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Endocrinology Ellen N. Behrend, VMD, PhD, DACVIM Department of Clinical Sciences College of Veterinary Medicine, Auburn University Everything I learned from my Diabetic Cat: Treatment I have been lecturing, researching and writing about diabetes mellitus (DM) for approximately 15 years. I feel I know a good bit about the disease, but being the owner of a diabetic cat was a "good learning experience" as the saying goes. Many things I took for granted or thought I knew were different when it was my own cat! DIAGNOSIS For the most part, DM is one of the easiest endocrinopathies to diagnose and a "no-brainer". Of course, it took me about 2 weeks to figure out if my own cat was diabetic or not! Madison was (unfortunately, we lost him to complications of FIV about 6 months after his DM resolved) a 12 year CM DSH that I adopted from Auburn University cat colony when he was approximately 2 years old. At the time of diagnosis of DM, the only clinical sign I noticed was weight loss. He was one of 3 cats, so assessment of food intake was difficult and he was always a chow hound (or chow cat :). I had not noticed pu/pd or polyphagia. I did a CBC/profile/UA and T4. Pertinent information was a blood glucose concentration of 274 mg/dL (normal 80-120) and 3+ glucosuria. T4 was low normal. Although 274 mg/dL is a little on the high side for stress alone, it could be stress hyperglycemia. Arguing for stress hyperglycemia was an apparent lack of clinical signs with the exception of weight loss. However, stress hyperglycemia is not expected to cause glucosuria, so the 3+ urine strongly suggested DM. I will cover the rest of the diagnosis during the lecture on monitoring, as the 2 use similar techniques. Question to ponder: What tests would you do now? TREATMENT Treatment of diabetes mellitus (DM) can be quite frustrating. Human recombinant Lente and Ultralente preparations, long used to treat DM in veterinary medicine, are no longer available. Vetsulin , a porcine Lente, is now available and is the only insulin approved for use in dogs. Glargine (Lantus ) is a genetically-engineered recombinant human insulin used in humans now for a number of years. Within the last few years glargine has been used in cats and initial reports are very promising for getting good control and, more importantly, for inducing remission of the DM. Therapy of any disease is ideally aimed toward the underlying abnormality. In Type I diabetes mellitus (DM), a lack of insulin exists, so treatment provides an exogenous source. Type I diabetics do not have the metabolic abnormalities present in Type II DM that are addressed by oral hypoglycemics. Consequently, administration of oral hypoglycemics to Type I diabetics is inappropriate, with the exception of acarbose. For Type II DM, oral hypoglycemic agents can be used initially, but as Type II DM progresses, exogenous insulin injections will be required. Dogs are mainly Type I diabetics.1;2 Accordingly, oral hypoglycemics have not been used widely in this species. Cats are believed to be mainly Type II, at least initially, but conflicting data exists. In any case, patients with advanced Type II DM and glucose toxicity, a population likely to represent the majority of diabetic cats, will have totally lost insulin secretory ability. Accordingly, some diabetic cats will respond to oral hypoglycemic agents but most will require insulin therapy. For cats, the best case scenario is to have the DM resolve. How likely this is in general is unclear. Older estimates were that 10-25% of cats had transient DM. Initial data on glargine (which involved only 14 cats) suggests that it could be much higher - 100% in newly diagnosed cats on glargine and the appropriate diet. I doubt that it really will be 100%, but 14/14 cats treated in this manner is still impressive! In order for the DM to resolve, as good control of BG concentration as quickly as possible is needed. Diet does play a role in this. For a number of years now, the recommendation for diabetic cats is a high protein, high fat diet, e.g. Purina DM or Hill's M/d. Following a high carbohydrate meal, cats have prolonged postprandial hyperglycemia.3 Cats already on insulin placed on a high protein, high fat, low-carbohydrate diet had their DM resolve or experienced a marked reduction in insulin dose. 4-6 The 14 cats on glargine mentioned above that had their DM resolve were on such a diet. In general, the canned version of DM or M/d is preferred as that is the lowest in carbos, but dry is fine. Canned kitten food would be all right as well. Whether glargine would be as effective without a concomitant high protein, high fat diet is unknown. Diet is not the only factor in remission, as some cats had their DM resolve historically while on high fiber diets. However, empirically, glargine is not expected to be as effective without a high protein diet. Caution should be used with these diets in cats with renal disease due to the high protein content. If a high protein diet is not a possibility, feeding a more standard diet and administering acarbose may achieve the same goal.7 (Madison was on glargine but a "senior feline dry diet" due to the presence of another cat in the house with renal issues and his DM did resolve.) High dietary fiber for treatment of diabetic dogs is still recommended. Through unknown mechanisms, dietary fiber can delay gastrointestinal glucose absorption, reducing post-prandial fluctuations in BG and enhancing glycemic control. Insoluble fiber can be beneficial in diabetic dogs.8;9 However, the response of diabetic dogs to fiber can vary between individuals, and a recent study showed that diets with high fiber and moderate starch were not advantageous for dogs with stabilized DM compared to a moderate fiber/low starch diet.10 Insoluble fiber, the type present in commercial feline high fiber diets, can improve glycemic control in diabetic cats.11 Although anecdotally I have heard of cats that appear to be early diabetics have their DM resolve with dietary management alone, I do not recommend this if the owners are willing to administer either insulin (much preferred) or glipizide, an oral hypoglycemic agent. The longer a cat has uncontrolled DM, the less likely the DM will resolve. Insulin therapy is your best chance of getting control of the BG quickly! The "latest and greatest" for the last few years for feline diabetics is use of a new human synthetic insulin analogue called insulin glargine in healthy and diabetic cats. Insulin glargine is produced by recombinant DNA technology, and is advertised as being "peakless" in people. The chemical structure of insulin glargine has been altered slightly from native human insulin. Glargine is a clear aqueous solution in 100U strength with a very acidic pH (pH=4). When insulin glargine is injected subcutaneously into a more neutral pH, the insulin forms micro-precipitates with a relatively constant absorption into the systemic circulation. The micro-precipitate formation and slow absorption are dependent on the pH of the glargine, so glargine cannot be mixed with other insulins or diluted.12 In diabetic cats, the use of glargine appears extremely promising. Glargine has a long duration of action and a predictable blood glucose lowering effect.12 In 14 newly diagnosed cats treated with a high protein-low carbohydrate diet (Purina DM canned), the diabetes resolved in all within 4 months.13;14 Although no difference was seen in control or remission in diabetic cats when Lente or glargine was administered once daily15, when Lente, PZI or glargine were administered BID to 8 cats each, all 8 on glargine went into remission as compared to 3 of 8 on PZI and 2 of 8 on Lente.14 Thus, I recommend glargine BID for treatment of newly-diagnosed diabetic cats, and that is what I started Madison on. Long-term diabetic cats have been switched to and treated with glargine as well with good success, but the diabetes has not resolved. Cost-wise, insulin glargine is comparable to PZI from Idexx. Note: although glargine is my 1st choice insulin in a newly diagnosed cat or a cat not well regulated on another insulin, if a cat has been a long-term diabetic and is well regulated, I would not switch to glargine. In long-term diabetics, obtaining diabetic remission with glargine is much less likely, and if the cat is controlled, I would not "mess with success". Recommendations are to start cats on glargine BID at 0.5 U/kg if BG is >360 mg/dL or 0.25 U/kg if BG is <360 mg/dL. For the first 3 days, 12-hr blood glucose curves should be performed (i.e. the curve should be performed for the interval between the a.m. and p.m. dose). The purpose of the blood glucose curve is to detect hypoglycemia, if present, and lower the dose of glargine as needed. Many cats require dose reduction within the first 3 days. The insulin dose should not be increased for the first week no matter what the curves look like!!! After the first 3 days, the cat should be sent home and then return for a curve 7 days later. Subsequent blood glucose curves should be performed 1, 2 and 4 wks later and then as required. Recommendations for dose adjustment are based on the pre-insulin blood glucose (compared to other insulins where we change dose based on the nadir). If at recheck, the pre-insulin BG is >290 mg/dL, increase the glargine dose 1.0 U/cat. The dose should not be changed if the pre-insulin BG is 220-290 mg/dL. In either of these first 2 scenarios, a curve should be done the following day to ensure that hypoglycemia is not occurring. The dose should be decreased 0.5-1.0 U/cat if the pre-insulin BG is <180 mg/dL. If biochemical hypoglycemia is present, the dose should be decreased 1.0 U/cat. If clinical signs of hypoglycemia are present, the dose should be decreased 50%. Administration of glargine insulin should not be discontinued within 2 weeks of starting treatment regardless of the curve - decrease the dose if needed, but do not stop the insulin (J. Rand, personal communication). To determine if a cat is in remission, insulin administration should be continued until the cat is receiving 1 U BID. Then, if the pre-insulin BG is <180 mg/dL, go to once-daily administration. If the next day, the pre-insulin BG is still <180, do not administer insulin and do a complete curve. If the pre-insulin BG is >180 mg/dL when receiving once-daily insulin, go back to BID. An attempt to wean the cat can again be made in a couple weeks. If performance of a curve is impossible due to temperament or financial issues, start insulin glargine at 2 U/cat SQ BID and have the owner monitor urine glucose concentration or water intake. A cat well-regulated on glargine should have trace urine glucose at most and urine glucose should be negative the majority of the time. If after 2 weeks of receiving glargine insulin, urine glucose is > trace, the dose should be increased 1 U/cat/wk until urine glucose is negative or water intake is <20 ml/kg/24h if eating canned food and <70 ml/kg/24h if eating dry food. At this point, keep the cat on the same dose for 2 weeks then start decreasing the dose by 1 U/cat/wk until urine glucose is positive or the insulin has been discontinued (J. Rand, personal communication). Although in 6 diabetic cats treated with glargine hypoglycemia was not documented13, in 1/3 of normal cats treated BID, mean blood glucose remained significantly suppressed at 24 hrs, indicating a carryover effect of glargine.16 Therefore, hypoglycemia is a possibility and should be monitored for as when using any other type of insulin. Nothing has been published to date about Levemir® (insulin detemir) in cats, another long-acting recombinant insulin similar to glargine. Anecdotal information suggests it is no more effective than glargine. Similarly, nothing has been published about detemir or glargine in dogs, but neither appears to offer any advantage over other insulins. Interestingly, in 2 of 9 healthy dogs to which glargine was administered, BG did not change after injection of glargine insulin suggesting possible lack of efficacy in dogs.17 Vetsulin (Intervet) is a purified pork Lente insulin relatively recently approved by the FDA for use in dogs. It has been available for many years in other countries under the name Caninsulin. Since the amino acid sequences of pork and canine insulins are identical, porcine insulin, at least in theory, may be the ideal form to use in dogs. (I don't believe that it is the ideal form.) Vetsulin is the only insulin approved for use in dogs. A study has been completed where 53 dogs with uncomplicated diabetes were treated with Vetsulin for 60 days after a variable initial dose determination period. Therapy was started once daily and was changed to twice daily as needed. The starting dose used was the one recommended in the product insert: 1 U/kg with a supplemental dose depending on body weight (dogs <10 kg received 1 U supplement, 10-11 kg 2 U, 12-20 kg 3 U and dogs >20 kg 4 U). Efficacy and safety were evaluated at the end of the dose determination period (time 0) and 30 (time 1) and 60 days (time 2) later. With treatment, 80-96% of dogs had resolution of polyuria, polydipsia and ketonuria. Mean BG was 370 mg/dL before treatment but was 151-185 mg/dL while receiving Vetsulin . At time 0, 1 and 2, 100%, 66% and 75% of the dogs were judged to be adequately controlled based on BG and clinical signs, respectively. At the end of the dose determination period, 57% were receiving Vetsulin twice daily (43% were receiving once-daily injections) and by day 60, 66% were receiving twice-daily injections. Overall, the median number of days to achieve adequate glycemic control was 35 (range 5-151 d). No unexpected side effects were observed, but 22 dogs had signs at some time that could have been caused by hypoglycemia and 2 dogs died of presumed hypoglycemia. For 7 dogs, owners reported swelling and/or pain at the injection site, but neither were noted by investigators on physical examination.18 Thus, Vetsulin appears to be a good option for use in diabetic dogs. The starting dose of insulin deserves consideration. Although some authors recommend a starting dose of 0.25 U/kg twice daily for dogs19, others recommend using 0.5 U/kg if the blood glucose is >360 mg/dL and 0.25 U/kg if <360 mg/dL.20 This author uses the former recommendation. Thus, the starting dose given in the Vetsulin insert may be high, and a lower dose may be more appropriate. Furthermore, in one study of dogs, 94% of dogs required twice-daily dosing regardless of insulin type used for adequate control.21 In addition, recent data suggest that human recombinant NPH may have a shorter duration of action than the human source NPH previously available22, further increasing the need for BID therapy if using recombinant human NPH. The site of insulin injection is another important aspect to consider. An appropriate location for an injection site must be chosen, as absorption of insulin from various sites in the body differs. For example in humans, insulin absorption from the abdomen is more rapid than from the thigh, and injection into an extremity may result in inconsistent insulin absorption depending on exercise and limb movement. In dogs and cats, the dorsal neck or scruff has commonly been used as a site for injection, but this site may not be ideal due to low blood flow and increased fibrosis caused by repeated injections. A better option may be to administer the insulin at sites along the lateral abdomen and thorax. The chosen area should be rotated daily in order to prevent fibrosis at an injection site.23 Glargine is acidic and may sting slightly when administered. Insulin syringes, as compared to other types, are recommended due to the small needle size, but a needle prick can always be an unpleasant sensation. Madison objected to the injections at first and it began to be an issue. Just as for performance of home glucose curves, a good practice is to make the injections (or blood draw if doing curves), part of a good experience. For diabetics that are meal fed and are very into their food, inject them as they are eating. For others, you can give the injections when doing a pleasurable activity. For example, Madison loved to be brushed and we already had a brushing session once daily. I made it twice a day instead, would brush him for a while, would pop him with the injection at some point and immediately go back to brushing. Within a few doses, he no longer minded. For any patient that needs a low dose, 0.3 ml syringes should be used for accurate dosing. These are referred to as "low-dose" syringes. The scale on the syringe is easier to read for small doses. Although this seems like a minor detail, believe me, giving insulin can be nerve wracking! The syringes are not that easy to read and a small error can have big consequences when you are only giving 2 U to begin with! Timing of feeding, especially as it relates to insulin administration, should be considered. In order to mimic physiological insulin release, insulin should ideally be given with each meal. In humans, insulin is administered at each meal or snack and blood glucose is monitored at the time of insulin administration as a guide to insulin dosage. Obviously this is not a practical situation in veterinary medicine. The absorption of nutrients and development of postprandial hyperglycemia depends on numerous factors, but, ideally, calories should be ingested when insulin is still present in the circulation. Classically, the recommendation has been to feed patients BID to spread out caloric intake. In a patient receiving insulin BID, giving the meals before the insulin additionally serves the purpose of ensuring the patient is eating. If inadequate calories are consumed, the insulin dose should be halved. Some dogs and (especially) cats as well as households are not amenable to a BID feeding schedule. At least when fed a high carbohydrate meal, meal feeding contributed to prolonged gastric emptying and prolonged postprandial hyperglycemia.3 Thus, animals that eat small amounts constantly throughout the day may actually best approximate the ideal situation as postprandial hyperglycemia will likely never be profound. Judging an individual animal's intake in a multi-animal household, however, can be difficult and may necessitate periodic isolation. Owners need be very strongly advised about the possibility of hypoglycemia as administration of a full dose of insulin in the face of inadequate caloric intake is more likely using this method. How much wiggle room is there in time of administration? That is an answer that we really do not know and likely will vary with the patient, the duration of insulin being used and the shape of the curves. For me, with, a full-time job and, at the time, 4-yr old twins, I tried for a 12-hr interval in insulin administration, but it was not always achieved. Realistically, the interval varied between 11 and 13 hours. Empirically to me, this may be another reason to use glargine in cats as flatter curves are obtained and a shift by 1 hour in either direction may be less significant in changing control. Glipizide can be tried in cats as a sole agent, but I do not recommend it. The primary action of sulfonylureas (e.g. glipizide) is to increase insulin release. Long-term success rate is estimated to be approximately 35%24;25, but which cats will respond can not be predicted. The ideal patient for treatment with glipizide is a stable, non-ketotic diabetic cat of optimum to obese body weight that has mild clinical signs with no complicating diseases. Patients that are emaciated, dehydrated, debilitated, have recently lost >10% of their body weight or have concomitant disease are not good candidates.26 Additionally, glipizide can be tried in any cat whose owners refuse to give injections. Adverse effects are minimal. Vomiting is most common (approximately 15%).24;27 Increased liver enzymes and icterus develop within 4 wks of initiating therapy in approximately 10%.24;25 Hypoglycemia occurs in approximately 12-15% of responder cats24;27; usually these cats are transient diabetics. Most cats that respond without continued adverse effects can be treated with glipizide for life2, but glipizide loses effectiveness in at least 5-10%.24;27 The period from initiation of therapy until failure is unpredictable, ranging from weeks to >3 yrs.2 Glipizide treatment should be instituted at a dosage of 2.5 mg/cat per os BID with food, and the cat examined after 1 and 2 weeks. A history, complete physical examination, body weight, BG and urine glucose/ketones should be evaluated. If no problems occurred during the first 2 weeks, the dosage should be increased (5.0 mg/cat BID). If ketonuria is found, the medication should be discontinued and insulin therapy initiated.2 If vomiting or icterus is present, the drug should be discontinued until the problem resolves. Most cats will tolerate the medication if started at a lower dosage and gradually increased. If hepatic enzyme elevation or icterus occurred with the first administration, liver enzymes and serum bilirubin concentration should be checked periodically after reinitiation. If problems recur, the drug administration should be stopped and the cat placed on insulin.2 Once a dosage of 5 mg BID has been given for 2 wks, the previously mentioned parameters and a 10-12 hr glucose curve should be checked every 4 wks.2 Response to therapy is evidenced by resolution of clinical signs, BG during the curve <200-300 mg/dL and lack of glycosuria.26 Time until response varies, so therapy at the full dosage should continue for 12 wks unless a contraindication develops.2 If no response is seen after 12 wks, glipizide administration should be stopped and insulin therapy instituted. To me, this is the big problem with glipizide. We really do not know at what point glucose toxicity becomes irreversible. The length of time this requires after development of DM probably varies betweens cats. Empirically, wasting 12 weeks trying glipizide worries me. If glipizide does not work, you may get control of the DM when you try insulin, but you are less likely to have the DM resolve. Resolution, to me, again, is the ultimate goal of treating diabetic cats. If clinical signs and glycosuria resolve and blood glucoses are <200 mg/dL, glipizide therapy should be stopped and the serum glucose concentration re-evaluated in 1 week.2 If hyperglycemia is present then, glipizide should be reinitiated.26 If normoglycemia is present, no medication is warranted. Glipizide can be used again, however, at any time if hyperglycemia recurs.27 The patient should be rechecked every 3 months to ensure ongoing control. Cats that have resolution of clinical signs according to the owner, stable body weight and normal physical examinations but serial blood glucoses >300 mg/dL present a clinical dilemma. Either the clinical signs have not truly resolved or the hyperglycemia is due to stress. Cats such as this should ideally be monitored by serum glycated hemoglobin (GHb) or fructosamine concentrations to determine overall glycemic control. If these tests are not available, urine glucose can be monitored at home when the cat is not stressed. If glycosuria is absent or GHb or fructosamine concentrations are normal, glipizide therapy can proceed. If glycosuria is present or glycated protein levels are elevated, insulin should be used instead.2;24 Other oral hypoglycemic agents do not hold much promise for treatment of DM in veterinary patients. Transition metals are insulin-mimetic. Low doses (0.2 mg/kg/day) of vanadium decrease blood glucose and alleviate clinical signs in cats with early type II DM (D.S. Greco, personal observation). Unfortunately this is not a population we see often. In cats treated with vanadium, mild gastrointestinal signs may occur and 1 cat developed reversible renal failure. Vanadium is available commercially as Vanadyl Fuel (˝ capsule daily on food). In one study, chromium had no effect in concert with insulin treatment in diabetic dogs.28 Large clinical studies on the effect of vanadium or chromium in diabetic cats are lacking. The biguanides (e.g. metformin) inhibit hepatic glucose release and improve peripheral insulin sensitivity. Doses of 25-50 mg/cat BID should attain plasma concentrations used for treating human DM, but results in diabetic cats are not promising.29 In the single published study, 6 cats (5 newly-diagnosed, 1 insulin-treated) received metformin at a gradually increasing dosage. One cat was found dead after 2 weeks and no response was seen after 6-7 weeks in 4 cats. In 1 cat, glycemic control improved after 7 weeks (dose = 50 mg daily) and metformin was used successfully for 5 months. Side effects noted in healthy cats include inappetence, weight loss and vomiting.29 -glucosidase inhibitors (e.g. acarbose) impair intestinal glucose absorption by decreasing fiber digestion and hence glucose production from food sources. In 5 dogs, a combination of acarbose and insulin provided better glycemic control over insulin alone. However, the final conclusion was that, due to expense and adverse effects, acarbose is primarily indicated for poorly controlled diabetic dogs for which the cause for the poor control cannot be identified.30 Acarbose may be administered at a dosage of 25-200 mg/dog or 12.5-25 mg/cat BID with meals. Side effects include flatulence, semi-formed stools or diarrhea. Thiazolidinediones increase target tissue sensitivity to insulin by binding to a novel receptor called the peroxisome proliferator-activated receptor- (PPAR- ); they have received little attention for use in diabetic cats. Recent work suggests that darglitazone has beneficial effects in obese non-diabetic cats to decrease insulin secretion and glucose concentrations in a glucose tolerance test31, but no work has been done in diabetic cats. References available from the author. Everything I learned from my Diabetic Cat: Monitoring Marked variation in insulin kinetics - particularly in cats - makes monitoring of diabetic control crucial. Options for monitoring include performance of glucose curves either in a hospital or at home, measurement of serum glycosylated protein concentrations, monitoring of presence and degree of glycosuria and assessment of the presence or absence of clinical signs of DM. Some of these same techniques can be used for diagnosis if need be. Let's return to Madison, my cat (see last lecture). We had conflicting data - no convincing clinical signs (only weight loss), a blood glucose concentration (BG) of 274 mg/dL, 3+ glucosuria. To add further confusion, his serum fructosamine concentration was normal. Clearly Madison was a diabetic as last lecture talked about his treatment, but how was that diagnosis made? One consideration is how accurate glucose test strips are for measurement of glucosuria. The test strips only measure the presence of a "reducing substance" and other compounds, e.g. cephalexin and enrofloxacin1, can cause false positive tests. In addition, the presence of ketones can decrease the sensitivity of the test. We did a small research project on the accuracy of the Bayer Multistix for measurement of glucose in canine and feline urine. On the Multistix chart, trace = 100 mg/dL glucose, 1+ = 250 mg/dL, 2+ = 500 mg/dL, 3+ = 1000 mg/dL and 4+ = > 2000 mg/dL and the sensitivity is 75-125 mg/dL. Thus, based on the color chart, we assigned a negative reading = <75 mg/dL, 1+ = 76-175 mg/dL, 2+ = 176-375 mg/dL, and 3+ = >750 mg/dL. The Multistix are not highly accurate at least in dogs, tending to underestimate urine glucose.
To get the most accurate measurement and to ensure that glucose is really present in the urine, based on these results, it is best to have the lab measure urine glucose concentration as they would serum. Madison's urine was positive. Given the difficulty of using the Multistix we did a small project looking at the use of glucometers for measurement of urine glucose concentration. We used the Alphatrak as well as the Accuchek in dogs and cats. Unfortunately, the results were not promising (unpublished data). Another possible means to differentiate stress hyperglycemia and DM is measurement of glycosylated proteins, either glycosylated hemoglobin or fructosamine. Glycosylated hemoglobin (GHb) is formed by non-enzymatic, irreversible binding of glucose to hemoglobin.2 Fructosamine refers to glycosylated serum proteins, mainly albumin.3 Both GHb and fructosamine form at a rate proportional to the average BG present, so the higher the mean BG concentration over time, the greater their concentrations should be. The levels of glycosylated proteins are also affected by the half-life of the native protein. Thus, GHb reflects glycemic control over the previous 2-3 months, while fructosamine reflects that over the previous 2-3 weeks. As with any laboratory test, care must be taken to use the correct sample handling techniques and methodology for measurement, and limitations of the test must be recognized. Cats may have lower normal GHb concentrations than dogs4 and normal ranges vary between laboratories, so it is necessary to be sure that the laboratory has its own established normal ranges for dogs and for cats and to use those in interpreting values obtained. Anemia may lower GHb concentrations. As with GHb, ranges for serum fructosamine concentration vary between laboratories. Within the normal range, serum protein does not affect fructosamine; however when serum protein concentration is less or greater than normal, fructosamine levels may be decreased or increased, respectively. Both parameters correlate with BG and are typically not affected by stress. However, the value obtained from the laboratory must be interpreted in conjunction with all other data. Normal animals or well-controlled diabetics can have elevated concentrations of either GHb or fructosamine, and, conversely, uncontrolled diabetic animals can have normal levels of either. Fructosamine may be elevated in sick, hyperglycemic, but non-diabetic cats. Madison's fructosamine concentration was at the high end of the normal range. So, again, conflicting information. Options at this point to prove the diagnosis included some type of home measurement. Given he was a lab cat at one time, blood draws were hugely stressful no matter where. A good option was monitoring of urine glucose - if he was always negative at home, then likely the hyperglycemia was simply stress. A good option for monitoring urine glucose at home in cats is the Purina Glucotest . We did a study at Auburn that showed that the Glucotest™ tends to overestimate urine glucose concentrations in the midranges (50-300mg/dL), even when exposed to urine glucose concentrations that directly correlate with the published color chart. However, the overestimation was by one category, e.g. 50 read as 150 mg/dL and would be likely clinically irrelevant. The color change read at 8 were more accurate than the initial readings, but the change over time is not consistent with the labeled 8-hr color stability claim. Again, the change over time was typically by one category.5 Madison had glucosuria at home on two separate occasions, so a diagnosis of DM was made. The Glucotest is designed for cats, but given the low accuracy of the Multistix, we have done a small project assessing the Glucotest for dog urine. Unfortunately, for dogs, the Multistix do not appear to be accurate (unpublished data). One question to ask, is what are we looking for in monitoring diabetics, or, in other words, what is the goal of therapy? At all costs, hypoglycemia should be avoided. On the flip side, how high can BG go? The goal of therapy is to get rid of the clinical signs in order to provide a good quality of life for the pets and clients. The strict control aimed for in human diabetics is not practical and may not be necessary in veterinary patients. Strict control in humans is required to avoid serious diabetic complications such as nephropathy, retinopathy, vasculopathy, etc. For whatever reason, these complications are not prevalent in veterinary populations. To get rid of clinical signs, BG needs to be below the renal threshold the majority of the time, i.e. < approximately 200 mg/dL in dogs and approximately 250-300 mg/dL in cats. Performance of in-hospital blood glucose curves has long been the gold standard for assessing diabetic control. To construct a curve, BG is measured in general every 2 hrs for one interval between injections, i.e. for 12 hrs if insulin is administered twice daily and for 24 hrs if insulin is given once daily. For glargine, the suggestion has been made to only measure BG every 4 hours, but I still measure BG q 2 hrs. When BG is <125 mg/dL, the concentration should be measured hourly. A normal insulin/feeding schedule must be maintained as much as possible. If a patient does not eat the normal amount of the normal food at the usual time, the serial glucose curve should probably not be performed. The patient should be fed its standard diet at the usual time and the insulin given by the owner in the hospital so the owner's injection technique can be assessed. Obtaining a fasting blood sample for measurement of BG prior to insulin injection can aid in appraisal of glycemic control, but this may not be possible if normal feeding time occurs before the hospital opens. Furthermore, feeding a dog or cat at home may ensure that the pet will eat. If the patient is fed at home, the insulin should then be given by the owner either at home or, especially if owner technique is questionable and needs to be assessed, in the hospital in front of a technician or veterinarian. Clearly, cooperation between client and veterinarian is necessary to maximize the information obtained with minimal disturbance to routine. If given a choice between obtaining a fasting BG sample or assessing owner injection technique, choose to assess the owner's technique. A curve should be performed the first day insulin is given. Glucose concentrations may be lower than expected after the first 24 to 48 hours of insulin therapy, especially in cats as stress hyperglycemia resolves 6. This first curve is done solely to ensure that hypoglycemia does not occur. If hypoglycemia is found, the insulin dose should be decreased 25% and another curve done the following day with the same goal in mind - to check for hypoglycemia. The insulin dose should not be increased based on the first day's curve. A patient requires 5-7 days on a dose of insulin to equilibrate and reach maximal effect. Another glucose curve should be performed 7 days after discharge. Based on assessment of the curve, the insulin dose can be increased or decreased as deemed necessary. A serial glucose curve should establish the time to peak insulin effect, duration of effect and degree of fluctuation in BG. The pattern of insulin effect should be used to determine dose, interval, and feeding schedule. Ideally, glucose concentrations should reach a nadir at 80 to 150 mg/dL. The highest glucose concentration should be close to 200 to 250 mg/dL in dogs or 300 mg/dL in cats. The actual nadir and peak concentrations in a patient will probably be lower, or higher, respectively, than measured because the exact time of nadir and peak effects of insulin are not known. Changes in the dose of insulin can usually be made without affecting the duration of effect. The glucose differential is the difference between the nadir and the BG prior to the next dose, and can be a measurement of insulin effectiveness.7 If the curve is relatively flat, e.g. differential of 50-100 mg/dL, the insulin, with the exception of glargine where such curves are expected, may not be having a desired effect. The absolute BG must also be taken into consideration. If all BG are < 200 mg/dL, the insulin is very effective. However, if all BG are between 350-400 mg/dL, then the insulin is ineffective at that dose, stress hyperglycemia is present or you have caught a patient post- Somogyi (for a number of hours after a Somogyi phenomenon, insulin resistance will be present). In assessing a glucose curve, whether it is the first curve performed on a patient or the last of many, two basic questions need to be asked. First, has the insulin succeeded in lowering BG? And, second, how long has the insulin lasted? By answering these questions, logical changes in dosing regimen, if necessary, can be made. Results of a serial glucose curve should always be interpreted in light of clinical signs. Curves in dogs can vary from day to day 8 and do in cats as well.9 Stress hyperglycemia can also falsely elevate results. If a patient is not polyphagic, polydipsic or polyuric and body weight is stable or increasing, diabetic control is likely good. The first aim in regulating a diabetic is to achieve an acceptable nadir. (Note: this is true for all insulins EXCEPT glargine. For insulin glargine, dose adjustment is made based on the pre-insulin glucose concentration.) In general, if an acceptable nadir is not achieved, the insulin dosage should be adjusted depending on the size of the animal and the degree of hyperglycemia. Usually changes of approximately 10% are appropriate. Obtainment of an acceptable glucose nadir may not be possible in some animals, however, if insulin with a short duration of activity is used. In these patients, the BG is typically quite high in the morning since there has been inadequate control for most of the previous day. Even if an insulin injection is capable of lowering BG, it does not have a long enough effective period to lower BG into an acceptable range. In other words, a glucose curve in this situation shows a noticeable but brief decrease in BG after the insulin injection. Hypoglycemia should always be avoided. No matter what other BG concentrations are during the day, if the value of the BG nadir is <80 mg/dL, a reduction in insulin dosage is indicated. Decrease the dose 25% if there are no signs of hypoglycemia and 50% if there are signs, and then do another curve to ensure hypoglycemia does not recur. Once an acceptable nadir is accomplished, duration of action, roughly defined as the time from the insulin injection through the lowest glucose and until the BG exceeds 200 to 250 mg/dL, can be determined by a glucose curve. If the dose of insulin is inadequate and the target glucose nadir has not yet been achieved, the dose must be increased until the nadir is acceptable before duration of effect of the insulin can be determined, i.e., duration and nadir cannot be assessed at the same time if one or the other is insufficient. Once control has been achieved, glucose curves should be performed to assess adequacy of glycemic control every 3 to 6 months or earlier if clinical signs suggest that control has been lost. The more precarious the control, the more frequently rechecks should be done. As during the initial curves, if the nadir is unacceptable, the insulin dose must be lowered or raised accordingly. If duration of action appears to have changed, then the same modifications as discussed above can be made. Admittedly, glucose curves are not perfect. As discussed above, they can vary from day to day. However, they serve 2 very useful purposes that other techniques do not. First, they can clearly show clinically undetectable hypoglycemia. A phenomenon exists in human diabetics referred to as "hypoglycemic unawareness". In this situation, the body does not respond to mild or even moderate hypoglycemia as in normal patients and clinical signs do not develop. However, when moderate to severe hypoglycemia occurs, profound clinical signs appear acutely without warning. Although unproven, I believe the same occurs in veterinary patients. I certainly have seen patients that the owners thought were doing well until they seizured. Certainly, it could be that the owners were not observant or were absent during the hours of the day when the patient was hypoglycemic, but I do not think that fits all such cases I have seen. A glucose curve will hopefully document mild hypoglycemia that can be fixed before a seizure occurs. Thus, periodic curves can be helpful even in a seemingly well controlled patient. Secondly, and more importantly, other techniques and clinical signs can suggest that control is lacking, but the only way to know how to change the therapy to gain control is by performance of a curve. Although performance of glucose curves in-hospital has been considered the gold standard, problems exist with this method as well. Owners can measure BG at home and perform other tests that can be helpful as well. Although owner observation of the presence or absence of clinical signs is very important, judgment of adequacy of control should not rely solely on owner reports. Recent emphasis has been placed on finding better monitoring methods. Glucose curves can be affected by the stress of hospitalization and deviation from normal routine. One study recently assessed day-to-day variability of serial glucose curves in diabetic dogs and found some change even on consecutive days.8 One important point from the study was that due to the variation, predicting the timing of a diabetic's nadir on the basis of previous serial glucose curves and obtaining a single sample at that time is unlikely to give a reliable result8, i.e. spot checking does not provide helpful information. It should also be recognized that glucose curves can vary day to day when done at home as well.10 In order to avoid some of the problems associated with in-hospital curves, performance of glucose curves at home has taken on new importance. For home glucose curves, it is not necessary for venous blood to be collected. Capillary blood is suitable.11 Choices of sites are the ear, gum, foot pads or elbow callus. To me, the gum and foot pads are not recommended due to associated pain. I have not tried using the elbow callus. Two types of lancing device are available. If using conventional automatic devices designed for pricking human fingertips, a device with a variable needle depth should be chosen. The appropriate depth for each patient can then be used.12 Warming of the ear with a hair dryer or a warm, wet washcloth enclosed within a plastic bag may be necessary but not well tolerated, and it may take up to 2 minutes to obtain an adequate sample.12 A device which creates a vacuum after lancing the skin (e.g. Microlet Vaculance, Bayer) does not require warming of the ear and generates an adequate drop of blood within approximately 30 seconds12, but mastery may be a bit difficult and require repeated instruction.11 A needle can be used as well, especially if the marginal ear vein is the site of blood collection.13 Glucometers that require minimal amounts of blood as well as those that "sip" the blood into the strip are desirable. Training of owners to perform home glucose curves takes time. Not all owners are suited to perform such a task. A small study of 9 owners of diabetic dogs (n=7) and cats (n=2) indicated that, at least in that population, the most frequently encountered problems were the need for more than 1 puncture to obtain a blood drop, the creation of a sufficient blood drop, the need for assistance in restraining the pet and the resistance of the pet. Two dogs became more resistant over time and the owners abandoned the technique. The 2 cats become more compliant, especially as the technique was performed in a place chosen by the cat.13 Continuous monitoring of glucose concentrations has also received attention of late.14;15 The CGMS (Continuous glucose monitoring system, Minimed) is a device that can be strapped onto a patient and a small needle inserted into subcutaneous tissue. Interstitial glucose concentrations are sampled every 5 minutes for up to 72 hrs. Using such a device gives many more data points for evaluation and avoids the stress of multiple venipunctures or catheterization. Indeed, the device could potentially be worn by a patient at home. However, 3 BG concentrations must be measured per 24-hr period. The device has been assessed in normal and diabetic dogs and cats. Interstitial and serum glucose concentrations were highly correlated overall.14;15 The working range of the CGMS is approximately 40-400 mg/dL, i.e. BG outside the range can not be measured. In certain cases, post-prandial increases in BG were not detected in the interstitial fluid.15 Some variation existed between patients and the differences between serum and interstitial glucose concentrations were more marked in some patients than others. The greatest discrepancies occurred at higher BG 15 No irritation resulted from sensor placement. 14;15 Preliminary results suggests that the data generated by the CGMS is useful for clinical management of insulin therapy, at least in diabetic dogs.15 For Madison, performance of glucose curves was simply not an option due to his temperament. As discussed in the last lecture, for use of insulin glargine in cats, a protocol exists for adjustment of therapy on the basis of urine glucose concentrations. Although this is what I did for Madison, and his DM resolved so things must have been going well, the limitations of such an approach need to be considered. First, based on the data we have so far, for cats Purina Glucotest is recommended as compared to any other technique based on accuracy as well as major convenience. Second, the significance of a negative urine glucose needs to be considered. Remember, all this means is that in the period since the last urination, the BG was below the renal threshold, i.e. <300 mg/dL in cats and <200 mg/dL in dogs. So, for example, the BG in a cat could have been 200 mg/dL or it could have been 40! The only way to know is to measure BG. If BG measurement is not an option, the risk of hypoglycemia is high. Measurement of urine glucose concentration at home can aid in monitoring. First, urine glucose levels can be determined as needed to aid in assessment of glycemic control, especially when other data are conflicting. Consistently negative readings on urine glucose may indicate that insulin dosages are either adequate or excessive. A serial glucose curve will differentiate between adequate insulin therapy and use of excessive doses that could result in hypoglycemic shock. Uniformly high urine glucose readings coupled with unresolved clinical signs indicate that the insulin dose may be inappropriate.16 Second, urine glucose concentrations can be determined regularly (at least weekly) to help in the assessment of ongoing control. Changes in urine glucose levels may alert the owner and clinician to loss of glycemic control and a need for reevaluation. If urine can not be collected, then, for cats, use of Glucotest (Purina) may help (see above). In general, I think one of the best uses of glycosylated proteins is to evaluate trends in glycemic control if measured at each recheck. Current recommendations are not to try to normalize serum concentrations of glycosylated proteins but to aim, in general, for a concentration slightly above normal. For Madison, his fructosamine was already normal! I did remeasure his fructosamine over time to at least make sure that it was not below normal. A fructosamine below normal indicates chronic hypoglycemia. Home monitoring of clinical signs alone has been advocated as an accurate method of diabetic assessment.17 In one study of 53 dogs, control was judged to be good or bad based on clinical signs, physical examination findings and body weight. Then, clinical determination of good or poor control was compared with fasting BG, serial glucose curve and serum fructosamine and GHb concentrations. Although all parameters of glucose control were significantly lower in dogs with good control, considerable overlap existed between the 2 groups for all. All BG measurements, fructosamine and GHb were consistent with good glycemic control in 60% of dogs judged to have good clinical control or with poor control in only 39% of judged to have poor clinical control dogs. The initial fasting BG was 100-300 mg/dl in 80% of dogs with good clinical control and in 21% of dogs with poor clinical control. The study's authors concluded that history, physical examination and body weight are sufficient for initial assessment of glycemic control and a glucose curve may not be necessary in a dog with apparent good clinical control when the initial morning BG is 100-300 mg/dl.17 Certainly, the importance of home monitoring of clinical signs cannot be over-emphasized. However, this author has some concerns with study methodology and conclusions and believes that glucose curves should be performed periodically in all diabetic patients (for aggressive animals or those who experience stress hyperglycemia in the hospital, the curves are most appropriately performed at home). References available from the author. Controversies (and New Information) in Canine Cushing's Syndrome Note: to convert cortisol reported in nmol/L to mcg/dl, divide the concentration in nmol/L by 27.59. Diagnosis ACTH Stimulation To me, which test to use to diagnose hyperadrenocorticism (HAC), a low-dose dexamethasone suppression test (LDDST) or ACTH stimulation test, depends on the situation. Recently I have heard eminent veterinary endocrinologists say that the ACTH stimulation test is worthless for diagnosis of HAC. I respectfully disagree. The ACTH stimulation test most certainly can have false positives and false negatives, but that is true of any of the tests we use to diagnose HAC. The sensitivity of the ACTH stimulation test has been reported to be between 73% and 95% overall if dogs with both pituitary-dependent HAC (PDH) and adrenal tumors (AT) were included in the study. 12;3 If these reports are combined with others looking at those with PDH or with AT alone, 279 out of 348 dogs with HAC tested positive on the ACTH stimulation test giving a sensitivity of 80.2%.1;42;3. For PDH, the sensitivity is 87.4%5, while for AT the sensitivity is 61.3%. In PDH, this may be attributable to early disease where adrenocortical hyperplasia is minimal. In AT, the tumor tissue may not have ACTH receptors and, therefore, will not respond to an ACTH injection. The ACTH stimulation test can not distinguish between PDH and AT.6 In comparison, the sensitivity of the LDDST is about 95%.6 On the flip side, the LDDST is less specific than the ACTH stimulation test. The specificity of the LDDST has been estimated to be 44%7, 70%8 and 73%.9;10 In general, the more severe the non-adrenal illness present, the more likely a false positive test result. 7 The specificity of the ACTH stimulation test is approximately 85%.7 To me, the big question clinically is which is worse, a false positive or a false negative, and that varies with the cases. In general, I make the following general recommendations: 1. If the dog has no known non-adrenal illness (NAI) and moderate to severe clinical signs of HAC, do the LDDST. 2. If clinical signs are mild or only laboratory abnormalities are present (e.g. increased ALP), do the ACTH stimulation test. 3. If NAI is present11, if the dog has received any form of exogenous glucocorticoid including topicals,12 or if the dog is receiving phenobarbital,13 do the ACTH stimulation test. For doing the ACTH stimulation test, there is no good substitute for Cortrosyn (cosyntropin, synthetic ACTH). The best option to reduce the cost of the test is to use a low dose of Cortrosyn (5 mcg/kg IV) with blood samples drawn before and 1-hr post injection.14 Unused, reconstituted Cortrosyn can be stored refrigerated in plastic vials for up to 4 months and frozen for 6 months.15 If freezing Cortrosyn, I recommend to do so in smaller aliquots as the effect of thawing and refreezing is unknown. The low dose has also now been shown to be effective for diagnosing HAC if given IM16 and for diagnosing hypoadrenocorticism.11 I prefer the IV over the IM route to ensure that there are no issues with absorption. Compounded ACTH may be used with caution. We performed a study in normal dogs in which we gave Cortrosyn (5 mcg/kg IV) and 4 different compounded forms of ACTH (all manufacturers recommended a dose of 1 U/lb IM with blood samples drawn before injection and 2-hr post). Administration of all 4 forms of compounded ACTH increased serum cortisol concentrations to a similar degree as a maximally stimulating dose of Cortrosyn when values were compared at 60 min following injection. However, serum cortisol concentration had returned to baseline by 120 min when using 2 of the compounded forms. Thus, due to variability in duration of response, I recommend that veterinarians using compounded ACTH products collect a sample before administration and samples at 1 and 2 hrs following injection.17 Combination dexamethasone suppression/ACTH stimulation test The exact timing of the post-dexamethasone sample in the combination test can vary.2;1018 To perform this test, I recommend that a baseline sample be drawn, dexamethasone be given (0.1 mg/kg IV, i.e. a "high dose"), a sample be drawn 4 hour later, and the ACTH stimulation test be started immediately thereafter. Some authors do not recommend the test at all. The sensitivity of this test has been estimated at 76%2, 86%3 and 93%.10 The author of the former 2 studies concluded that due to the low sensitivity, the test was not helpful and could not be advocated. Part of the confusion may result in how the test is interpreted. If the test is evaluated as a whole, i.e. a diagnosis of HAC is made if an animal does not suppress in response to dexamethasone and has an elevated response to ACTH, then the sensitivity may be relatively low. However, if the diagnosis is made on the basis of the ACTH stimulation portion alone, the sensitivity would be expected to be similar to that of performing an ACTH stimulation test without previous dexamethasone injection (as long as the ACTH is given within 8 hr of the dexamethasone). Thus, it is subject to all caveats as the ACTH stimulation test alone. The dexamethasone suppression portion can then be viewed as a differentiation test since a high-dose is being given. In this light, an advantage of the combined test is that screening and differentiation between PDH and AT can be performed simultaneously. Serum alkaline phosphatase measurement Measurement of serum alkaline phosphatase (ALP) activity has been used as a screening test for HAC. However, the best way to use measurement of ALP activity may be as a means to rule out the diagnosis of HAC. The sensitivity of this laboratory test is high, as ALP is above normal in 90% of dogs with HAC.19;20 Indeed, 15% of boarded internists and dermatologists do not pursue a diagnosis of HAC if ALP is normal.21 However, the specificity is very low. Scottish Terriers are now recognized as a breed that have higher serum ALP activity than do dogs of other breeds.22 (Of note, similarly, vacuolar hepatopathy is not specific for HAC either.23) The corticosteroid-induced isoenzyme (CAP) has also been assessed and suggested to be a good screening test for HAC24, however specificity remains low. As with the total ALP activity, CAP activity is elevated in the vast majority of dogs with HAC or that have received exogenous corticosteroids. However, elevated CAP activity, either as absolute levels or as a percentage of total, occurs in dogs without exposure to exogenous corticosteroids or HAC. In general, CAP appears in a large number of samples when ALP is high for any reason.25 Dogs with, for example, non-hepatic neoplasia, liver disease, pyometra, pneumonia, congestive heart failure and pancreatitis can have a CAP activity accounting for at least 50% of the total.6 More importantly, dogs more likely to be screened for HAC, e.g. those with hypothyroidism or diabetes or those given exogenous glucocorticoids or phenobarbital, can have elevated SAP levels with >50% CAP activity. 26:27 Conversely, although CAP can be induced within 6 days of glucocorticoid administration, some dogs with HAC or that have received steroid therapy may have no to little CAP elevation.6 Overall, the sensitivity of elevated CAP activity for glucocorticoid exposure (i.e. HAC or glucocorticoid therapy) is approximately 95%, but the specificity may be as low as 18%.28;29 In one study, the predictive value of a positive test and of a negative test was 50% and 80%, respectively; in other words, a dog with an increased CAP activity had a 50% chance of truly being exposed to glucocorticoids while a dog with normal CAP activity had a 20% chance of glucocorticoid exposure.28 Occult hyperadrenocorticism A syndrome termed "occult" HAC has recently been coined and refers to dogs that have clinical signs suggestive of HAC but normal ACTH stimulation test and/or LDDST results. Measurement of 17-hydroxyprogesterone (17OHP) has been advocated for diagnosis of "occult" HAC and is available through some commercial laboratories. The protocol requires ACTH stimulation testing with measurement of serum 17OHP concentration pre- and post-ACTH. The first report of clinical signs thought to be due to sex hormone elevation described diffuse bilaterally symmetrical alopecia and hyperpigmentation in 7 Pomeranians.30 Classic HAC was ruled out. Numerous sex hormones were measured pre- and post-ACTH; several abnormalities were noted and hypothesized to be due to a partial deficiency of 21-hydroxylase, an enzyme needed for cortisol synthesis.30 In humans with 21-hydroxylase deficiency, cortisol is not synthesized and cortisol precursors, most notably 17OHP and androgens, accumulate.31 More recently, a study of 23 dogs with clinical and laboratory findings suggestive of hyperadrenocorticism (HAC) was reported. Of the 23 dogs, 11 had an elevated cortisol response to ACTH. Of 10 dogs with a normal ACTH response, 6 had a positive LDDST. All 23 had an elevated 17OHP response to ACTH.32 The conclusion of the study was that serum 17OHP concentration post-ACTH stimulation is elevated in dogs with classic as well as occult HAC and that measurement of serum 17OHP concentration is a marker of adrenal dysfunction. However, I believe inadequate substantiation exists that elevated serum sex hormones are clinically significant in PDH (adrenal tumors may be different). In humans, evidence suggests that elevated serum 17OHP does not cause clinical signs. Clinically silent 17OHP-secreting adrenal tumors occur.33;34 Massive elevations in serum 17OHP occur with 21-hydroxylase deficiency, yet clinically affected patients show signs either of aldosterone deficiency or androgen excess.31;35 Clinical signs of HAC do not occur despite 17OHP concentrations ranging from 3,000-40,000 ng/dl (reference range 20-600).35 Lastly, a "cryptic" syndrome of 21-hydroxylase deficiency exists in which affected people lack 21-hydroxylase and have hormonal abnormalities but no clinical signs. The factors that impose the phenotypic variability on the genotypic abnormality are unknown35, but abnormal sex hormone elevations by themselves are not sufficient to cause clinical disease. In dogs as well, the relationship between elevated serum sex hormone concentrations and disease is unclear. First, of 6 sex hormones assessed in the alopecic Pomeranians, only serum 17OHP post-ACTH stimulation was significantly different between affected and unaffected dogs. When affected males and females were assessed separately, the males did not have an elevated serum 17OHP.30 In 28 dogs diagnosed with Alopecia X, treatment with melatonin led to partial or complete hair regrowth in 64% despite no change in serum sex hormone concentrations.36 Furthermore, in 276 dogs with Alopecia X including 63 Pomeranians, 73% had at least one basal or post-ACTH sex hormone concentration greater than the normal range. However, despite the preponderance of elevations in sex hormone concentrations, no consistent sex hormone abnormalities were identified, and it was concluded that it is more appropriate to refer to this syndrome as "alopecia associated with follicular arrest rather than equating it with an adrenal hormone imbalance".37 Lastly, the specificity of the test may be as low as 70%, i.e. the chance of a false positive result is 30%.38;39 In one study of 35 dogs with neoplasia who did not have adrenal disease, 30% had an elevated serum 17OHP concentration post-ACTH stimulation.38 Thus, dogs without adrenal disease clearly can have elevated sex hormone concentrations as they do cortisol concentrations, and sex hormones may be more likely to be falsely elevated by NAI as compared to cortisol. Second, problems exist with the study that attributed occult HAC to elevated serum 17OHP concentration. Classifying all 23 dogs as having occult HAC was inappropriate as 17 had a standard AST or LDDST consistent with HAC and were not occult. Six dogs had an LDDST consistent with HAC and a normal standard AST, but this discrepancy is not surprising given the relative sensitivities of the 2 tests.6 Three dogs had a normal standard AST and low plasma cortisol throughout an LDDST, results not unusual in dogs with adrenal tumors. Only 3 dogs were diagnosed with pituitary-dependent HAC despite having both a normal standard AST and LDDST.32 This suggests that occult HAC accounts for only a small percentage of HAC cases. In 64 dogs documented to have HAC, no dog was negative on both the AST and LDDST, even calling into question the likelihood that occult HAC exists.1 More importantly, follow-up in 2 of the dogs refutes the idea that 17OHP could cause the supposed syndrome. When treated with trilostane, an inhibitor of cortisol synthesis, these dogs improved despite an increase in serum 17OHP concentrations.32 Two mechanisms have been proposed for progesterone's ability to cause signs of glucocorticoid excess. Progestins, synthetic forms of progesterone, may either bind glucocorticoid receptors40 or may displace cortisol from its binding protein thereby elevating serum free cortisol concentration.41 Indeed, progestins can suppress endogenous ACTH secretion and cause adrenal atrophy, an action suggestive of glucocorticoid activity.42-44 Accordingly, progesterone may do the same. Examination of Pomeranians with Alopecia X, however, refutes the likelihood of either mechanism occurring. If elevated serum 17OHP concentration as seen in those dogs is sufficient to cause clinical disease due to glucocorticoid actions of 17OHP, endogenous ACTH concentration should be suppressed due to negative feedback at the pituitary. To the contrary, Pomeranians with elevated serum 17OHP concentrations had higher plasma ACTH concentrations than healthy dogs.30 Similarly, during diestrus when serum progesterone concentrations are highest, adrenal secretion of cortisol in response to ACTH is greatest.45 Thus, directly equating activity of progesterone with that of progestins is inappropriate.46-48 In cases of pituitary-dependent occult HAC, how or why normal adrenocortical tissue should have altered steroid synthesis is unknown. As such, how likely activation of the pituitary-adrenal axis from NAI would be to also cause a shift toward synthesis and secretion of sex hormones is unknown. In a study we performed, linear regression analysis found significant correlation between post-ACTH serum cortisol, 17OHP and corticosterone concentrations both in dogs with neoplasia and those suspected of having HAC, suggesting that as adrenal function is increased either by adrenal disease or non-specifically by non-adrenal disease, production of all hormones increases proportionately.38 Unfortunately, the ability of chronic NAI to affect sex hormone testing has not received critical appraisal as has the standard ACTH stimulation test. Besides 17OHP, the endocrine lab at Tennessee will also measure cortisol, estradiol, progesterone, testosterone, and androstenedione pre- and post-ACTH. However, the clinical significance of this test has not been determined. Two studies have determined that 30% of dogs with NAI but without HAC have elevated 17OHP concentrations post-ACTH.38;39 The likelihood of elevations in any of the other sex hormones measured for diagnosis of occult HAC has not been evaluated at all. Routine pituitary imagining Although radiation therapy is not a great means of controlling HAC49;50, radiation done for local control of a pituitary mass is more effective and provides better outcome and prognoses the smaller the mass and with no or minimal neurological signs present.49;51. When compared with untreated dogs, radiation therapy for a pituitary mass, with or without the presence of HAC or without or without the presence of neurological signs, significantly increased survival. Median survival in the treated group was not reached in the study, but mean survival was 1405 days vs. 359 for those not treated. Radiation also significantly increased control of neurological signs.52 Thus, recommendations for routine imaging of the pituitary in patients with HAC have recently been formulated.53 The true incidence of pituitary macroadenomas is unknown, but has been estimated to be as high as 25%. The clinical progression of pituitary tumors is also widely unknown. Out of 21 dogs recently diagnosed with PDH and untreated but that had no neurological signs, 11 had a pituitary mass visible on MRI.54 The visible masses were 3 to 13 mm at greatest vertical height and 10/11 filled a major portion of the sella turcica and extended dorsally beyond its confines.54 Thirteen of the 21 had follow-up imaging at one year. Five had no visible tumor originally whereas 8 did of 4-11 mm greatest vertical height. One of the dogs with a visible mass had not been treated whereas the rest had been with mitotane.55 None of the 5 dogs with no mass visible originally had neurological signs at follow-up; 2 had a visible pituitary tumor of 6 and 7 mm height while in 3, the mass was still not visible.55 Of the 8 dogs that had a visible mass at first imaging, 4 had no apparent change in their tumor size whereas in 4 the tumor had enlarged. The untreated dog was in the latter group. Overall, 4 developed signs of CNS dysfunction (19% of the original 21 and 36% of the 11 dogs with tumors visible at the first scan). Tumor size appeared to correlate with the development of signs as no dog with a mass <10 mm had neurological dysfunction. There was no apparent correlation between pituitary mass size before treatment and increase in size over the year.55 Based on this information, recognizing that the number of dogs studied is small, the recommendations are: All dogs with PDH should have a CT or MRI at the time of diagnosis. If no mass is visible, medical treatment should be implemented and no follow-up is needed. If a mass 3-7 mm in greatest vertical height is seen, medical therapy should be implemented with a repeat scan in 12-18 months. If a mass > 8 mm in greatest vertical height is seen, radiation therapy should be done and medical therapy used only if clinical HAC fails to resolve within 3-6 months of finishing radiation. These recommendations are based on clinical experience and theoretical considerations53 and no studies have been performed to date to assess their validity. Treatment Trilostane In Europe, trilostane is used to treat HAC. Trilostane inhibits the adrenal enzyme 3 -hydroxysteroid dehydrogenase, suppressing cortisol and aldosterone production. A few studies have been published regarding the use of trilostane in a total of 119 dogs with pituitary-dependent hyperadrenocorticism (PDH).56-58 The 3 studies are a bit hard to compare as treatment goals, doses and monitoring protocols were different. Trilostane is highly effective for treating PDH.56-58 In 3 studies of dogs with PDH, pu/pd resolved over the first 6 months (mainly within 1-2 mths) in 91% while polyphagia resolved in 81%.59 In one study, 62% of dogs with dermatological abnormalities, marked improvement occurred that took up to 3 mths. In 8 dogs, signs were poorly controlled.56 A second study looked at 11 dogs. All had dermatological problems and 10 were pu/pd. Coat and skin condition returned to normal in 9 within 6 mths; in 1 dog improvement was noted after 1 yr. All 10 had a decrease in water intake within 7 wks and 9 had complete resolution at a median of 11 wks. Polyphagia decreased in 9/10; in 1 dog it took approximately 6 mths. Of 4 dogs that had increased panting, improvement was noted in 2 and resolution in 2. By 6 mths, 9/11 owners were pleased with the results.57 Originally, the recommendation for initial starting dose was 2-10 mg/kg once daily.59 In about 50% of dogs, dosage adjustments, both up and down, were required. Authors of one study noted that in most dogs there was an initial sensitivity to the drug followed by a need for an increase in dose. After time, the dose required hit a plateau.58 Interestingly, the final dose required varied greatly between studies. The discrepancy may relate in part to the differences in what was considered the ideal post-ACTH serum cortisol concentration. However, in one study the median final dose was 6.1 mg/kg57, while another study found the therapeutic dose for most dogs is likely to be 16-19 mg/kg.58 In any case, each dog should be started on the recommended dose and the dose adjusted according to ACTH stimulation test results. Survival is at least as good as achieved with mitotane.56-58 Reported adverse effects for the most part are relatively mild, including lethargy and vomiting, but fatality has occurred.56-58 Although some studies found relatively low incidence of side effects, mild, self-limiting side effects such as diarrhea, vomiting and lethargy were noted by 63% of owners in one unpublished study.59 Trilostane can affect aldosterone secretion, so an Addisonian crisis can occur.56;58 Excess adrenal suppression can occur at any time during therapy.56;58 One dog died despite appropriate treatment for hypoadrenocorticism, and the true cause of death remained undetermined.56 As with mitotane therapy, excess adrenal gland suppression can occur and warrants discontinuing medication temporarily (see below) and lowering of the dose. Although, in theory, the effects of trilostane should be reversible within a couple days, suppression can last weeks to months. In a few cases, cortisol secretion remained low for 6 wks to 4 mths after discontinuation of trilostane therapy, eventually returning to pre-therapy levels.58 In an additional case, glucocorticoid and mineralocorticoid deficiency occurred in a dog being treated with trilostane and bilateral adrenal necrosis of an undetermined etiology was documented.60 The hypoadrenocorticism likely would be permanent. How often acute iatrogenic hypoadrenocorticism will occur in dogs treated with trilostane is unknown, however it may be more common than originally thought. In one small study the adrenal glands of 7 dogs treated with trilostane, 6 with PDH and 1 with AT, were examined histologically. The glands of the 6 dogs with PDH had moderate to severe diffuse or nodular cortical hyperplasia, mainly in the zone that secretes cortisol. Five of the 7 dogs had variable degrees of adrenal necrosis, which was severe in two of them, and 3 had variable degrees of cortical hemorrhage. In some of the dogs, the lesions were severe enough to lead to hypoadrenocorticism.61 A few questions still need to be answered. First, the optimal post-ACTH serum cortisol concentration should be determined. The goal for post-ACTH cortisol concentration in one study was below 250 nmol/L56 but the goal was 30-70 nmol/L in a second study57 and 25-125 nmol/L in a third.58 The ideal timing of post-pill sampling also needs to be elucidated. Post-ACTH cortisol may vary with the interval between dosing and testing.62 Based on their experience, the authors of the third study recommended doing an ACTH stimulation test 3-8 hr after the last dose58 while another author specifically recommends testing at 4-6 hrs post-pill.59 Lastly, the appropriate starting dose and interval (daily or BID) needs clarification. How long control must be maintained throughout the day needs to be elucidated. For example, is control for 12 hours adequate or does it need to last 24 hours? Original recommendations were for once daily administration (2-10 mg/kg) once daily. If minor side effects are seen, stop the drug for 3-5 days and then restart giving trilostane every other day for one week before continuing with the initial dosing scheme. An ACTH stimulation test should be performed beginning 4-6 hrs post-pill at 10-14 days, 30 days and 90 days after being on a full dose. If the post-ACTH cortisol concentration is <20 nmol/L, stop the trilostane for 48-72 hrs.59 At this point, Dr. Neiger recommends restarting the trilostane at a lower dose59, but given the long-term suppression seen in some cases, I believe that, ideally, an ACTH stimulation test should be performed and trilostane not reinstituted until cortisol secretion has recovered. If the post-ACTH cortisol is >200 nmol/L, increase the trilostane dose. If the post-ACTH serum cortisol concentration is 20-200 nmol/L but clinical signs are continuing, then BID therapy should be used. The same dose given once-daily should be given twice (e.g. if giving 30 mg once daily then give 30 mg BID). Once the dog's clinical condition and the dose have stabilized, an ACTH stimulation test should be performed every 3-6 mths and serum potassium concentration measured to check for hyperkalemia. Given the worry about adrenal necrosis, the manufacturer recommendation are to start at a lower dose of 2-5 mg/kg daily. More recent data suggest that more frequent dosing may be more appropriate. Trilostane may begin to lose effectiveness at 8-10 hrs post-pill.63 One recent study assessed the use of trilostane BID in 44 dogs with PDH.64 The initial dose of trilostane was 15 mg, PO BID for dogs <5 kg, 30 mg BID for dogs 5-20 kg, 60 mg a.m. and 30 mg p.m. for dogs 20-40 kg and 60 mg BID for dogs >40 kg. At the first recheck (7 days later), the ACTH stimulation test was started 4-6 hr post-pill to assess the maximum effect of the drug. Good control was judged on the basis of clinical signs and a serum cortisol concentration pre- and post-ACTH of 30-110 nmol/L. Dose was adjusted by 25-50% increments. On further rechecks, the ACTH stimulation test was initiated 8-12 hrs post-pill. Good control was believed to be a post-ACTH cortisol concentration of 30-250 nmol/L. Mean initial dose of trilostane was 6.2 mg/kg (range 2.4-15.0) divided BID. The dose was not changed over the course of the study in 10 dogs, increased in 19, reduced in 5 and both increased and reduced in 10. Over the course of the study, at all rechecks the mean dose was between 6 and 8 mg/kg divided BID, but the range was approximately 2-20. Adverse reactions were seen in 25% of cases related to low cortisol concentration. In 11%, trilostane therapy was discontinued due to prolonged suppression of serum cortisol concentration. In 4 dogs adrenal function returned to normal and no further treatment was needed; one dog was treated as an Addisonian. Mean survival time was 930 days.64 The best drug to use to treat AT is unknown. Trilostane has been used to treat a few dogs with adrenal tumors.59;65 Not enough information is available to ascertain whether the treatment protocol or efficacy varies if treating dogs with PDH versus those with an adrenal tumor. However, trilostane is not cytotoxic while mitotane is. In other words, mitotane is truly a chemotherapeutic drug in this instance, killing primary neoplastic cells and, perhaps, metastatic cells as well. Trilostane simply would control tumoral secretion, not growth. In fact, in dogs with PDH treated with trilostane, the size of the adrenal glands increased.66 Whether trilostane would be a better alternative to ketoconazole therapy to control the clinical signs of HAC pre-adrenalectomy remains to be determined. A few disadvantages exist for using trilostane. The largest is availability. At the current time, trilostane is not approved for use in the United States. To obtain trilostane in the U.S59: A) Complete the 13 part letter - addressed to Toni Wooten, Division of Compliance HFA-230, Center of Veterinary FDA, Metro Park North, 7500 Standish Place, Rockville MD 20855; fax: 301-827-1498. (Toni Wooten, phone 301-594-0796, e-mail:twooten@cvm.fda.gov). You need a new letter for each request for each specific patient! Information in the 13 part letter [information in square brackets can be used]: 1) Vet's name, address and phone number; 2) Clinic name and address; 3) Client's name and address; 4) Patient name and non-food species; 5) Name of drug [Vetoryl®, trilostane];6) Drug family or class [steroid analogue]; 7) Name and address of drug supplier [Arnolds Veterinary Products, Cartmel Drive,Harlescott, Shrewsbury, Shropshire SY1 3TB, UK]; 8) Legal status of the drug in the foreign country [approved for treatment of canine PDH in UK]; 9) Amount of drug to be imported - must be small, non-commercial quantities [100 capsules of 60/120 mg]; 10) Disease condition to be treated [canine/feline HAC]; 11) Reasons why an approved human or animal drug will not treat the disease condition; 12) A statement that i) you will notify the animal owner that the drug is not approved; ii) that the drug will not be used in any food animal; iii) and that you agree to notify the FDA if there are any adverse reactions; 13) How did you learn of the existence of this drug. B) FDA will send a letter back approving the request (1 to 2 wk turn around) which authorizes a 90 day supply MAXIMUM. C) Arnolds Veterinary Products needs a Faxed copy (+44 01743462111) of the FDA letter and a prescription before they will ship, along with your credit card details. D) Steps A) thru C) must be completed for each additional request of a 90 day supply and for each additional patient. E) Current cost: approximately $130 for #100 of 60mg; $202 for #100 of 120mg; courier will be about $40; you can then add a processing fee (most US universities add about 15%). Secondly, trilostane cost will be 2-3 times that of mitotane depending on a dog's size.58 Since ACTH stimulation testing is needed with mitotane or trilostane, the cost of monitoring would be the same for either drug. Last, until the questions about required duration of action are answered, I recommend use of mitotane in dogs where serious complications of HAC exist and breaks in control could be detrimental, e.g. dogs with pulmonary thromboembolism. References available upon request. Diagnosis of Polyuria/Polydipsia: Case-Based Approach CASE 1 Signalment: 12 year-old, castrated male mixed breed dog History: Polyuria/polydipsia past few weeks; having accidents in the house. Lives in Alabama. Mainly indoors. Up-to-date on vaccines and heartworm preventive. No travel history. Physical examination: Obese Laboratory data: Complete CBC, profile, urinalysis done. Abnormalities were: Calcium (mEq/L) 11.8 (9.0-11.2); urine specific gravity = 1.009 with 1-2 WBC/hpf and 2-3 RBC/hpf WHAT IS POLYURIA/POLYDIPSIA? Polyuria has been defined as urine production > 45 ml/kg/24 hr in dogs and 40 ml/kg/24 hr in cats.1 Polydipsia has been defined as water consumption > 100 ml/kg/24 hr in dogs and cats2 but some difference may exist between species and another definition given is > 90 ml/kg/24 hr in dogs and > 45 ml/kg/24 hr in cats.1 Values below these, however, may still be consistent with such a diagnosis. Other factors also need to be considered when deciding if polyuria/polydipsia are present. Animals that eat canned food drink less than those that eat dry food. Also, normal habits should be assessed. For example, even if water consumption is below 90-100 ml/kg/24 hr in a particular dog, if this is more than twice normal for that pet, a diagnosis of pu/pd may be warranted. If any doubt exists as to whether polyuria/polydipsia (pu/pd) is present, its presence should be verified. To verify the diagnosis of pu/pd, water intake should be quantitated at home, as hospitalization can alter drinking habits. Urine specific gravity (USG) assessment may also be helpful. If USG is >1.015, it is unlikely that pu/pd is present. A USG showing maximal renal concentrating ability (>1.030 in dogs, >1.035 in cats) rules out the possibility of pu/pd.1 If the USG is >1.030 and the owner believes the patient is polyuric, the history should be re-evaluated to make sure the problem is not dysuria, incontinence or a behavioral problem.3 WHAT ARE THE CAUSES OF POLYURIA/POLYDIPSIA? To answer that question, understanding of the mechanisms regulating thirst and urine production is helpful. Anti-diuretic hormone (ADH) is released from the posterior pituitary, with the main function of causing water retention. Without ADH, dilute urine is excreted. When ADH is present, pores open in the membranes of the collecting ducts allowing passive movement of water from the hypotonic tubule lumen to the hypertonic medullary interstitium and concentrated urine is produced.4 Since reabsorption of water in this part of the nephron is passive, the osmotic force responsible, i.e. the concentrated renal medullary interstitium, is crucial. The main stimulus to ADH release is increased extracellular fluid (ECF) osmolality. Below 280 mOsm/kg, serum ADH concentration is very low to non-detectable. Above this point, even a 1% increase in ECF osmolality stimulates ADH secretion. Maximal ADH secretion occurs at an ECF osmolality of 320 mOsm/kg. Anti-diuretic hormone is also released in response to a 10% decrease in circulating blood volume.4 Thirst is controlled similarly with major input from ECF osmolality and lesser input from blood volume changes. Hyperthermia, pain, emotion and certain drugs also increase thirst. Production of concentrated urine has 3 requirements: 1. Adequate serum ADH concentration and the ability of the kidneys to respond to ADH. 2. Function of at least 33% of total nephron number, i.e. when >2/3 of the nephrons are lost, urine concentrating ability is lost. 3. A concentrated renal medullary interstitium. Causes of pu/pd can be divided into those causing primary polydipsia vs. those causing primary polyuria (see Table).4 Primary polyuria is divided into the categories of osmotic diuresis, central diabetes insipidus (CDI), primary nephrogenic diabetes insipidus (NDI) and secondary NDI.4 CDI is caused by lack of ADH. In NDI, the kidneys' ability to respond to ADH is compromised. In primary NDI, the problem is intrinsic to the kidneys. With secondary NDI, a non-renal problem interferes with the kidneys' response to ADH.4
A complete history and physical examination should never be underestimated as an important tool for diagnosis of any disease. For pu/pd, the presence of post-obstructive diuresis or drug administration as a cause can be ruled out on the basis of history. Medications that can cause pu/pd include corticosteroids, phenobarbital, and diuretics. In dogs, use of progestins can lead to acromegaly. The owner should also be asked about any recent diet changes since the water content in food is an important water source and low protein diets can lead to low renal medullary tonicity.3 Questions specific to possible differential diagnoses should also be asked. A CBC, biochemical profile and urinalysis alone can rule out a number of differential diagnoses. If the cause for pu/pd remains unknown after the minimum database has been performed, a urine culture should be submitted regardless of the urine sediment exam to determine if occult pyelonephritis is present. Pyelonephritis is not always accompanied by fever and perinephric pain, and in dilute urine, the sediment exam can be misleading. If the cause is then still not apparent, hyperadrenocorticism should be ruled out in dogs by use of an ACTH stimulation test or low-dose dexamethasone suppression test.4,5 Pu/pd may be the only clinical sign present. CASE SUMMARY: Ionized calcium was measured and was normal. Urine culture was submitted and an E. coli grew (>100,000 cfu/ml). Dog placed on appropriate antibiotic for 4 weeks. Culture performed 1 week after starting antibiotics and 1 week after antibiotic therapy stopped. Both negative. Pu/pd resolved. Plan: Reculture urine 4 weeks later. CASE 2 Signalment: 12 year-old, castrated male mixed breed dog History: Polyuria/polydipsia past few weeks. Mainly indoors. Up-to-date on vaccines and heartworm preventive. Physical examination: Normal. Laboratory data: Complete CBC, profile, urinalysis done. Abnormalities were: neutrophils 12.5 x 103/ l (3.0-11.5); lymphocytes 0.7 x 103/ l (1.0-4.8); ALT: 130 IU/L (10-120); ALP: 322 IU/L (11-210); urine specific gravity = 1.011 with inactive sediment; protein 1+. Urine culture negative. As with any other diagnostic work-up, look for the more likely and more common causes first before moving on to less likely diseases. In dogs, the 3 most common causes of pu/pd are renal failure, hyperadrenocorticism (HAC) and diabetes mellitus. In cats, the 3 most common causes are renal failure, diabetes mellitus and hyperthyroidism. Trying to diagnose psychogenic polydipsia, CDI or primary NDI should be the LAST step in a diagnostic work-up for polyuria/polydipsia. First, psychogenic polydipsia, CDI and primary NDI are uncommon. Second, results of the modified water deprivation test (MWDT), a test that can be performed to differentiate these three conditions, can be interpreted miscorrectly if all secondary NDI causes have not been ruled out first. Secondary NDI can look like primary NDI or partial CDI with respect to results of the MWDT. Last, the MWDT is a time-consuming and potentially expensive test to perform. In this case, serum ALP activity is not very high and no other signs of hyperadrenocorticism (HAC) besides pu/pd is obviously present. However, Cushing's needs to be tested for. Approximately 10% of dogs with HAC have a normal serum ALP activity. In addition, about 66% have proteinuria and/or hypertension. This dog may be proteinuric (1+ protein on urinalysis; a urine protein/creatinine (UPC) ratio is needed to quantify) and blood pressure should be measured. Even if the only abnormality identified (with measurement of liver enzyme activity, UPC, blood pressure, etc) were pu/pd, HAC should still be tested for. In cases such as these, the ACTH stimulation test is preferred. Assessment of hepatic function via measurement of bile acids is not indicated in this case given the (lack of) clinical signs and laboratory findings. However, if liver function is at all questionable or liver enzymes (ALT and/or ALP) are moderately to severely increased then bile acids should be measured before an MWDT is performed. CASE SUMMARY: An ACTH stimulation test was performed. Serum cortisol concentration pre-ACTH was 224 nmol/L (reference range 10-160 nmol/L; 8.1 g/dL reference range 1-5 mcg/dl) and post-ACTH was 832 nmol/L (reference range 220-560 nmol/L; 30.1 g/dL reference range 8-20 g/dL). Systolic blood pressure was 190 mm Hg. UPC was 3.4. A diagnosis of HAC was made. CASE 3 Signalment: 4 year-old, FS, Standard Poodle History: Recurrent vomiting/diarrhea past 1-2 mth. Treated with fluids and antibiotics and always got better but then relapsed. Past 2 days anorectic, vomiting ~ 8X/day. Physical examination: Thin, 5% dehydrated Laboratory data: Complete CBC, profile, urinalysis done. Abnormalities were: Hematocrit 35% (37-55); BUN: 50 mg/dl (7-28); Creatinine: 2.0 mg/dl (0.9-1.7); Albumin: 4.7 g/dl (2.7-4.5); Na: 128 mEq/L (145-158); K: 6.2 mEq/L (4.1-5.5); Cl: 95 mEq/L (106-127); Total CO2: 12 mEq/L (14-27); urine specific gravity = 1.015 with inactive sediment. The most likely differentials for this dog are hypoadrenocorticism and/or renal failure. Care should be taken in evaluating USG in azotemic patients in which a cause for pu/pd other than renal failure may also be present. A combination of inadequately concentrated urine and azotemia does not necessarily denote renal disease. Any cause of CDI or primary or secondary NDI can prevent the kidneys from concentrating urine in the face of prerenal causes of azotemia such as dehydration. If the cause for pu/pd is corrected, the azotemia will resolve if the kidneys are normal CASE SUMMARY: An ACTH stimulation test was performed. Serum cortisol concentration pre-ACTH was <14 nmol/L (reference range 14-160 nmol/L; <0.5 g/dL, reference range 1-5 mcg/dl) and post-ACTH was <14 nmol/L (reference range 220-560 nmol/L; <0.5 g/dL, reference range 8-20 g/dL). A diagnosis of hypoadrenocorticism was made and therapy initiated with DOCP and prednisone. At recheck one month after stabilization, serum Na, K, BUN and creatinine concentrations were normal and the USG was 1.032. CASE 4 Signalment: : 8 yr old FS yellow Labrador History: For the past 2 weeks she has been lethargic and has had a decreased appetite. Over the past month, she has had some accidents in the house. Physical examination: normal Laboratory data: Complete CBC, profile, urinalysis done. No abnormalities on bloodwork. Urine specific gravity = 1.004 with inactive sediment. Urine culture negative. ACTH stimulation test normal. Now is the time to do an MWDT. If the decision is made to perform a MWDT, decrease the patient's water consumption slowly e.g. 120 ml/kg/day 72 hrs prior to the test, then 90 ml/kg/day 48 hrs prior and then 60-80 ml/kg/day for the last 24 hours.4 Prolonged pu/pd leads to renal medullary washout, and this gradual decrease allows for reconcentration of the renal medulla. The patient should be watched carefully during this time for dehydration. When the test begins, stop all access to water. At this point the patient needs to be monitored carefully as dehydration can occur quickly. Empty the bladder and obtain an exact body weight. Measure USG and, if possible, a urine and serum osmolality. A BUN should be measured and hydration status assessed.4 Do not do an MWDT if azotemia, dehydration, hypercalcemia or significant systemic disease is present. During the test, empty the bladder every 60-120 minutes and measure USG and, if possible, urine osmolality. Assess body weight and hydration hourly. Measurement of serum osmolality periodically is ideal but not always available.4 An endpoint to the test is reached when: USG is >1.030 in dogs or 1.035 in cats; the patient is clinically dehydrated, azotemic or appears ill; the serum osmolality is 320 mOsm/kg; or there is a loss of 5% of body weight.4 There is no specific time limit to this test, and in patients with mild pu/pd, an MWDT can take longer than 12 hours. If the endpoint has not been reached when the clinic is closing, the patient can be transferred to an overnight facility for continuation of the MWDT, or the animal can be provided with a maintenance water amount (2.75 ml/kg per hour that the animal is unobserved). The next morning, the patient should be weighed, the USG measured, the water withdrawn and the test continued until an endpoint is reached.3 If the patient has concentrated adequately at the endpoint, the diagnosis is psychogenic polydipsia. If there is inadequate concentration, the bladder is emptied, water is still withheld and aqueous ADH administered (0.55 U/kg IM with a maximum of 5 U per dog or cat). The bladder is then emptied every 30 minutes for 1-2 hours.4 Alternatively 10 to 20 mg of the sterile preparation of desmopressin acetate (DDAVP, Rhone-Poulenc Rorer), a synthetic vasopressin analogue, can be given intravenously or 20 mg of DDAVP (approximately 4 drops of the 100 mg/ml intranasal preparation) can be administered into the conjunctival sac.6 Measurement of USG or urine osmolality should occur every 2 hours for 8 hours and then at 12 and 24 hours. The maximal response to intravenous desmopressin usually occurs 4 to 8 hours after administration, but it may take up to 24 hours.3 If adequate concentration occurs (i.e. USG > 1.018 or urine osmolality increases at least fivefold), the diagnosis is CDI. If urine still remains unconcentrated, the diagnosis is NDI. CDI can be differentiated into partial, where ADH release is subnormal but still present, and complete where no ADH release occurs. In an MWDT, those with partial CDI show some concentrating ability in response to absolute water deprivation and then increase another 10-50% in response to administration of exogenous ADH. Those with complete CDI will not concentrate in response to dehydration but will when given exogenous ADH.4,7 CDI can be congenital, idiopathic or due to trauma or inflammation or a pituitary tumor. In a dog >6 years old, the most common cause of CDI, either partial or complete, is a pituitary tumor. Even if neurological signs are absent, diagnostic imaging is warranted.7 An option to the MWDT when psychogenic polydipsia, CDI and primary NDI remain as the only possible differential diagnoses is to evaluate response to DDAVP therapy. In some clinics this has become the test of choice as compared to the MWDT for differentiating these three causes of pu/pd. The patient's 24-hour water intake for 2-3 days is measured allowing free-choice water. A urine sample is collected at a given time each day to check urine osmolality and USG. After these initial days, the patient is treated with DDAVP by administering the intranasal preparation (1-4 drops placed in conjunctival sac) or the oral tablets (0.1 mg) every 12 hours for 5-7 days.6 Water intake is monitored and a urine sample obtained on the 5th to 7th day at the same time of day as before treatment. A dramatic reduction in water intake and/or increase in urine concentration (i.e. >50%) provides strong evidence for CDI. Moderate response is consistent with partial CDI.4 A mild response is suggestive of psychogenic polydipsia. If no response is seen, NDI is present. CASE SUMMARY: An MWDT was performed and complete CDI diagnosed. A CT scan of the brain was normal. Therapy with DDAVP was initiated. After a few months, the medication costs were decided to be too much. The dog remained outside during the day when the owners were not at home. Plenty of fresh water was available at all times. She was brought inside at night and given a dose of DDAVP. References available from author upon request | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
