---start---- sys path 9.23.97 Dr. Hendrick Thursday we have lab 10-12. there will be 8 stations of gross specimens. [my group, #10, will start at station 5 along with group #9, and then you move after ten minutes to the next higher numbered station. this is going to leave 20 min at the end for reflection :)] Written Bruce reports are due by the end of Friday. Turn them in to Dr. H in rm 305 Rosenthal, or the secretary (Anita) on that floor which is rm 311. NO LATE BRUCE REPORTS so. we talked the other day about a lot of stuff. any questions? Ok. continuing on with parathyroid diseases. remember that you can tell by looking at the sizes of both parathyroids and the calcium level you can tell what kind of problem you have. PRIMARY hyperparathyroidism most commonly associated with the functional adenoma. these are rare but are most commonly seen in the cat. so, if you have a functional adenoma of the parathyroid making excess parathormone, you get increased blood calcium levels persistently. you tend to see some muscle weakness, constipation, due to decreased neuromuscular excitability, due to excess calcium. SECONDARY hptism is rare. PSEUDOhyperparathyroidism seen in anal gland CA of dogs, esp in females. hypercalcemia and pseudohyperparathyroidism is also more commonly associated with LSA. the neoplastic cells here do not secrete the PTH-analog that the anal gland cells do. they secrete some kind of osteoclast activating cytokines that have similar effects on bone resorption. not all LSA will do this. but many will. if animal has hypercalcemia, this should be checked out. decreased PTH level rare - seen usually if you accidentally remove parathyroid when surgically removing thyroid in a cat that is hyperthyroid. sometimes is very hard to identify and leave in the parathyroid. if you remove the parathyroid abruptly, you cause a sudden decrease in serum calcium. these animals are very sensitive,they are very excitable, have muscle tremors and tetany can even develop. everyone who removes thyroids should always monitor for this. slide: a pair of glands from a cat. these are thyroids. the parathyroids are large, hyperplastic, nad whitish yellow. severe bilateral parathyroid hypertrophy or hyperplasia. so what's the problem? a secondary problem, cause both are affected. on to the ADRENALS very important organs. a lot of endocrine pathology goes on here. adrenal glands have a cortex and a medulla, and are histogenetically diverse - cortex and medulla are, that is. they have different functions. cortex has different zones: gomerulosa, fasciculata, reticularis - and all make different hormones. the glomerulosa makes ALDOSTERONE - the water volume regulator which affects the renal tubules so that sodium is conserved and K+ is excreted (renin/angiotensin pathway- review that...) The zona fasciculata is the biggest zone and makes cortisol (glucocorticoids) and reticularis makes mainly androgens which can become estrogens, and a little bit of cortisol as well. cortisol is basically a multifunctional hormone. major function is on metabolism and use of glucose vs lipid or protein for energy. cortisol tends to spare glucose and enhance metabolism of lipid and protein, so in effect it is opposite insulin's effect on the body. cortisol also suppresses the inflammatory response. in general it also decreases immune response and inhibits wound healing and collagen synthesis. what happens when you have too little or too much cortisol? PRIMARY HYPOFUNCTION OF THE ADRENAL CORTEX is called PRIMARY HYPOADRENOCORTICISM or something, also ADDISON'S DISEASE: an idiopathic process whereby animal has destruction or loss of all three zones of the adrenal cortex. you can get this rarely by inflammatory lesions, or neoplasms that destroy the area but that is very very rare. usually it is idiopathic and we never find a cause. we've seen that in humans there are sometimes autoantibodies so there may be an autoimmune component. when you lose all three zones, you have a whole range of clinical signs that are very hard to figure out. usually when you find this at autopsy, addison's wasn't even on the differential list (argh.) If animal loses glomerulosa, you have problems with Na+/K+ - you lose sodium and keep potassium, leading to dehydration and hypovolemia and hyperkalemia. some of these things don't have clear clinical signs - animal can be weak, etc...and you may not know why animal is lethargic, weak, etc. the severe hyperkalemia is sometimes associated with heart block/conduction problems. can get complete heart block and death, sometimes. Other signs of lack of cortisol are really vague. usually the animals present with a manifestation of loss of mineralocorticoid (aldosterone). it's hard to know how common this is since it is so often not diagnosed. in post room here at VHUP they get say one every three months, so it isn't common, but it's severe and it is out there and should be considered when you see these vague signs. there can also be secondary hypofunction of the adrenal cortex due to pituitary lesion which diminishes or obliterates secretion of ACTH. obviously, only the inner two zones would be affected then, not the outer zona glomerulosa. ADRENAL HYPERFUNCTION - CUSHING'S DISEASE this is much more common. can occur many ways. when we discuss this hyperfunction, we really mean hyperfunction of the cortisol producing zona fasciculata. basically, there are three ways to cause hypercortisolemia. one is primary hyperfunction - a functional tumor of the adrenal. this is probably close to the most common if not THE most common type. you usually see a well demarcated cortical adenoma in one adrenal, and then because of the feedback loop, through hypothalamus down pituitary, etc, ACTH production is decreased, so the non-tumorous cortex will be atrophied. another cause of hyperfunction is a functional ACTH producing tumor of the pituitary, leading to bilateral hyperplasia of adrenal cortex. this is the classic human cushing's disease, and this is secondary hyperadrenocorticism. this is also common in dogs. classic breeds that get cushing's dz are poodles, dachsunds, etc. it's pretty common. the third way to get hyperfunction is iatrogenic. too much steroid given to tx skin dz, allergy, whatever - body sees an increase in cortisol and doesn't care if it's endogenous or exogenous, and responds to it. again, you can tell by looking at both adrenals, what's causing the problem. slides: - drawing of normal adrenal cortex anatomy/histo - overall shape of adrenal can vary drasticly between species. in dogs you will often see the phrenicoabdominal vein coming in and a kinda boomerang shape. the ratio of cortex to medulla should always be about 1:1. - normal horse adrenals. 1:1 cortex:medulla ratio. this is constant throughout all species, pretty much. - histo: normal glomerulosa, fasciculata, reticularis and medulla. just realize how big the cortex is, full of lipid rich cells making hormones. - histo: addisonian adrenal cortex. cortical: medullary ratio decreased. cortex very acellular, a lot of fibrosis, lymphocytes/plasma cells present, some lipofuscin laden macrophages, that's about it. the inflammatory cells are what led people to believe there may be autoimmune etiology. - two adrenals from a dog. one is small and one is large. the large one has a large, well circumscribed lesion - probably a functional adenoma, because we see atrophy of the nontumorous cortex. - two adrenals from another dog- cortices of both adrenals are large. moderate to severe bilateral cortical hyperplasia of the adrenals. probably secondary to functional ACTH producing pituitary tumor. - two adrenals from yet another dog. both are small with atrophied cortex. morph dx: severe, bilateral adrenocortical atrophy. probably iatrogenic secondary to steroids. another differential is a destructive pituitary tumor causing failure of pituitary to secrete ACTH, and of course idiopathic addison's disease. would want to know clinical history. depending on - or, regardless of which type of cushing's disease you have, you see the same effects in the animal. there are standard appearances to these animals. they have same skin diseases as other endocrinopathies: thin, alopecic skin, there will be lordosis as they redistribute body fat and develop abdominal fatpads and abdominal muscle weakness. all of these signs can't be completely explained by the increase in cortisol, but they are standard occurrences. one of the main reasons is you get muscle weakness, because cortisol promotes breakdwon of fat and protein instead of glucose, so animal uses its own fat and muscle for energy. there is also a liver change, a standard thing we see with excess cortisol - steroid hepatopathy - livers accumulate glycogen in specific pattern - the midzone of the lobule. you get enlarged, orange-yellow liver. so all this promotes the potbellied, weak, hairless, bowlegged appearance. but you will see this a lot in older small poodles and dachshunds and they will walk in and you will know they have cushings and you'll have to figure outthe cause. one specific change in cushings which isn't seen in other endocrine dermatopathies, is that there will be mineralization of collagen - calcinosis cutis. this is not clear re: why it happens, but there is some rearrangement of collagen and mineral deposits there. it can be very dramatic. soem will get ridge of mineral and even bone along their back. this is very specific to cushings dz. these animals also have increased susceptibility to bacterial infections- again, because of antiinflammatory properties. cushings == anything that leads to a chronic persistent excess of cortisol note re: iatrogenic cushings --> what happens is, you end up with addison's if you abruptly stop giving the steroids, because the adrenal cortices are really atrophied. you have to wean the animals off. slides: - cushinoid poodle. thin sparse haircoat, potbellied appearance. - large, orange/red/yellow, rounded, friable liver - glycogen deposition, steroid hepatopathy. this will cause low increase of liver enzymes. ADRENAL MEDULLA: again, totally separate histogenetically. derived from neuroectoderm and makes catecholamines - epi and norepi - fight or flight suckers. interestingly, medulla isn't essential for life. you could remove the medulla and patient would live just fine. so there are no diseases of hypofunction of medulla, but there is a disease of hyperfunction - PRIMARY PHEOCHROMOCYTOMA of ADRENAL MEDULLA. this means "dung colored tumor" and is a dark brown tumor, rich in epi and norepi in brown granules (tyrosine/dopa metabolism). you can ID these tumors by applying potassium dichromate stain, which will oxidize the catecholamines and make an even more intense dark brown color. if you fix the tumors in this solution and look at a slide, granules will jump up and bite you. they will be very obvious. these are not common tumors. are usually in dogs and aged bulls. the vast majority of them are found sort of incidentally at PM as small, well demarcated tumors sitting in the medulla of one or both adrenals. it isn't rare in endocrine tumors to have bilateral neoplasms. we don't know why that is. the pheochromocytomas, when you find them incidentally in adrenals at PM, there's no way to tell if they were functional. excess epi and norepi would cause signs of feeling anxious, stressed, sweating, increased blood pressure. many of these things are not easily evaluated in our animals. in people, the person feels these things and complains about it. but animals don't talk much about their feelings, so we don't find out about it. we can test functionality by screening for metabolites of epi and norepi in the urine. if they are there, then yes, probably excess catecholamine production is occuring. some of these tumors get large, invade through the capsule of the adrenal, into the vena cava, and metastasize to the liver and cranial mediastinum. slides: - two adrenal glands. both have pheochromocytomas in the medullae. color is light grey, dusky. these are small and were an incidental finding at autopsy. - large pheochromocytoma, large, compressing cortex, no medulla left. this tumor is stained and is dark brown. if you see a large tumor sitting in the medulla and extending into cortex you can stain it like this to see what it is. - adrenals in situ - one is very enlarged, with mass extending into vena cava. the tumor is white/grey with areas of hemorrhage, so wasn't obviously a pheo, but when stained, it was one. this obviously affected venous return and stuff, but could have been silent for a long time. most animals do not die from their pheochromocytomas. they have vague signs, are investigated, a big mass is seen, and they are then euthanized, and you find this. -----break------- 11-12 one of the most important diseases of all DIABETES MELLITUS: involves the endocrine pancreas. remember the islet cells which histologically look different from acinar cells, but which look really similar grossly. alpha cells make glucagon, beta cells make insulin, delta cells make somatostatin, and f cells make pancreatic polypeptide. these all look similar histologically. INSULIN is secreted in response to increased blood glucose. like parathormone and serum calcium levels, insulin is very responsive to immediate fine tuning of glucose levels. no complex feedback loop here. insulin promotes the utilization of glucose over protein or fat energy sources. it facilitates the uptake of glucose into many cells all over the body, and is very important. GLUCAGON in general produces the opposite effect of insulin SOMATOSTATIN mediates release of glucagon and insulin. the important dz of the endocrine pancreas is DIABETES MELLITUS which is caused by insulin deficiency or diminished effectiveness of the secreted insulin. this is an important distinction. classically, it's been classified into types. TYPE I and TYPE II (this is all based on human disease) TYPE I or "juvenile onset" diabetes mellitus: these individuals have onset early in life and it is associated with an absolute loss/decrease in islet cell mass and production of insulin. the islet cells will be missing or gone. in humans there are many theories about why this occurs - in some it is genetic (autosomal recessive), or immune mediated in some. it's been seen to occur in keeshonds as an autosomal recessive trait. from the very beginning these individuals don't have the normal number of islets and don't make neough insulin TYPE II or "adult onset" diabetes mellitus: this is much much much much much more common. 10% of people over 65 are affected, and 1 in 200 mature female dogs. in some of these instances, one can find a physical reason for it. so, sometimes there has been destruction of pancreas/islet cells by inflammation or neoplasia, but that is in a small percentage of the cases. in the majority of cases, the islets in the humans or animals are histologically normal. they look normal, there are the right amount of them, etc. when you measure insulin levels in the blood, it will be normal or increased or slightly decreased. the main thing is usually that there is peripheral insulin resistance at the target cell level or somewhere in the system. some resistnace to the effect of insulin. they know now that one of the major causes of this is insulin antagonism. anything that leads to persistent prolonged hyperglycemia will or can eventually result in increased secretion of insulin in response to that, and eventual exhaustion of the beta cells. it appears that the beta cells have a mitogenic liimit. they can only divide so long. if you keep stimulating them via persistent hyperglycemia, they will eventually poop out. so first you see high levels of insulin, early in dz, then normal, then low, then it's gone. so really, you also classify DM as insulin dependent or non-insulin dependent, as well as type I or type II. early in type II, patient isn't insulin dependent. late in dz, patient is insulin dependent. so what can cause persistent hyperglycemia? the ways you can get it in animals are: - obesity or chronic high CHO/glucose diet -> chronic hyperglycemia -> overstimulated beta cells ->etc. 4 out of 5 humans with diabetes start this way. - Cushing's disease -> increased cortisol -> anti-insulin effect -> persistent hyperglycemia -> etc. many animals with cushings will develop DM. - (seen in cats a lot lately) high levels of growth hormone. cats with functional pituitary tumors that secrete growth hormone get this. GH has priming effects on insulin. It tends to decrease the affinity of receptors on target cells for insulin -> insulin won't work well -> hyperglycemia -> etc. these cats tend to get DM secondary to functional pituitary tumors. also they can get acromegaly from the excess growth hormone. these cats will have facial structures of acromegalic cat - big bones, big jaws. will have big organs as well. Frankenstein type facial structure. but main importance is increased peripheral resistance to insulin. so you have hyperglycemia, and all the cells are being presented with a lot of insulin. what happens to the receptors? the receptors are very labile. if there is too much hormone hitting the receptors, negative cooperativity kicks in - you end up with decreased affinity of the receptors for the hormone and decreased numbers of receptors. so not only will you have eventual islet cell exhaustion, but you won't have any receptors there to bind the insulin that will be available!! there is no set time frame for this to occur. Q: can't DM be reversible? in non-insulin dependent type II DM, you can manage by diet alone in many cases, or by some oral hypoglycemic medications. this is because you have not yet pooped out the beta cells. so, if you treat an animal for cushings, it's possible they will go back to normal. it's only if you are born with it - type I - or if you have lost pooped out all your beta cells in type II - that you have to tx with insulin. most cats are type II non-insulin dependent, and most dogs are insulin dependent. either their islet cells burn out faster or there is a different predisposition. if you are insulin dependent type II, how do you use insulin if your receptors are resistant? receptors are *labile*. they can go up and down. so when you give insulin replacement, receptors will COME BACK. they only went away because there was TOO MUCH insulin. you do not see lesions in the pancreas, grossly or histologically, with diabetes mellitus. there may be transient DM after a bout of acute pancreatic necrosis or something, but that will go away. the VAST majority of time, there are no gross or histologic pancreatic lesions in a DM patient. that isn't where you look. you CAN look, but you won't find anything. you should be looking at the other factors we've discussed. depending on how you get DM, the clinical presentation is pretyt much the same: hyperglycemia, secondary glycosuria are the hallmarks chemscreenwise. some other lesions/changes are seen in these animals. they are PU/PD, mostly polyuric because of all the glucose in urine acting as osmotic draw, and PD because they get thirsty. Polyphagia: can't use glucose so get really hungry. Probably most consistent gross lesion seen w/DM is fatty change of the liver. this is because animals aren't using glucose, tend to break down their fat stores in more persistent/dramatic way, but liver can't handle increased lipid being brought in so it stores it. so a diabetic animal almost always has moderate to severe fatty change. also, because of all these lipids trying to get turned over, you get excess ketones being made. then you can see ketoacidosis, etc. another change you see often in dogs is cataract formation. they form because in the lens, the normal breakdown of glucose is to lactic acid, but enzyme cascades are overwhelmed, so glucose is converted to sorbitol, which builds up in the lens and acts as an osmotic draw, causing swelling and breaking of lens fibres and cataract formation. one other thing that's in the books about what you see with DM is that amyloid in islets of cats is the cause of DM in the cat. in most pathologist's experience, 80% of aged cats have islet amyloid, but 80% of aged cats do not have DM. therefore, it is unlikely that this is the cause of DM in cats. it may be, in some instances, we suppose. so even though you read that this is the cause, it's actually a common incidental finding. slides: - pancreas histo. normal pancreas. this is what you see in diabetes mellitus most of the time. - cat pancreas with an islet cell that has some amyloid. this cat does not have diabetes mellitus. DM in cats probably has to do with peripheral resistance, obesity, perhaps excess GH - fatty liver - severe diffuse fatty change of the liver is the most common change seen with DM> what about hyperfunction of endocrine pancreas? of course, caused by functional beta cell tumor or INSULINOMA. this is very common in ferrets and is also seen in dogs. the beta cells autonomously produce excess insulin leading to hypoglycemia. this hypoglycemia fluctuates in severity depending on time of day, eating schedule, etc. signs will be weakness, ataxia, poor exercise tolerance, occasional convulsions, stupor, coma. this shouldn't be a hard diagnsosis. you can test them by doing chem panel or seeing if signs improve with food or glucose bolus. these tumors may be VERY SMALL and hard to find during surgery. also, since there can be nodular hyperplasia of the pancreas which is normal and insignificant, it can be hard to distinguish the islet cell tumor. tumor may be a bit more grey. hard to tell. in the ferret, most of these tumors are benign and cured by excision. in dogs, more than 50% are malignant and will metastasize to the liver and elsewhere. slides: - islet cell tumor in ferret pancreas. it is very small. it's about 2 mm by 3 mm. unfortunately, they are also often right near a major blood vessel. - same thing from dog. this one is bigger and more obvious, but if you werne't looking for it it would still be hard to differentiate. - metastatic islet cell tumor in dog liver - multifocal yellow pinpoint to 2 cm masses randomly distributed throughout liver. questions? no. quick review of one last endocrine organ and its disease and that is: HEART BASE TUMOR aka AORTIC BODY TUMOR: recall the chemoreceptors spread around the body - aortic body, carotid bodies, etc. these chemoreceptors are usually not noticed but may occasionally esp in dog become neoplastic, and usually the aortic body is involved, and it lies right at the heart base. another term for these tumors wherever they are is a CHEMODECTOMA. tumor tends to be benign, but these are in a bad place. as they grow, they tend to compress and obstruct the local veins and lymphatics in that area. so that the most common presenting sign will be hydropericardium, filled with thin, serous fluid. this is because there isn't proper drainage of the normally secreted pericardial fluid. you will see a round heart appearance on radiographs. this can get so bad that you end up with cardiac tamponade - the fluid builds up and compresses the heart so it can no longer pump normally. it tries, but it fails. this tumor occurs mainly in brachycephalic breeds like boxers and boston terriers. can also get decreased perfusion to head and neck, so may see edema of head and animal looks funny. slide: ugly heart base tumor. ---end---