, stimulates ACTH release from pituitary, ACTH then stimulates production of cortisol and maintains integrity of adrenal gland. without ACTH you not only do not make cortisol, but your adrenal cortex atrophies. with too much, you make too much cortisol and your adrenal cortex gets hyperplastic and hypertrophied. cortisol feeds back to decrease secretion of CRH from hypothalamus and ACTH from pituitary. Screening tests: (tests WILL be on exam) 1. resting plasma cortisol - can't do it - don't - it's a waste 2. ACTH stimulation test - good test. 3. low dose dex suppression test - good test. 4. combined dex supp/ACTH stim test - more common in other areas of country; controversial; some like it, some hate it. 5. urinary corticoid/creatinine ratio ACTH stimulation test: realize you take a cortisol measurement first. then you give ACTH - asking the question "what is the capacity of adrenal gland to secrete steroids? is it low (addisons) normal or high(cushings)". so you can screen for hyperadrenocorticism - but only with 75% accuracy. 25% of cushingoid dogs will have normal results. you can also use it to tell apart spontaneous hyperadrenocorticism from iatrogenic cushings. if there is iatrogenic disease, there is adrenal cortical atrophy, and there will be no response to the ACTH (or a low response). can also use this test to dx addison's or to monitor response to lysodren. remember - iatrogenic cushings- associated with clinical signs of Cushing's, but there is really adrenal atrophy. so the ACTH stim in a spontaneous cushing's case will produce a high response, and in an iatrogenic case it would produce a low response. so if a dog comes to see you and dog is or was on steroids, this is the only test to use. no other test will tell you the truth. only this test will work, b/c youwant to know is it iatrogenic or is it spontaneuos? Low dose dex suppression test: take presample, give dex, then in normal dog, cortisol production goes down due to negative feedback - but a dog with cushings has a raised threshold for negative feedback, and we do not see suppression. so we use this to screen for hyperadrenocorticism. we also look at pattern of suppression. if you have normal suppression but then you pop back up at 8 hrs, you have cushing's dz - but because you did initially suppress, you must have pituitary dependent form. in 40% or more of dogs given this test, we can tell pituitary dependent from adrenal dependent dz. this test measures the integrity of the negative feedback loop. urine corticoid creat ratio - quick screening test for hyperadrenocorticism. evaluate two consecutive moring urine samples. if it's normal, animal is not likely to have cushings. if it is positive, try another test. ---break---- combined dex supp/ACT stim - controversial. This test is conceptually a good idea and some people like it; others do not like it. Just know it exists.And do not believe the naysayers b/c it is a good test. No adrenal function test is 100% and some of these tests are controversial. We look at specificity and sensitivity - different for each test. only ACTH stim is useful in dogs that have been on steroids. Distinguishing PHD (pituitary dependent) from AT (adrenal tumor) again - think of the axis PDH: excess CRH from hypothalamus maybe, definitely excess ACTH from pituitary. this causes increased cortisol secretion, and hyperplasia and hypertrophy bilaterally of adrenal cortex. there is a raised threshold for negative feedback. AT: unilateral tumor making excess cortisol. cortisol activates normal negative feedback loop causing low CRH and low ACTH secretion, causing normal adrenal gland to atrophy. the autonomous tumor continues to secrete excess cortisol. main differences: AT - low ACTH, normal neg feedback, if you give dexamethasone nothing will change since neg feedback loop is already in full effect so no matter how much you give there is no suppression; PDH - high ACTH, raised neg feedback threshold, dex will suppress cortisol response at high enough doses. high dose dex is good for differentiating and so is ACTH assay low dose dex and combined test may have results consistent with PDH high dose dex supp: this dose of dex will suppress cortisol in PDH dogs but not AT dogs. this test can't dx AT. ACTH assay can tell apart PDH and AT - if ACTH is low, animal has AT. if ACTH is normal or high, it is PDH. there is some overlap. you can have PDH or AT and be in normal range on this assay. but you can tell apart AT and PDH other tests: CT scan - pituitary, abdominal abdominal rads abdominal u/s treatment in dogs: remember, pituitary form is way more common. there are many treatments... now, do not panic, but to tx PDH you can treat at level of pituitary or adrenal gland. the culprit is a pituitary tumor. if you can get rid of that tumor you could cure the animal...ways to do that: hypophysectomy (not done) deprenyl - new medication - MAO inhibitor directed at CNS, designed to enhance dopamine secretion. we think central dopamine depletion is part of the problem - it is in horse, and in some dogs. this should work in some dogs. there are a couple of dogs from here on deprenyl. we don't use it, don't recommend it. never use it with concurrent illness present b/c it doesn't work fast enough or in every dog. it has some advantages - dogs feel better - but it has nothing to do with their cortisol level. has few side effects. Dr Zerbee wouldn't use it on her own dog. bromocriptine cyproheptadine valproic acid octreotide radiation adrenal target: decrease cortisol production somehow... adrenalectomy lysodren - drug of choice for dog - adrenocorticolytic agent - destroys zona fasciculata and reticularis, which make glucocorticoids - usually leaves the glomerulosa alone so mineralocorticoid secretion is maintained. lots of side effects. used correctly is good. know about lysodren and how it works!! also how ketoconazole works. ketoconozole - used in lysodren resistant dogs or lysodren-hating owner owned dogs. inhibits enzymes in cortisol synthetic pathway. need to give twice a day, expensive (lysodren expensive too), when stopped, cortisol levels return to high metyrapone - used in cats Lysodren: induces cortical necrosis. used as loading dose and maintenance. slide: box plot- most dogs fall into the low boxed in area, then there are outlyers up above. after lysodren therapy, we want the pre cortisol value and the post ACTH cortisol value to be at the low end. you need to destry most but not all of the adrenal cortical cells. once you've loaded dogs to this point, you can put them on a maintenance dose. b/c the dz is pituitary dependent and yuo are treating the adrenal, you're just managing this. now, in the netherlands, they usually overdose dogs on lysodren, destroy the cortex, then treat them for Addison's disease. we sometimes accidentally do that. Complications of lysodren therapy: vomiting, diarrhea, weakness, anorexia, ataxia. V/d/inappetance/nausea can occur as direct effects. dividing dose into twice a day and giving with food is helpful with these problems. also it can cause a too-rapid decrease in cortisol level, or too much of a decrease, and this may also cause v/d/weakness/anorexia/ataxia from that, so we also give physiological doses of steroids while loading the patient. some patients are so used to having high levels that they get sick when you lower the level rapidly. over time, a number of dogs require increases in their dose of lysodren. you have to monitor them. AT therapy: slide of liver from dog with adrenal carcinoma mets. this disease is approached with adrenalectomy or lysodren therapy. lysodren will lyse and cause necrosis of adrenal carcinoma/adenoma cells. if patient has pulmonary mets or local mets, we can treat with lysodren and they will often respond very well, though they may require 3-5x the typical dose of lysodren. mets can disappear, though (and you create addisons disease). the best kind of cushings to have is unilateral benign adrenal adenoma. you just remove the tumor and you're cured. Shhh. don't tell Dr. Holt. you do have to supplement with glucocorticoids til other adrenal kicks back in. only about 10-15% of patients have tumors though, and half are malignant. Cobalt irradiation: expensive and so rarely used. but with large pituitary tumors causing CNS signs, we can use radiation to shrink the tumor - but it won't decrease ACTH secretion so you have to use concurrent medical treatment to control the Cushings - the radiation only treats the signs due to the presence of the bulk of the tumor. Iatrogenic cushings: review this on your own use short acting glucocorticoids, slowly reduce dose, monitor with ACTH stimulation test.make sure you understand this disease. when you treat concurrent dz - remember cortisol causes insulin resistance. lysodren decreases cortisol, so insulin requirements decrease, and you have to adjust insulin doses or you can cause hypoglycemic crisis and death. the hair will grow back, pyodermas go away. prognosis: about 2.2 yrs post diagnosis, 50% of dogs are still alive. some dogs live 9 years after diagnosis. One staff member here owns a dog with Cushings dz...has been on lysodren over 5 yrs and is doing fine. so dogs can do very well with treatment. about 93% of dogs that died early died of disease *totally unrelated* to Cushings disease! usually dogs that have cushings are older dogs. so consider that. -- Hypoadrenocorticism HPC: Addison's dz - aka adrenocortical insufficiency this is a glucocorticoid and/or mineralocorticoid deficiency - almost always there is concurrent mineralocorticoid deficiency. Cushings doesn't generally involve mineralocorticoids at all. types of HPC: primary - idiopathic or secondary adrenal destruction - problem is at level of adrenal gland, that's what primary means. #1 cause in people for years was TB. idiopathic is main cause in dog. there is adrenal cortical atrophy, cortisol is decreased, so ACTH is increased a lot, but there is no response. this is primary dz. secondary -common in dog - either pituiatary/CNS lesion (rare) or iatrogenic (common in dog). pituitary type: reduced ACTH, adrenal cortex atrophies, cortisol decreases, can't increase ACTH in response. iatrogenic: you stop giving steroids, can't make more ACTH, don't make cortisol, animal looks cushingoid from exogenous steroids, but you cause an acute addisonian crisis Primary: mostly what we see - adrenal cortical atrophy with loss of mineralocorticoid and glucocorticoid secretion. seen in young/middle aged dogs and also cats though less common.mostly female dogs probably immune mediated. in cats, no sex predilection and no breed predilection (although we think it was in a line of English Pointers, and have seen it in black Standard Poodles) hypocortisolemia: -GI signs, often intermittent (V/D) -impaired gluconeogenesis and glycogenolysis -> hypoglycemia -reduced stress tolerance -> collapse on way to vet -impared abillity to excrete water load -> dilute urine hypoaldosteronism -impaired conservation of sodium - hyponatremia - reduced ECF, hypotension, dehydration, azotemia -impaired excretion of potassium - hyperkalemia, arrhythmias -loss of renal concentrating ability is common -inability to retain HCO3 and Cl - acidosis and hypochloremia history: intermittent weakness, GI signs, depression, lethargy, shaking, PU/PD, acute collapse/shock, transient response to fluids or steroids - ADR dog, prolonged steroid or o,p'-DDD therapy clinical signs are nonspecific: weak femoral pulses tacky gums bradycardia (*unusual with dehydration, so remember this! it' due to K+) dehydration abdominal pain lethargy/depression vomit diarrhea cushingoid appearance remember - bradycardia with dehydration - not a lot of ddx for that. CBC: hemoconcentration (increased PCV) mild anemia (masked by dehydration) increased eosinophils or lymphocytes (correct the handout) biochemical abnormalities: electrolyte changes: hyperkalemia, hyponatremia are most common; hypochloremia, hypercalcemia. Na/K ratio is sometimes checked. hypercalcemia may be a good sign, b/c Ca++ protects the myocardium, whereas K+ is detrimental to myocardium azotemia (pre-renal) - usually seen. In the face of dehydration, you should be concentrating urine- but these animals can not. when you are azotemic with dilute urine, that is the definition of kidney failure. so, ddx: primary renal failure, or severe GI disease of any type you may also see hypoglycemia - reported incidence is low, but we've seen dogs die of it. glucose may be 20 or 30 mg/dl and probably leads to some of the comas we see, certainly the mental stupor. so please measure BG. it's easy to correct that. may also see decreased total CO2. radiographic findings - we won't discuss. all related to low blood volume EKG - gnerally due to hyperkalemia, exacerbated by hyponatremia and acidosis. poor correlation b/w EKG changes and severity of K+ increase. normal EKG doesn't mean K+ is normal. Know what the EKG changes are. P waves are often decreased, PR intervals increased, and increased T wave amplitude (spike T wave). later we see bradycardia, loss of P wave, presence of sine wave. sine wave appearance is "preterminal" dx: indirect: hx and signs, lab tests direct: ACTH stimulation test - to see what the reserve capacity of the adrenal gland is. this is an important test. no reason not to give ACTH stim test. FLUIDS -in a patient in crisis, number one tx is fluids. give fluids. you can replace steroids, butif you do not give fluid, you will still lose them. always check BG!!!! place catheter get pretreatment blood start fluids give ACTH give steroids correct hypoglycemia or acidosis for myocardial toxicity: if EKG abnormalities - give insulin to drive K+ into cells- give with dextrose! sodium bicarb to correct acidosis calcium gluconate - calcium to protect heart - doesn't change K+ level you can turn dog from comatose to normal looking in 24 hrs with proper treatment. ---end----