Well, welcome to part five. Great that you all can be here. This is the final chapter. You've made it to the end of clinical pathology. We saved endocrine testing for the end. So I'm excited to share these cases with you today. 

So just like we've done for all our other topics, this is going to be a case based review. And so we're going to review diabetes mellitus, thyroid testing and adrenal testing. And then at the end, just like we've done before, we will have some test your knowledge cases. 

All right. Without further ado, let's get started on case one. All right. And case one is Midnight, he is a ten year old male, neutered domestic shorthair cat. He's previously been healthy, but he is, was overweight. He's up to date on his vaccines and he has a one month history of polyuria, polydipsia or PUPD. And he's been losing weight even though he has a good appetite. So on his physical exam, here are his physical exam findings, and you'll note that there's really not anything too significant other than his body condition score is now a three out of nine. And so he is underweight. 

So we're going to run some bloodwork on him and let's start out with his serum chemistry results. So I will just give you a second to take a look at those. And then just like we learned about in lecture three, if we're going to do serum chemistries, we're also going to do a urinalysis as well. And here are the results of Midnight's urinalysis. Okay, so what can we conclude or what can we learn from Midnight's blood work? So let's start by looking at his serum chemistries and highlighted on the right the abnormalities. We can see that he has hyperglycemia, hypercholesterolemia and a mild increase in his alkaline phosphatase. If we take a look at his urinalysis, we'll see that his urine specific gravity at 1036 is adequate, and he has three plus glucose in his urine, which we call glucosuria one plus ketones in his urine, which we call ketonuria. And so in summary, we can say he has hyperglycemia with glucosuria and mild ketonuria, mild hypercholesterolemia and a mild increase in his ALP. 

So let's take a look at our blood glucose and we're just going to go back to learning a little bit of some pathophysiology and physiology. So if you remember back to your early days of vet school, you'll remember that insulin is the most important hormonal regulator of blood glucose. Insulin is produced by our pancreatic beta cells and it's released in response to an increase in blood glucose. And so what insulin does is it functions to decrease our blood glucose by increasing tissue uptake and inhibiting ongoing glucose production. 

Along with our insulin, we have counter regulatory hormones that basically antagonize or act against insulin. And insulin is working to lower our blood glucose. Our counter regulatory hormones are working to increase our blood glucose. So they do that by stimulating glucose production to increase the blood glucose. So the big counter regulatory hormones that we think although there are many hormones that fit in this category, glucagon, catecholamines, so that would be epinephrine and norepinephrine, corticosteroids, and growth hormone. 

All right. So why do animals or people become hyperglycemic? So there are a variety of different reasons why hyperglycemia can occur. One of the most important that we think about is decreased insulin production or a decrease in insulin release. Conversely, if we have an increase in our counter regulatory hormones, that is also going to act to increase our blood glucose. So, for example, in the case of stress, we have an increase in our catecholamines, and this is particularly important in cats. And this is really important to remember. Typically, it's a transient increase in the blood glucose. So blood glucose does return to normal, but it can be pretty pronounced. So it's not unusual to see a stress hyperglycemia even in the 3 to 400 milligrams per deciliter range. And so that's a very important cause of hyperglycemia in cats. In dogs, endogenous hypercortisolemia or hyperadrenocorticism can similarly cause hyperglycemia due to an increase in circulating cortisol. And similarly if we administer corticosteroids, they similarly will increase blood glucose just like hyperadrenocorticism can. Really important in catts primarily, but also in some small dogs, I've seen this happen. We have to differentiate a stress induced from a pathologic hyperglycemia. 

All right. So when we look at hyperglycemia, we always look at the urine as well. And so what is the relationship between hyperglycemia and glucosuria? So glucosuria occurs when the blood glucose is greater than the renal glucose threshold. What's really important to remember is that glucosuria alone doesn't distinguish between stress and pathologic hyperglycemia. All it tells us is that the renal threshold has been exceeded. In dogs, the renal threshold is about 150 to 200. In cats, the renal threshold for the glucose is significantly higher, it's 250 to 300. And so it doesn't tell us about how long the blood glucose has been increased, only that we've exceeded the renal threshold prior to urine sampling. So for example, if you have a cat who's in their carrier, they, a cat who normally lives at home, pretty stress free life, they get put in a carrier, get driven to the veterinary hospital, they get sat in a waiting room, maybe around dogs, and then they get their blood drawn. That renal glucose threshold is probably going to have been exceeded at some point due to stress in that process. And you will see glycosuria. Now just as an, an aside, there are some renal tubular defects that can cause a glycosuria with a normal blood glucose that's typically in dogs. It's very uncommon. So it's uncommon to see that. 

So how do we diagnose diabetes mellitus? Because that's really the important distinction that we're trying to make, is when is hyperglycemia truly pathologic? So remember that in diabetes we have a decrease in insulin production or release or insulin resistance, which results in hyperglycemia and diabetes mellitus. Now we're not going to really talk about the pathogenesis of diabetes mellitus today. That's that's not what we're looking at. We're looking at how we can just diagnose this with clinical pathology. And remember, we're always going to interpret our data in light of our clinical picture. So our clinical signs of diabetes mellitus typically are PUPD, so increased drinking and urination and weight loss despite a good appetite. In dogs if we see a sig, significant hyperglycemia, so that's usually a blood glucose over 250 to 300, let's say, plus glycosuria, so glucose in the urine and we have these clinical signs, we can feel fairly confident saying that that dog has diabetes mellitus. However, in cat cats we've got to remember that the stress hyperglycemia can increase our blood glucose even into the 3 to 400 milligrams per deciliter range. And so we've got to look back at the clinical signs and the clinical picture to help us rule out stress as a cause of hyperglycemia before we're going to diagnose diabetes mellitus. 

Now there's something else we can use to evaluate for diabetes mellitus, and that is a fructosamine concentration. So what is fructosamine? So glucose irreversibly binds to serum proteins, and most importantly, because it's the most abundant serum protein is albumin. And fructosamine is essentially a measure of these glycosylated serum proteins. And so because albumin has a half life of 2 to 3 weeks that gives our fructosamine half life, similarly, a similar time range. So it can give us information about the blood glucose over the preceding 2 to 3 weeks. Now what that tells us is that the hyperglycemia that we're seeing, it tells us about the duration of that hyperglycemia. So when our fructosamine is increased, that indicates that hyperglycemia has been present for at least 2 to 3 weeks. So that can help us distinguish between diabetes mellitus and stress hyperglycemia. In diabetes mellitus we'll see an increase in our fructosamine. And with stress hyperglycemia, our fructosamine will be normal. We can also use fructosamine to help us assess glycemic control in diabetes management. So generally speaking, a lower fructosamine indicates better glycemic control. 

So what else can we see in animals with diabetes that might give us some idea that this is the underlying pathology? So it's fairly common to see hypercholesterolemia and hypertriglyceridemia due to alterations in lipid metabolism. Dogs have fairly consistently an increase in that alkaline phosphatase, and that's due to a vacuolar hepatopathy due to glycogen deposition in hepatocytes. Cats, it's less common to see this, but we can still see it. A stress leukogram due to concurrent disease is not uncommon and you can look at lecture one for more information on that. Glycosuria typically causes an osmotic diuresis, and so we would expect to see a decrease in our urine specific gravity. And then remember that a lot of animals with diabetes mellitus will have a concurrent urinary tract infection. And you may see bacteriuria with or without an active sediment. Remember that glucose in the urine makes it a really good medium for bacterial growth. And because the urine is more dilute and because patients with diabetes mellitus are immunosuppressed, we may not see an active sediment. So it's always important to perform a urine culture in these patients, even if the UA looks normal. Excuse me. 

So let's take a look at ketones. We noticed in Midnight that he did have a low amount of ketones in his urine. And so what does a dipstick ketone tell us? So when we're talking about ketonuria, it's really important to remember that the urine dipstick doesn't detect beta hydroxybutyrate. It only detects acetoacetate. Now, in most cases metabolically, by the time you detect ketones in the urine that the beta hydroxybutyrate has been converted to acetoacetate. But there are some rare cases where you don't detect ketonuria even though it's present because the ketones are in the beta hydroxybutyrate form. It's important to remember that you see ketonuria before you see ketonemia. So you're finding ketones in the urine before you're seeing them in the blood. Ketonuria tells us that energy metabolism has been altered or changed. So essentially what that means is that fat is being used as an energy source instead of glucose. And when we if you remember back to physiology and biochemistry, you'll remember that fat as an energy source produces ketone bodies. Now in most cases ketonuria is due to unreg, unregulated diabetes mellitus and essentially it's due to an absolute deficiency in insulin. Less commonly, we can see that it can be due to starvation or malnutrition, but that's less common. But what's really important to remember, and again, we're not really going to focus on this today is that ketonuria does not equal diabetic ketoacidosis. Diabetic ketoacidosis occurs when you have a patient who is sick and if you remember from last week also has metabolic acidosis. So ketonuria alone in a patient that's otherwise healthy with diabetes mellitus does not equal diabetic ketoacidosis. 

All right, so let's go back to Midnight. So in Midnight's case, the clinical history is suggestive of diabetes mellitus. So if you remember, midnight has a one month history of increased drinking and urination and weight loss with a good appetite. On the bloodwork, we have hyperglycemia with glycosuria, so our renal glucose threshold has been exceeded, and we also see hypercholesterolemia. So that's suggestive of diabetes mellitus. The fact that we have ketonuria and glycosuria is also suggestive of diabetes mellitus. Now if we just look at the PUPD and weight loss alone, that could indicate hyperthyroidism in a cat and that's something that we'll talk about shortly. So often on a senior blood panel you'll find a thyroid hormone level. So that's a fairly routine part of senior blood work in the US. So we need to be aware of that and we need to be looking at that. In Midnight's case, his total thyroid hormone level was at 1.7, which if we look at our normal range is normal. We we were fairly certain that he was diabetic, but we did confirm with a fructosamine level and in his case his fructosamine was significantly increased, which tells us that he has had a more prolonged hyperglycemia. So that supports our diagnosis of diabetes mellitus. 

Now, just as an aside, we're going to talk about as we're on the subject of glucose, we're going to talk about hypoglycemia as well. Remember that in adults, hypoglycemia is pretty uncommon. And in cats that aren't receiving insulin, it's very, very rare, very rare to see hypoglycemia in an adult cat who is otherwise healthy. So if a patient is clinically normal, one of the most common causes of hypoglycemia is actually artifact. And so it's really important to remember that blood cells consume glucose and this happens even if you've got a serum separated tube. So even if you have a blood collection tube that has a serum separated gel in it, so unless you separate that serum promptly, the cells are still going to consume glucose. The rate of glucose composition sorry, consumption, depends on a lot of different factors, but storage temperature of the sample isn't refrigerated rapidly, that will increase glucose consumption. So I've seen cases where patients have been misdiagnosed with hypoglycemia due to delays in sample handling and the way that you can get around that is fairly simple. You can get that patient to come back in and recheck blood glucose with a handheld glucometer. So that gives us a very quick and, you know, complimentary reading to tell us whether or not we think that blood glucose is really low or if it was a an error in our sample handling. 

Now there are some situations where hypoglycemia is real and is significant. So particularly in young or neonatal animals, hypoglycemia is a cause for concern and is real. And generally speaking we're finding that out using a handheld glucometer when we have a sick puppy or kitten come into us. Is particularly common in small or toy breed dogs. Sepsis, of course, is another big cause of hypoglycemia, but usually those animals are coming in looking very, very sick. So we're going to look for other changes, such as an inflammatory leukogram. Hypoadrenocorticism can also cause hypoglycemia and we'll talk about that more shortly. And then in older dogs, it's important to think about an insulinoma. So an insulinoma is a tumor of the pancreas, that, of the pancreatic beta cells that secretes excessive amounts of insulin. So this results in hypoglycemia and sometimes these patients will present with weakness or collapse or seizures due to profound hypoglycemia. The way that we can diagnose an insulinoma is by performing an insulin glucose ratio which we can run on blood. But it's really important that we have to run this blood on a patient when they are hypoglycemic. So we can't run this after we've given this animal intravenous dextrose. This ratio isn't going to be valid if the blood glucose is normal when you pull this ratio. So you can only interpret this ratio if there is hypoglycemia at the time of the blood draw. Okay.