My name's Melissa Cavigan. I'm an endocrinologist at Indiana University, and I have the pleasure of welcoming our speaker today. This is Dr. Janecik from Georgetown University. She's an assistant professor of, associate professor of medicine there. She has a long list of things she's done, very active in research and clinical work and graduate medical education. And she has taken on the topic, a challenging topic I think we all find daunting at times, of water metabolism. So thank you very much for educating us on diabetes insipidus. Looking forward to it. Thank you for having me. Can you hear me? Yes, good? Okay. Wow. When I came 15 minutes ago, I got a little concerned because the weather is beautiful. This is such a nice place to be, and I thought you'd trade at this nice marina instead of coming here, but I'm really glad to see so many faces. I've been enjoying meeting. I hope the same with you. It's been quite a fun. So let's get started. It is sometimes complicated topic, but I love sodium metabolism. When fellows interview in our, you know, considering, when they consider Georgetown endocrinology program, we tell them they will get a mini nephrology fellowship in addition to endocrinology because my boss, Joe Verbalis, many of you may know him, is truly world expert in sodium metabolism, and I've done a lot of research with him on hyponatremia. We were involved in covaptan studies, and of course, sodium is dear to my heart. Okay. And if, you know, I think we'll save questions for the end as usual. So let's get started. So as you already know, today we are not talking about honey diabetes. We are talking about tasteless diabetes, okay? That's what diabetes insipidus stands for. Okay. So let's go through some physiology. So this is one of the slides I borrow from Dr. Verbalis, and just reminds us of the, that the fluid composition in the body, water is the largest component of our body, and since the major determinant of body water is AVP, regulated water excretion by the kidneys, it follows logically that AVP must be the most important hormone in the body. Okay, that's definitely for us, Dr. Verbalis. Also, as a fellow that I was initially at Georgetown, he tells all the fellows never use the word ADH because he thinks that's mostly for nephrologists, so we endocrinologists prefer to use the AVP. Of course, we are talking about the same hormones, so feel free to use ADH or AVP, but during my presentation, I'll be using AVP. Okay, so what stimulates the AVP? The main stimuli for AVP secretion are hyperosmolality, hypovolemia and angiotensin II, and then some negative stimuli come from baroreceptor and nitriuretic peptides. There are two types of vasopressin receptor. There is a V1 receptor. That's the one primarily involved in vasoconstriction. We are familiar with use of vasopressin for a pressor effect, oops, and the V2 receptor, that's the one that it's really important in sodium metabolism. That's the receptor in the kidney, and that's the one, of course, involved in renal water reabsorption. Okay, so our favorite organ, the pituitary and hypothalamus. So the AVP is synthesized in the supraoptic and paraventricular nuclei, and then it's transported down the axons of the pituitary stalk and released into systemic circulation. So the posterior pituitary is only the storage of AVP. This is one of my questions for medical students, and then I usually ask them what other hormones is stored together. Who is the roommate of AVP, and you guys know that. That's oxytocin, and of course, I like to ask them why we need oxytocin, and why do men actually have oxytocin, since men don't give birth and don't lactate. So I'll let you answer that yourself later. But it's a fascinating research just on the side, on the effects of oxytocin in the body. So a little more about, so we already mentioned what are some stimuli for AVP secretion. So both changes in plasma smallality and changes in blood volume stimulate AVP. What's important to recognize is that very small changes in plasma smallality, as little as 1% will stimulate AVP. So the body's plasma smallality does not fluctuate widely. While it takes much larger changes in blood pressure or blood volume to stimulate AVP. So two different stimuli and two different thresholds for release of AVP. This is our friendly kidney. Just to kind of orient you, the red part, that's the blood side. The yellow part, that's the urine side of collecting duct, and of course we have that inside collecting duct cell. We have a lot of actions here happening. So on the basolateral membrane, there is the vasopressin receptor. Vasopressin receptor is one of those seven transmembrane G-protein couple receptors. When vasopressin activates the vasopressin receptor, it go through cyclic AMP, it results in insertion of the aquaporin channels. You know, the easy way of think of aquaporin channels is I refer to them as water gates, and when they are inserted, the collecting duct membrane allows the watery reabsorption. That's why this hormone is also called antidiuretic hormone, because you are causing the water reabsorption, or antidiuresis. Okay, that was our nephrology lecture here. So we have several different types of diabetes insipidus. The central, then there is nephrogenic, which can be also hereditary or acquired. Then the other cause of diabetes insipidus is something called primary polydipsia. Of course we have gestational DI, and then there is osmoreceptor dysfunction. So all the conditions here listed will result in polyuria and polydipsia. Okay, so let's talk first about the central DI, sometimes referred to as a neurogenic or pituitary. It's characterized by decreased secretion of AVP. So basically those patients don't have any AVP levels. If we are talking about the complete central DI, of course in the partial, there is some still preserved AVP secretion. So I think I'm kind of of the central DI more like a type one diabetes where there is no insulin secretion. How common is central DI? It's rare, it's about one in 25,000. Anybody wants to venture how many people in San Diego area have central DI? I'll give you the answer, about 50 to 55. How do I know that? I just divided the 1.4 million by 25,000. That's the population of San Diego. So I presume roughly that's number of people. Most common cause is the hypothalamic lesion, about 50%. It could be tumor infiltrative conditions such as sarcoid histiocytosis. Pituitary lesions itself are usually not sufficient to cause DI unless it occurs in a post-op period. Idiopathic DI contributes to about 20 to 30% of cases, probably autoimmune, not completely understood. And genetic causes are less than 5%. So what are some of the most common tumors? You have seen this in your practice, I'm sure. Patients with craniopharyngioma, that's probably one of the more common one. Germinoma, meningioma, sometimes lymphoma, and of course metastasis. What tumors metastasize most commonly into pituitary? Lungs and breast are some of the most common one. This is the patient with intracranial germinoma that was supercellular as well as in the pineal region. Let me see if I, I don't know if I can use the pointer. Not really, but you have the arrow showing there. Okay, so Langerhans cell histiocytosis is one of those infiltrative lesions that can present with DI. And the infiltration can be inside the pituitary or it can involve both stock and the pituitary itself. And this is a study that was published in New England Journal of Medicine now, wow, hard to believe, but 20 years ago. And it just shows the progression of the disease. Lymphocytic infundibular neurohypophysitis, that's probably the longest word I will ever say today. So we commonly refer to this as a LIN. And actually when I was fellow 20 years ago, we had a patient and I presented at Endocrine Society one case of LIN. So those are relatively rare patients. Some people refer to this as a Hashimoto's of the pituitary stock. So the biopsy of the pituitary stock, sometimes it's indicated if we cannot otherwise come to conclusion what is the cause. And there is a pituitary stock thickening. In this particular case, immunostaining using a monoclonal antibody directed against the lymphocyte antigen is found. And this is one easy example of, I think even people in the very last row can see that this pituitary stock is thickened. I strongly encourage you, and I'm sure you do that, but when you order MRIs, pituitary MRIs, don't just try, if you can get hold of the actual images and look at them yourself, because sometimes things settle things like pituitary stock thickening, or as I will show you, the posterior pituitary bright spot. Sometimes radiologists may not even comment on that. Okay, so when you find thickened pituitary stock in a patient with central DI, what are the tests that you should order? Well, in addition to some blood testing, often those patients do need spinal tap, and we analyze the CSF for the ACE level, alpha-fetoprotein, and beta-ACG, trying to rule out some of those tumors, including germinomas. And then we send the CSF for cytology and flow cytometry. And if you are suspecting infiltrative disease, chest X-ray, CT, bone surveys. If everything is negative, then a serial follow-up of those patient is warranted. Okay, so we said that the most cases of central DI are due to infiltrative lesions, but there are some hereditary cases. It's very rare, but mutations in AVP gene have been associated with hereditary central diabetes insipidus, and it's transmitted in autosomal dominant manner. Extremely rare, but you know how it is, especially on boards. The rarer the condition, the more likely you'll see it on your exam. In pan-hypopit, DI may not initially be clinically manifested if the patient also has steroid deficiency, because steroid deficiency impairs free water excretion, and polyuria may be only unmasked when cortisol deficiency is treated. So you may have a patient that is post-op and developing a DI, but at the same time has adrenal insufficiency, and before you give them steroids, they may not have much of their water excretion, but once when you start steroid treatment, you will notice profuse diuresis. So this is important to know. And also, if you suspect adrenal insufficiency in patient, you will notice that once when you give steroids, regardless of the diagnosis of diabetes insipidus, you have increased water clearance with steroid replacement. So you may want to watch if that patient, especially if they were hyponatremic, you may have a rapid correction of sodium. Once polyuria is confirmed, which is the first initial step, is 24-hour urine collection. Other causes of increased urination should be ruled out, such as diabetes mellitus, hyperglycemia, hypercalcemia, and hypokalemia are the most common electrolyte abnormalities that will result in polyuria. Okay, so nephrogenic DI is even less common than a neurogenic or central DI, and this makes a really common board question because now here you have familial N-acquired forms, and among familial, you have two types. You have the X-linked recessive N, which is due to mutation in an AVP receptor, and then you have the autosomal dominant, which is due to mutation in aquaporin 2-channels. So two different defects and two different types of inheritance. There is acquired nephrogenic DI, and I already mentioned some causes, such as hypercalcemia. It typically has to be pretty high calcium, more than 12 or 13, so you won't see it with mild hypercalcemia. And then severe hypokalemia can lead to polyuria, polyuria, and then of course medications, the most notorious one being lithium. Lithium makes my favorite question for students because I usually ask them just to, you know, give me as many metabolic abnormalities as they can think of, and lithium does cause quite a few, both endocrine and metabolic in general. Okay, so the mutation in vasopressin 2-receptor gene, we already mentioned are associated with a hereditary nephrogenic DI. This has been extensively studied, and there are quite a few mutations, so don't worry, you won't have to memorize them whatsoever. Okay, and I just happen to know, the person that worked, that done a lot of work on this is Dr. Daniel Bishop, who is in Montreal in Canada, and that's where I did my PhD. Okay, the aquaporin 2 gene also has mutations, so we already talked about that. So let's go into diagnosis. I know you are here because you really wanna know, okay, how can I recognize those patients once when I find them, what do I do in terms of diagnosis and treatment? So the first step is to, you know, establish that patient has hypotonic polyuria. What is the excessive amount of urination? Well, in 24-hour urine volume, anything more than 50 milliliters per kilogram typically comes to over three liters in 24 hours. It's considered abnormal. Of course, there are some variations to this. There are people that just drink very large amount of volumes always and urinate more, but in general, this more than 50 ml per kg, that's typical what you'll see in books. This is coupled with urine spec graph that it's low, less than 1.0, and urine ozome less than 300. And then the last thing is you want to exclude other causes of solidiuresis, for example, high glucose. So failure to meet any of those criteria needs further, renders further evaluation unnecessary. Meaning, if your patient 24-hour urine volume is less or if they have a larger volume, but their urine ozome is above 300, definitely if it's above 800, they don't need further investigation. Primary polydipsia is probably the most common thing you'll see in your clinical practice, and there are two types. There is one dipsogenic, which is the really recent threshold. It's sort of like, you know, with SIDH, we have reset osmostat. And then psychogenic, that's the one we all think when we say primary polydipsia. We try to avoid the word psychogenic because it has a little sometimes negative connotation, so people often just group all of this into primary polydipsia. But indeed, psychogenic is just increased fluid intake for no other reason, you know, other reasons, not just thirst. And, you know, as far as the psychiatric condition, most commonly seen in patients with schizophrenia. Okay, so how useful is plasmosmolality in trying to distinguish, you know, etiology of polyuria? Well, this was studied by Dr. Robertson, who is another big name in sodium metabolism. You can see that in general, plasmosmolality is going to be somewhat lower in patients with primary polydipsia, while it's going to be elevated both nephrogenic and central DI. So it's not very helpful in distinguishing nephrogenic and central, but typically primary polydipsia patients will have lower sodium levels and lower plasmosmolality. Okay, so I mentioned earlier pituitary bright spot. So the pituitary bright spot is something that you will see on a non-contrast sagittal MRI image. And it's really hard to miss if it's there. Presence of posterior pituitary bright spot almost completely rules out diabetes insipidus. However, about 20% of healthy people without DI do not have a posterior pituitary bright spot. So if you see it there, it's great. It makes DI very unlikely, but if it's not there, it's not, you know, completely conclusive. So what gives this bright spot? It is the stores of AVP levels, and AVP and oxytocin in posterior pituitary. It conveniently shows as a very bright. Okay, so the water deprivation test is sort of like a standard, you know, traditionally standard test that we have used for diagnosing diabetes insipidus. The mini water deprivation test, or the overnight water deprivation test, typically used as an initial screen, basically something that you will instruct your patients to do at home, and includes withholding all the fluids, typically after dinner, and patients, so patient doesn't drink anything whole night, they go to the lab first thing in the morning, and you order serum sodium, and you're in awesome. If the urinosome is above 800, that eliminates the DI diagnosis, so you can reassure the patient they don't have a DI, and you know, you don't need any further workup. More than 600, most cases rolls out. So this is sort of like measuring your 8 a.m. cortisol before you go to STIM test. It's a quick, easy way to sort out who really needs to go to more formal testing. Formal water deprivation test is typically you need to bring patients to be admitted in a hospital, or if you have like a clinical research unit where you can do this, but we, and I listed the test, you know, procedure here, but you withhold, again, all fluid until body weight decreased by three to five percent, urinosome plateaus at least for a couple of, two to three successive measurements, or serum sodium reaches above 145, so it has to be 146 or more. At that point, you administer DD-AVP, and keep monitoring urinosome and volumes. If the urinosome increases more than 50% after DD-AVP administration, that indicates the central DI. If increases less than 10%, that usually indicates nephrogenic DI. Of course, a lot of times, patients fall into this intermediate category where it's not always easy to tell what form of DI they have, and I'll show you in the next few slides some other ways how we can sort this out, especially patients that have partial nephrogenic, partial central, or primary polydipsia. Okay, so this is very helpful slide. Again, it shows you the, how to interpret water deprivation test, so the very top purple line is the normal response. In response to withholding water, the healthy people will just concentrate urine definitely at least 800, sometimes even more, and then there will be no further changes even after DD-AVP administration. Patients with a nephrogenic DI will have, if it's usually no response, or as we said, less than 10% response after DD-AVP, so pretty much flat line. Patients with complete central DI, they do not change urinosome, but when you give them DD-AVP, the urinosome goes up over 50%, so that's usually pretty easy to distinguish. The one that I said are a little trickier sometimes. It's distinguishing between the partial, central, and primary polydipsia. In primary polydipsia, patients do concentrate urine because they really, you know, but they don't concentrate to as high level as normal. Why? Because many times due to excessive fluid intake over time, they wash out that gradient, their kidneys are unable to get to 800 or 1,000, but they often can get to at least 600, and then there is no change after DD-AVP administration because they already concentrated to the maximum and they don't have any defect in AVP. Patients with partial central DI, they have ability to concentrate to some degree, usually less than half of what normal people, and then they do respond to DD-AVP, so they respond similarly like a complete central DI. The main difference is that even initially on their own, they can concentrate urine at least to 400, 500. So at the end of water deprivation test, I always look at this little slide and try to, you know, place where a patient would fall. Okay, so this is our friendly vasopressin gene. It's one of those also genes that it's encoded by 145 amino acid pro-hormone, and then it's enzymatically cleaved, and one of the protein, it's a glycoprotein called COPEPTIN. So COPEPTIN is the name that you may be already familiar, but if you are not, you will definitely hear more in years to come. Okay, so the AVP itself, you know, people say, well, why don't we just measure AVP level and find out if patient has no AVP, they must have central DI, and you know, it's as simple as that. Well, there are a lot of technical issues with measuring AVP. I can tell you over the years, you know, half of the time when we would send the AVP levels, no matter how clear instruction you give to the lab and nurses, it either gets messed up, it's not done properly, and the assay itself is difficult to perform. So the COPEPTIN is being proposed as a surrogate for measurement of AVP. COPEPTIN, we already said it's a precursor. It's much more stable. The sample handling is more straightforward. So it gives us the same information, but in much easier way. Okay, so this is one of the slides that I like to show you about how useful is COPEPTIN. And COPEPTIN, so on the right-hand side, you have the water deprivation test results, and you can see that in a patient that, you know, if you just do water deprivation test and measure COPEPTIN, it's still not as easy to distinguish between primary polydipsia and the central, or especially partial central DI patient. However, if you perform hypertonic saline infusion test, and then you measure COPEPTIN, you get clear separation between primary polydipsia and the central DI. And I'll give you some examples. But the diagnostic accuracy after hypertonic saline infusion, it's 96.5%. So it's turning out to be a really helpful test. Not to forget to mention something interesting, relatively rare, but a form of DI called adipsic diabetes insipidus. I'm sure, again, you have seen in some of your patients, unfortunately, most often after removal of craniopharyngioma, that's one of the common one we see, but again, some metastasis can do it, sometimes from anterior communicating artery aneurysm. This is very devastating to patients because those patients, due to distraction of osmoreceptor, they don't have any sense of thirst. And I think right now we have three or four patients that we actively follow at Georgetown, and I can tell you it's sort of a nightmare because they get admitted almost every couple of months, if not more often, to a hospital. You have to treat them by prescribed fluids. Literally, they have to line up their glasses of water or bottles of water and drink them at a certain interval because they have no sense of thirst whatsoever. And often, something happens, they forget to drink, and next thing you know, they are admitted. So we have some frequent flyers with this condition. Okay, so we already know that water is the therapy for diabetes insipidus, and of course, before the other therapies were available, a lot of those patients, yes, they would still survive and they would thrive as long as they had access to water. Of course, the quality of life was really bad because some of those patients can be urinating 10, 15, 20 liters a day, so pretty much it turns out into full-time job of drinking and urinating. So fortunately, we have some ways to help them. So of course, for our central DI patients, we use the synthetic DDAVP or desmopressin. That's the mainstream treatment. And then for nephrogenic DI, we don't have as elegant treatments, but what has been used and tried is diuretics such as thiazides and amyloid, as well as indomethacin. So the goals of treatment for all forms of diabetes insipidus is to correct any pre-existing water deficit, reduction of ongoing excessive urine losses, and how do you calculate pre-existing water deficit? Well, I'm sure you know this formula or you have it in your phone. The question often comes when we are seeing those patients in inpatient setting, how quickly to replace this. So in adults, we should correct 50% of the deficit in the first 24 hours, and the reminder over the next 24 to 48 hours. And this is above the estimated urine output plus insensible losses. So don't forget that. In children, correction is a little less. And then the volume replacements include, I already said, not only calculated deficit, ongoing insensible urine water losses. And, okay. So I thought this was an interesting study published recently. Basically, it looked into this question that we often see in inpatient setting is, okay, do I have to be careful how quickly to correct hypernitremia? We all know that with correction of hyponatremia, you have to be careful, and we have clear guidelines because we want to avoid central pontine osmotic demyelination. How about high sodium? Do you have to be as careful? Well, what this group showed here, that this was, you know, in this particular study, they had about 122 patients, and their sodium were pretty high, above 155. And then they look into rapid correction, which was defined as more than 0.5 millimoles per liter per hour versus slow correction, which is less than 0.5 milliliters per kilogram per hour. And at the end, there didn't seem to be any significant difference, no adverse outcomes, which was very interesting. So I think it, you know, we are probably, most of the time, probably a little more careful than we need to be with correction of hyponatremia. And this was now over 10-year-old study, but interestingly also confirms what I just said, that actually undercorrection of hyponatremia is associated with the worst survival. Okay, what are some reasons for undercorrection besides, you know, physicians being a little too cautious? Well, it's underestimation of ongoing insensible and sensible fluid losses. So we are pretty good about plugging the sodium level and using that formula, but I think we often forget about those other losses. And the insensible fluid losses can really amount to significant amount, and I put some here, some reasons and what constitutes that. Okay, so as I said, we are very lucky that we got our DD-AVP as a treatment for diabetes, central diabetes insipidus. This is just contrasting difference between vasopressin and DD-AVP molecule. Desmopressin therapy also makes a great board question and question for my students and residents because it's one of the rare medications where actually can be given, first of all, it can be given three possible ways, parenteral, intranasal, and oral. And it's also one of the rare examples where you have peptide hormone that you can give by mouth. Of course, you know, now we have inhaled insulin, which, you know, 20 years ago, that was not an option. Now we have drugs like ribelsis that can be given by mouth. But the DD-AVP was one of those first medications that although it's a peptide, can be given by mouth. And the question is, well, how is that possible? How comes it doesn't get digested by and destroyed by the enzymes? Well, the secret is very obvious when you look at the dosing. So what's the dosing for parenteral or sub-QRI DD-AVP? It's one to two micrograms. What's the dosing for intranasal? 10 to 20. What's the dosing for oral? 100 to 200. So I think everybody sees the pattern here. So the idea is when you give oral, you are giving 100 times more than you give sub-Q or IV. And you don't care if you lose 90, 95%. Even 1% absorption is enough to achieve that effect. So how come we cannot give oral insulin? Well, because with insulin, you don't have that luxury. You want to have a really, you want to be able when you give 100, let's say you give 100 micrograms of insulin orally, you want to make sure that you get 100% absorption because even small variation will produce larger fluctuation in blood glucose. How do we know this? Actually, a while ago, we were part of Georgetown of the study for oral insulin. And it's not that it didn't work, it just was extremely unpredictable. So yes, at the end, that study never moved on. However, here, with the DVP, that's not a problem. So, okay, let's, how are we doing with time? I think we are doing good. So I have two cases. First case is a 25-year-old healthy woman who presented with complaint of severe polyuria polydipsia. She described drinking five to seven liters of water a day. The patients with DI also prefer cold water. They have preference for cold water. They don't drink hot tea, coffee. They are very much into cold drinks. She has noticed that she's more fatigued. She carries the water bottle thermos with her. And post-medical history significant for giving birth to her first child nine months ago, persistent amenorrhea since that time, and she only breastfed for three months. Her physical exam unremarkable, except for small amount of expressible galacteria bilaterally. So I think some of you, or most of you, probably already know what the diagnosis is here. Okay, her initial laboratory testing was significant for sodium of 146, and what else we have? Her plasmas molality was 300, so it was decreased, and urinosin was only 95, so very, very low. Okay, so what is the differential diagnosis, and is formal water deprivation test necessary to make diagnosis? Well, the patient has all the classic symptoms, right? Polyuria, polydipsia, nocturia, and she has preference for cold fluids, so all the signals point to DI. Those symptoms can occur in primary polydipsia, but the fact that her sodium is 146 makes primary polydipsia extremely unlikely. Most patients with primary polydipsia run sodium in a kind of 135, even sometimes to a lower level. Okay, so let's get to the next one. So, consequently, the serum sodium is generally of a limited value, except when it's a very low, as I said. If it's in a, you know, like a 135 or less, that's highly suggestive of primary polydipsia, but let's say if it's 140, that's still non-conclusive, because patients with DI are also drinking a lot, so they may manage to keep that sodium somewhat down. However, patients with DI rarely overcompensate by drinking so much that exceeds their renal capacity excretion, so the high serum sodium is very suggestive of DI. Okay, and let me go to next. Is the formal water deprivation test indicated? No, it's not, since patient is already hyperosmolar. So, in water deprivation test, you want that sodium to get, as I said, 146 or above. This patient already has sodium 146, so she has done her own water deprivation test. She, you know, her AVP level is already maximally stimulated, and at the same time, her urine is completely inadequately concentrated. Remember, her urinosome was 95, therefore, she meets criteria for diagnosis of the diabetes insipidus. The only remaining question is to differentiate now, does she have a central DI or nephrogenic DI, and this can be done. In this particular patient, you can just give her a DDAVP, and you can observe her response. If she has central DI, she is going to respond quite well. If she has nephrogenic DI, there will be no response. I know, given the history of amenorrhea and giving birth and all of that, I know everybody's thinking, yeah, but we are not really concerned about nephrogenic. Everything points to the central. So, the most likely, and I should have put the MRI here, I didn't show you, but in this particular patient of mine, what she turned out to have is actually LIN, the lymphocytic infundibular neurohypophysitis, the autoimmune process we already talked about that has invasion of the pituitary stalk, and often due to the stalk compression, they have higher prolactin level, and because of increased prolactin, she developed amenorrhea and a small amount of expressible galacteria. So, that was her diagnosis. So, the million-dollar question is then, how do you treat LIN? There is no good consensus. Steroids have been tried, and a lot of time people would use prednisone, with some success. The other issue is when, you know, if the lesion, if the stalk thickening is increasing in size, of course, there is always concern that it could be cancer, one of those tumors, or infiltrative conditions, so sometimes the biopsy is truly indicated, but in a setting of the postpartum, where we do see more of the LIN, one should assume that this is LIN, and as I said, attempt treatment with steroids, which we did in this case, and she improved in about six months. However, sometimes the DI does persist and doesn't reverse. Okay, so I already disclosed the cause of the hyperprolactinemia, which is stock compression, and the DI, DD-AVP, is the treatment for her DI. Okay, that was the first case. I do have one more case. This was a patient that came to us. She was 55 years old, and she was already on lithium for many years, for her bipolar depression. She was drinking a lot of, lot of water, and recently, I think psychiatrists noticed that her B1 has been increasing, and suspected possible lithium toxicity. She initially went to another center where she had the water deprivation test, so the results of water deprivation test that I'm showing here, we did not do at Georgetown. She brought those results to us. You can see that she started with a weight of 80 kilograms, and her sodium, interestingly, was only 135 at that time, and her, I mean, sorry, her urinose malality was 135, and her serum sodium was 137. Her water deprivation test lasted 10 hours, and it was terminated when she lost about 4% of her body weight. Remember, one of the criteria we set is to stop water deprivation test if there is at least 3% body weight loss. Her urinosome only went from 400, after one hour of DD-AVP, went from 405 to 455, and that was about 12%, 12.5% increase. So, it was not less than 10%, which would be consistent, for example, with nephrogenic DI. It was not more than 50% increase, which would be consistent with central DI. So, this was one of those patients that falls into this gray category. However, here is my question to you. Do you think that based on the way the test is conducted, do you think that we can make a diagnosis of central DI, lithium-induced nephrogenic DI, probably conclude that she has primary polydipsia, or question the way the test was conducted? And the last thing is, do you think that they should have used the AVP instead of the DD-AVP? I think that you can easily exclude. This is not the audience response system, and it's not really meant to be a tricky question, but I'll just go back and point that look at her sodium level when the test was terminated. It was only 143, and that is the problem. As I said, we didn't do this at Georgetown. If she was with us at that time, and her sodium was still only 143, but she already became symptomatic, she lost more weight, what else, anybody wants to shout, what else could have been done to stimulate maximally that AVP and make this test valid? Hypertonic saline. Hypertonic saline, excellent, excellent. So, I don't know why that was not done, and therefore really the proper answer here is that the diagnosis cannot be accurately determined because that sodium never got to 146 or above, and that's the problem in this case. Although, of course, it's tempting to say that because she's been on lithium for more than 20 years, yes, a large percent of those patients will develop nephrogenic DI. So, the water deprivation test still remains the preferred diagnostic test for diagnosing DI, as well as differentiating various type of DI. The original description of water deprivation test called the Miller-Moses test, including measuring the urinosome in response to AVP administration. However, subsequent study indicated high rate of false diagnosis when only this criteria is used. Consequently, it is necessary to measure plasma AVP level at the end of water deprivation test and before the DD-AVP is administered. I already, this is especially true when you are in this gray zone, when urinosome changes between 10 and 50 percent, so more than 10 but less than 50 percent in response to DD-AVP. So, the initiation of water deprivation test depends of the severity of DI. With moderate polyuria, deprivation can begin the night before. Patient that have severe polyuria, you should do the test in the morning because some patients with DI will really become very symptomatic within four to six hours. When do you stop the test? You stop the test, again, when weight decreases at least 3 percent to 5 percent, urinosome plateaus for two to three consecutive hours, and or sodium is 146 or higher. So, I already mentioned the copeptin. These days, instead of measuring AVP, we do measure copeptin. I put this slide here. I know it looks very busy, but I just want to point to a couple of things, especially that if you have a patient that, you know, you suspect the DI and at the baseline, if the copeptin level is more than 21.4 picomoles per liter, that is consistent with nephrogenic DI. So, the very high copeptin level consistent with nephrogenic DI. If very low level, usually less than 2.4, you can then do the hypertonic saline infusion, and if it's more than 4.9 copeptin level after hypertonic, that's consistent with primary polydipsia. If it's less than 4.9, that's consistent with central DI. So, the combination of hypertonic saline infusion and measurement of copeptin can help to distinguish most of those, you know, gray zone or previously ambiguous diagnosis where we had an issue, especially measuring AVP levels. I think this is my last slide. It was a pleasure talking to you, and I'll be happy to take as many questions as you want. Thank you. Thank you very much. That was terrific. For those of you who have questions, can you just approach the microphone? Do you see any problems for prolonged DDAPUs like significant weight gain or hyperlipidemia? Any other problems? Yeah. So, good question. To my knowledge, there are no known metabolic abnormalities that are found such as cholesterol, glucose. One of the issues, of course, with DD-AVP is making sure that patients that are treated with DD-AVP don't drink also too much water because that sets them up for hyponatremia. So, if you have a patient that's prone to that, we ask them at least once a week to kind of skip the dose of DD-AVP, wait until they start urinating a lot, kind of what we call to escape as a safety to avoid hyponatremia. So, I think the major risk of DD-AVP treatment is if the patient is drinking a lot of water causing hyponatremia. Go ahead. Thank you for the great talk. I'm familiar with this because I'm visiting this a lot. My older daughter goes there. So, thank you for having this picture. My question is about familial central DI. Just it happened I inherited two patients and one of them, her daughter, decided not to have any children. So, it stopped there. The question I have is genetic counseling. How, like, when you inherit this, you recommend it because it's autosomal dominant. At what age from birth, like, that can happen at birth, right? So, it's a great question. Again, it's such a rare condition. I have to say, personally, I have not managed any of those patients. I hope you, wherever you practice, I don't know if you mentioned where you practice. In Connecticut, Central Connecticut. Yes. So, I'm sure at Yale they probably have a good genetic counselor. You know, once when that person starts thinking about family and reproduction, I'm sure that would be a good time. But, as I said, personally, due to the rarity of that condition, I have not managed any of those patients. Thank you. With DDAVP replacement, do you see differences in brands versus generics or is it just my patient population that thinks there's a big difference? Great. Actually, no. You know, it's not like Sintra where some patients are very passionate about the brand. When it comes to DDAVP, no, not really. I haven't had many patients making specific requests. So, I'm sure there is something if you Google, that Dr. Google tells them that one form is better than another. And, you know, when it comes in general to medications, generic versus brand, since patients are asking us for different medication, this question. What I tell them is that I believe that most generics are as good as brand. There are some drugs, and I had personal experience with patients that were on Lipitor, two patients actually, that clearly didn't get the right product because the cholesterol went through the roof. So, there was a recall of Lipitor, one particular batch. So, yes, once in a while, the generics may have, you know, recall, but we have seen recall with brands as well. And, since the cost is often a significant difference between generic and brand, I try to reassure them that whatever it's, you know, covered by their insurance. In this particular DDAVP, I haven't really noticed or patients have not been asking much. So. Hi. Thank you for the great talk. And I'm one of the attending professors at the Southern Illinois University in Springfield, Illinois. So, I just wanted to ask about those patients who have impaired thirst mechanism. I know you touched base about those. How do you manage those? I mean, I recently picked up a patient who is on very high doses of DDAVP, and she has impaired thirst mechanism. And she, normally her sodium runs in 150s. She's asymptomatic. And it's just, it's really hard to bring her levels down and, you know, for her to control. Yeah. It's very hard. It's very hard. And, yes, they often come to hospital with sodium of 160 or well above 150, and they seem to kind of get, you know, they get used to those high sodium levels. So, may not be as much symptomatic even at the high sodium levels. I think what, you know, what's important, if possible, involve the family members. Helping a patient, again, setting reminders. We have, you know, I have asked patients to put the alarms on their phone, to alarm every two hours to remind them, you know, send the messages. Just the little tricks, how to, how to really keep up. It's, it can be challenging. We have one patient that, daughter works during the day, and the patient just, just doesn't, doesn't want a drink because she's not thirsty. It really goes to, you know, explains, tell us how important is this thirst mechanism and how we don't necessarily, you know, crave any drinks if we don't have the thirst receptors. So, I think you have to try involve the family and other means and ways of reminding patient. It's almost like, you know, some patients with insulin, they also need to set the reminders to take their insulin. It's, before eating here is, it is even more intense because it's not just three times a day. It's, it's around the clock. So. Thank you. So, how do you decide whether to do the water deprivation test versus the copeptin saline, hypertonic saline test? Is it dependent on availability or? So, so again, if you follow this, if you follow this algorithm, if you have a patient with, if you have a patient that it's sort of in that gray zone, so urinosome is, you know, less than 800, so yes, they may have the DI, but the serum sodium is between 136, 146, so it's not above 146. It is reasonable now that we have the copeptin to do the baseline copeptin, and if the baseline copeptin is more than 21.4, that, that's nephrogenic DI, then you don't have to really do anything else. If it's less, then you do have to proceed to hypertonic saline to further distinguish between the central and primary polydipsia. So, that, this is the one route. So, clearly for patients with very high copeptin levels, you can pretty much with certainty rule in nephrogenic DI. Matt Levine with Scripps here in San Diego. I thank you also for a great talk. In case one of the two cases that you showed, was that patient given only prednisone because of the likely LIN diagnosis, or was DDAVP also given in addition? Yeah, yeah, yeah, sorry. She was given, of course, DDAVP for her diabetes insipidus, but we used the prednisone to treat her LIN. Although, as I said, it's somewhat controversial. Not everybody is using it. Since we don't understand exactly, we think there is an autoimmune component, so like a lot of autoimmune conditions steroids may be helpful. But yeah, she, her DI was treated with DDAVP, and prednisone was strictly for LIN. Hi, thank you for the talk. My question is, I have two patients that I'm suspecting they have gestational diabetes insipidus. So for that, is there any use in measuring copeptin? I have not seen, I have not seen the data for copeptin in a gestational diabetes insipidus. But, you know, and I didn't spend too much time on gestational DI, but yes, usually it appears in the second and third trimester of pregnancy, where you have the degradation of the vasopressin level by the enzyme from placenta. In pregnancy in general, we, you know, if in doubt, one, one should treat and see what kind of response you have. I would not hesitate to do the empiric treatment. I'm not aware of the, you know, measuring copeptin in pregnancy per se. Okay. Thank you for the talk. So, we know that the absorption of intranasal DDAVP can be affected during upper respiratory infections or rhinitis. So do you give any specific advice in a patient who has well controlled DI, who is on intranasal, I mean nasal spray? Yeah, that's a good question. So if, if somebody has really, you know, significant upper respiratory infection, I would, I would change them to, for example, if they were on intranasal, change them to oral during that time. Same as we don't use intranasal immediately post-op, you know, post, after pituitary surgery where there is still, you know, when they have a nasal packing and there may be significant swelling of the mucosa. So when you're starting the DDAVP, do you typically give a script for? I, I usually, I usually tell them to notify me. It has not been okay, it has not been an issue with most of the people with the milder respiratory infections. So the, you know, if they may, if they're, again, the DDAVP is a very forgiving. So even if they don't get the maximum absorption, even partial absorption, most of the time it's sufficient. Of course, we are not monitoring sodium levels frequently in the outpatient setting. So I'm sure if somebody has quite a lot of nasal congestion, yes, we advise them also to use nasal spray to alleviate the congestion. And probably the DDAVP is not as effective, so their sodium level may go up a little bit. Again, we don't monitor that but in general, since that's such a short-lived, you know, condition, I don't typically give them prescription for oral as well. I don't think it's necessary. It has not been an issue. I have one more question. Sure. So DI in pregnancy, due to the action of placental vasopressinase. Yes. Do you prophylactically increase during second or third trimester or what is the best way of monitoring? I mean, we just monitor. We go, we monitor sodium level. I mean, I wouldn't empirically increase. Again, not like with synthroid where we know kind of, you know, how to proactively increase and what percent. Here, it's more we monitor, we check sodium a little more often, and then we go based on sodium levels. Thank you. Okay. That's perfect timing unless there's another question. All right. Great. Thank you again. Thank you.

water metabolism

diabetes insipidus

polyuria

polydipsia

central nervous system dysfunction

nephrogenic factors

primary polydipsia

gestational factors

osmosis receptor dysfunction

vasopressin