So, I don't have any disclosures that pertain to this talk, and it will be a journey. I will move fast through several aspects that hopefully will be useful for you with regards to when to suspect what we used to call central diabetes insipidus, how to make the diagnosis, how to treat it, and if we still have time, we'll talk about changes with the vasopressin after pituitary surgery. So, first and foremost, we have experienced some nomenclature changes. The Working Group for Renaming Diabetes Insipidus proposed in 2022 that central DI becomes arginine vasopressin deficiency, AVPD, and nephrogenic DI becomes arginine vasopressin resistance, AVPR. And that's because of the confusion that some patients have experienced in terms of diabetes mellitus versus diabetes insipidus. Now, in the slides, I'll try to use the new nomenclature as much as possible, but when I present slides from literature that was published before, you will still see diabetes insipidus. So, when to suspect it. In the outpatient setting, in your clinics, the scenario that you'll be faced with most frequently is polyuria. So, when you think of polyuria, there are two main paths you can go onto. First, exclude what's more frequent, and that is the solute diuresis, because most common cause of polyuria is uncontrolled diabetes mellitus. Also, we can see with the new onset therapy with SGLT inhibitors, some polyuria through natriuresis. Other situations are less frequent, such as urea diuresis or sodium diuresis from administration of normal saline or after relief of bilateral urinary tract obstruction. And of course, mannitol given for cerebral edema or increased intracranial pressure will also cause this. But what we're going to focus today on is water diuresis or hypotonic polyuria associated with polydipsia in general. So, the differentiation between these two scenarios is based on the urinosmolality. Pretty much when it's greater than 600 milliosmol per kilogram, that's solute diuresis. So, that's the first scenario that you're going to experience in clinic. The second scenario you're going to experience in the inpatient setting, hospitalized patients with hyponatremia. And the same two scenarios apply, solute or water diuresis. With a caveat, though, it's very rare for patients with AVPD, formerly called central DI, to have hyponatremia, only if they don't have access to fluids or if they have an impaired thirst mechanism. So, let's go through each one of them and briefly understand their pathogenesis. So, let's start from the left, central diabetes insipidus or AVPD. Most of the time is from destruction of the neurohypothesial neurons, and that is the acquired situation. It can also result from AVP mutations, and that's hereditary. The neurons that produce vasopressin or AVP are the neurons in the paraventricular and supraoptic nuclei of the hypothalamus. That's where the bodies of these neurons are, and then the axons, you find them in the stock or the infundibulum. So, in this way, vasopressin is transported to the posterior pituitary, which is like a storage for the AVP. So, it's not the place where it's produced. Now, if we look up to the right, gestational diabetes insipidus or AVPD during pregnancy, that happens in some pregnant women, a minority of them, due to excessive AVP degradation by the vasopressinase, the enzyme which is produced by the placenta. And finally, right lower corner, nephrogenic DI or AVPR from resistance. That's either from decreased response to AVP or from mutations, either in the vasopressin receptor type 2 or of the aquaporin type 2. So, what are the most frequent situations of acquired nephrogenic DI or AVPR? Hypercalcemia, medications, in particular lithium or the meclocycline, kidney amyloidosis, sometimes sickle cell disease with kidney involved in this, polycystic kidney disease, and ureteral obstructions. So, moving closer to AVPD, it affects about 1 in 25,000 people, and only 5% of this is hereditary through pathogenic variants of AVP gene or syndromes such as Wolfram syndrome type 1, with the abbreviation stands for diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. And other situations of congenital hypopituitaries, with or without septoptic dysplasia, for which we don't yet have a mutation, but I'm sure we'll learn more about that. So, how about acquired? So, that's when postoperative situation has a central role, surgery for cellar and supracellar masses. Traumatic brain injury, especially severe in hospitalized patients, can cause AVPD in about 20% of these situations, but most of the time it resolves. Permanent AVPD is only in 7%. Post-radiation is rare, neoplasm, we'll talk more about it in a minute, autoimmune, infiltrative and infectious diseases, rarely apoplexy within the pituitary, and you see the drugs there that can cause AVPD. Immune checkpoint inhibitors are notorious to cause anterior hypopituitaries. There are only case reports of AVPD. And when we don't know what's going on, that's idiopathic. So, I'm going to go through some cases from my experience and hopefully make it more entertaining for you, and we learn different points with going through these cases. So, in this case, a 35-year-old female presents one week postpartum with nausea, headaches, and bitemporal hemianopia. Blood pressure is 90 over 60, pulse is 80. This is her MRI showing a homogenous enlargement of the pituitary gland, and after empiric hydrocortisone administration in the emergency room, she develops polyuria and polydipsia. So, this patient has autoimmune lymphocytic hypophysitis, and this case gives me the opportunity to discuss about the crosstalk between AVP and ACTH. AVP released into portal system stimulates ACTH. Glucocorticoids exert tonic suppression on AVP. So, there are two main clinical consequences here. One, glucocorticoid administration, even replacement, can unmask partial AVPD. And two, untreated hypocortisol stimulates AVP secretion and can cause hyponatremia. Hypophysitis is a rare condition. The case that I showed you is very illustrative because it happened postpartum, and that's a primary autoimmune circumstance that affects females more than men. As we saw, there are consequences in terms of mass effect and endocrine abnormalities, and there are other histological types than lymphocytic, such as granulomatous or xanthomatous. Xanthomatous is very rare. In this beautiful review by Donegan and Honegger published in Endocrine Practice in 2022, they really went through all the cases that were published up until that point. And what I highlighted there with that pale beige color was something that I feel that if we were to do the numbers again, maybe in 2025, we would see a much larger proportion of immune checkpoint inhibitor-induced hypophysitis, because they are used in so many malignant conditions nowadays, as well as IgG4-related hypophysitis. IgG4 disease is a relatively new entity, and it can affect the pituitary gland. Now that we know about it, we see it more and more. For example, in this case, this is a 73-year-old gentleman who presented with AVPD and submandibular gland enlargement a few years after an episode of acute pancreatitis. What you see on the left, all those arrows, the yellow arrows, are pointing at the enlargement of the infundibulum and pituitary. And what you see in the right four panels is really the submandibular gland enlargement. So, plasmacytic IgG4-related hypophysitis. Rheumatologists go by the level of IgG4 in the circulation. It has to be above normal range, but we have become aware more and more that some IgG4 RH cases-related hypophysitis do not have an increased IgG4 level in the circulation. Pituitary gland is rarely affected. This is a situation that affects males more than females at an older age compared to primary autoimmune hypophysitis. And you can see the many other organs and systems that are potentially affected by the IgG4 disease, including thyroid with Riedel's thyroiditis. This is an entity that responds very well to prednisone in the range of 30-40 mg per day, so not quite 1 mg per kilogram per day. But there is a possible relapse when we taper the dose. Showing you another case now, a 59-year-old man with vision loss with one month prior to an admission for altered mental status. Lumbar puncture is done and showed lymphocytic pleiocytosis and increased protein. Blood work with hypernatrinia, dilute urine, and multiple anterior pituitary deficiencies. This is the sagittal view on a brain MRI, and you see there a stellate, a mass that involves the hypothalamus, the stalk, and also the pituitary gland is more round and plump than we would expect. Chest CT shows higher lymphadenopathy. This patient did have hypothalamic biopsy, and that was compatible with sarcoidosis. Neurosarcoidosis, hypothalamic pituitary neurosarcoidosis is quite rare. And when my fellow at that time and I looked at the literature, I'm sorry for the typo, that was in 2016 when we published that. We looked at the cases from our database and also at the literature. So we found that men are more commonly affected by hypothalamic pituitary neurosarcoidosis and suggestive clinical manifestations might be cough and rhinorrhea. Plasma ACE level, if it's elevated, then it's supportive. If it's normal, it does not mean that neurosarcoidosis cannot be present. The other interesting point about neurosarcoidosis is this can affect the thirst mechanism, and the patient can have primary polydipsia and hyponatremia. So these patients can have either AVPD or hyponatremia from drinking too much water. And one of the cases we presented was in that situation. So how about another case from looking back at those that presented with AVPD in my practice? This is a 23-year-old man with 10 months history of polyuria and polydipsia. He actually measured and he was urinating about 11.5 liters. He also had some fatigue, decreased libido, and then recently started to have some problems with one of his ears. The lab showed sodium at the high end of normal, 144, and dilute urine at 87 millismol per kilogram. He also had quite pronounced central hypogonadism and hypothyroidism, as well as mild hyperprolactinemia. This was his MRI. You can see the mass involving the hypothalamus and proximal part of the stock, while his pituitary gland looked normal. He had normal tests in the blood otherwise, including ACE level, ACG, and AFP. So the easiest way to do is to go after that lesion in his ear. And that showed Langerhans cells histiocytosis. I'm showing you now the rest of his MRI, showing an enhancing lesion of the right parietal calvarium, and then on PET-CT, this was the only other lesion that we found in his body. He was treated by hematology with cytarabine for 12 months with excellent response. He's now about five, six years out and with resolution of his lesions. He remains with hypopituitarism requiring replacement. So Langerhans cells histiocytosis, a rare granulomatous disease, abnormal expression, expansion of dendritic cells, more common in children than in adults. In fact, young adults are rarely affected, and it can be localized or multifocal. And there are two ways of treating this. One, what you've just seen, non-targeted chemotherapy, which can actually in many cases lead to long-term remission of disease. But then the progress in this is that more than half of the patients have mutations or pathogenic variants of BRAF, and that's why there is the possibility of treating them with targeted therapy. There are BRAF inhibitors, or other patients have MAP kinase pathogenic variants, and there is an inhibitor there that can be used. The problem is you have to use them in the long run. So it's a little bit interesting and controversial how to treat Langerhans cell histiocytosis. Another case, a 41-year-old woman presented with a syncopal episode and irregular menses with bitemporal hemianomia on exam, ACH and TSH deficiency, and once the hydrocortisone replacement was started, as mentioned in the first case that I showed you, she also started to have polyuria, so partial AVPD. So she presented with a panel that is shown on top, A through C, a large cystic lesion that is pushing upward on the optic chiasm. She went to surgery, and the fluid was drained from the cyst, so that's the panel in the middle, D through F, with resolution of the mass. Actually, all her symptoms and hormone issues resolved completely postoperatively. So about 18 months later, she came and she said, I think the fluid is reaccumulating because I'm having the same symptoms that I had when you first diagnosed me with this. And indeed, that's the lower panel, G through I. So she went back for surgery, and this time the lesion was rejected completely, and since then it hasn't come back. So that's a Radke's cleft cyst. And this brings me to the point, what kind of neoplastic lesions can cause AVPD? So besides Radke's cleft cyst, craniopharyngiomas, which also have a supracellular location, are notorious to cause AVPD at presentation. Less frequently seen germinomas, meningiomas, tracytomas, they can also cause AVPD on presentation, and even less frequently metastasis, which either are localized in the posterior pituitary or in the stalk. Not pituitary adenomas. So we do not see AVPD at presentations because these originate from the anterior pituitary gland, and even if it was for them to expand superiorly and have supracellular expansion, they grow slowly and they do not cause AVPD. So let's move on to how to make the diagnosis of AVPD. Well, sometimes it's easy, like in some of the cases that I've shown you, and sometimes it's not. So when you have increased plasma sodium and decreased urine osmolality, specifically below 300 milliosmol per kilogram, you have the diagnosis right there. But I've already mentioned to you that patients who drink Perfirst will rarely have hypernatremia. So the differential of polyuria, polydipsia, and low urine osmolality includes AVPD, AVPR, or primary polydipsia. And in pituitary clinics, primary polydipsia is not rare. It can happen in patients with psychosis. And there are lots of patients who drink water compulsively, and they think it's healthy to do so. And I've mentioned already the neurosarcoid that can also alter the thirst mechanism. So you have this patient in clinic. They come in with polyuria and normal plasma sodium. First and foremost, you can see their solute diuresis. And once you rule that out, then you, with the urine osmolality, then you have your diagnosis of water diuresis. What I put there in yellow is what I go by when I think about polyuria, because we all come in different sizes. And I think it's good to kind of do 50 milliliter per kilogram per day, just to understand how much that patient urinates before going into further workup. So asking them to measure how much they drink and urinate over 24 hours. So once you feel that you're dealing with water diuresis, if you suspect AVPR, so the kidney problem, let's say someone who takes lithium, then you can do a trial of desmopressin. And if the patient does not respond, then your diagnosis is confirmed. But if you feel that they might have a problem with production of AVP, then you're considering a water restriction test. And with the water restriction test, to the extreme there in red, you see the fairly easy situations to interpret. So all the way to the left, an increased plasma sodium and plasma urine osmolality achieved as a result of the water restriction test will be followed by desmopressin administration. And that's kind of how you'll figure out whether it's AVPR or AVPD. All the way to the right, if during water restriction, the urine osmolality goes above 700 milliosmol per kilogram, all you did was restrict the access to fluid. That's your primary polydipsia diagnosis. In the middle is where most patients are, where their plasma sodium is not yet high enough during the test, and maybe you are not able to put them in a hospital to continue the test. And that's when you can consider, if you're equipped for that, to infuse 3%, because the most potent stimulus for AVP production is increasing the plasma osmolality. So how do we interpret the response to desmopressing during water restriction test? Well, we administer it usually subcutaneously, and we measure urine osmolality every 30 minutes for two hours. So it's, again, easy to interpret if there is no change in urine osmolality. That's complete AVPR. And then you can have partial AVPR if there is a minimal increase in urine osmolality, but it doesn't go above 300 milliosmol per kilogram. It's also easy to interpret if it goes up significantly, like doubling or more of the urine osmolality and the absolute level above 300 milliosmol per kilogram. That's a situation of complete AVPD or central diabetes insipidus. If it goes up, but not quite as much, but the urine osmolality is above 300, that's partial AVPD. The problem is when it goes up by very little, but it is above 300. That's non-diagnostic, and most of the time it's either partial AVPD or primary polydipsia. So why are we unable to differentiate from these two in some cases? The reason is that with chronic water diuresis, one can have compromised renal medullary concentration and downregulation of the kidney aquaporin 2 channels. If you would like to do a water restriction test in your office, there are several things you must know. So first of all, the goal is to raise plasma osmolality as the most powerful stimulus for endogenous AVP release. Second, you may shorten the duration of the test in your testing unit if you tell the patient to start the restriction at home the night before. But be careful, because there are patients who have complete AVPD who may actually become hypovolemic and hyponatremic during that time. So it's good to know where is their urine osmolality before asking them to do that. Only if baseline urine osmolality is greater than 100, suggest that they may start the fluid restriction earlier. If you're wondering, am I going to be able to answer this during the eight, nine hours when the patient is going to be in the testing unit in the outpatient setting? You can anticipate that by that formula, which considers the weight of the patient, and you should know in advance how much that patient urinates based on a fluid intake and output that they filled out. You stop the test if the weight decreases by more than 3% from baseline. And of course, primary polydipsia will not respond to vasopressin administration, but most likely you're not even going to get there if the urine spontaneously concentrates. And we've already discussed that it's difficult to differentiate partial AVPD from PP. And that's where copeptin comes in. The group in Basel in Switzerland led by Dr. Chris Crane has done a lot of work on this and a lot of other centers have done studies and confirmed the value of copeptin. So copeptin is the C-terminal glycoprotein moiety of pro-arginine vasopressin. So it's a surrogate of AVP secretion. The AVP goes in one direction, the copeptin goes in the same direction. And if you're asking, why aren't we using AVP, well, it's not very helpful. It's a small peptide with rapid clearance. It's quickly metabolized. Copeptin is more stable. So this is how I look at copeptin use in the diagnosis of polyuria. Baseline measurement of copeptin. Whether you've seen the patient in clinic and you're sending them to the lab is only helpful if you suspect AVPR because it's going to be a very high number, right? But if that's not the case, baseline copeptin is not helpful. In that case, you want to decide to do water restriction test with or without hypertonic saline or arginine infusion. So both of them will stimulate copeptin level if there is enough secretion of copeptin. Otherwise, as you've seen in red, the cutoffs for these tests are a little different, 4.9 and 3.8. So this is how copeptin is helpful in differentiating complete or partial AVPD from PPE. There is a recent meta-analysis that was published in Endocrine Practice, and all these studies were done in Europe, and they used either hypertonic saline or arginine. And the most recent stimulatory test for copeptin is actually glucagon. And as we discussed, it's non-stimulated. Copeptin is only good to tell you that the patient have AVPR. It's really good at this. But otherwise, just fasting baseline copeptin is not useful. And you see that I tried to put the studies on what kind of stimulation or water deprivation test, water restriction test they've done. So the value is pretty good, of course, stimulated copeptin with sensitivity and specificity both above 90%. If you look there, the one where it just says WRT, that's the least valuable. So if you plan to just measure copeptin during your classic WRT, that may or may not help you. So in summary, unstimulated levels are useful for AVPR diagnosis. Stimulated levels help differentiate PPE from AVPD. In particular, if you administer a hypertonic saline after WRT. And of course, you have to consider the potential adverse events with hypertonic saline. Most patients actually still appreciated this approach because it's a shorter time. With WRT, they spend hours and hours like this. But there are side effects from hypertonic saline. And of course, you have to be set up to get the sodium level stat back. The newest kid on the block is apelin. This is a neurovasoactive peptide found in plasma brain and kidney, which is co-localized with AVP in the supraoptic and paraventricular hypothalamic nuclei. Studies in healthy volunteers suggest that apelin and AVP, when it comes to water metabolism, act in opposite directions. So from the same group in basal, they've looked at apelin levels after stimulation tests when they measured both copeptin and apelin. Apelin is not as good. AUC stands for area under the curve, which is only 49% for apelin and 97% for copeptin. How about MR? You hear even patients coming to you and say, you know, I had an MRI and I don't have the bright spot. I must have diabetes insipidus. So this bright spot indeed represents stored AVP or oxytocin in neurosecretory granules in the posterior pituitary. But be careful because you can have an absent bright spot in AVPD, but not in all cases, just 70% of them. And you can have an absent bright spot in up to 40% of patients with PP or healthy volunteers. So don't go by that. Instead, look carefully at the hypothalamus and the stalk, especially if you have a neuroradiologist or a neurosurgeon, because this is going to tell you more as in cases that I've just shown you, in particular, significantly thickened stalk. Moving on to treatment goals, patients with AVPD would like to wake up less at night so they can rest better. So that's what we aim to control first, nocturia, and of course, reduce daytime polyuria. In the patient who doesn't have an intact thirst mechanism, we want to avoid hyponatremia. And in all patients in whom we're going to provide treatment with desmopressin, we want to avoid hyponatremia. This is a highly individualized treatment and it does require some experience in several, more than just several patients with this. It's an empiric process, but start with small doses and just stop if you feel that you've reached some control of the polyuria. So we use desmopressin or DD-AVP, which is a synthetic analog of AVP. It binds on vasopressin type 2 receptors, has a long half-life, is resistant to vasopressinase activity. It can be administered in pregnant women. In patients who have partial AVPD, they may be able not to take DD-AVP. Instead, they could try low solute diet, so low salt, reduced protein diet. Many times, if that's combined with hydrochlorothiazide, 25 milligrams, that's to reduce the amount of water that is available for vasopressin in the collecting tubules. And even 1.5 kilogram weight loss reduces urine output by 50% in these patients with partial AVPD. So it's something to consider. A deep sick AVPD patients are very challenging sometimes and, you know, they're family members. They have to have a support system and you have to work with them. So there is a standardized water intake, standardized DD-AVP doses, daily weights, and frequent monitoring of plasma, sodium, and urine osmolality. I have patients who do this every month. So desmopressin can be administered on different routes, subcutaneously, orally, intranasally, sublingually, as a melt in some countries. And there are some conversion charts and this one is from the Endocrine Society guidelines on hypopitreate that is released in 2016. But keep in mind that there is no perfect conversion because the metabolism can vary. And for example, taking the DD-AVP pill with meals will reduce its bioavailability. So just, it's again a empiric dosing approach to some extent. In terms of adverse events, we want to make sure that patients don't get hyponatremic. This happens often and in elderly patients it can have detrimental consequences. So we repeat the plasma-sodium after we initiate desmopressin or increase the dose and then biannually. We advise our patients to omit or delay one dose of DD-AVP per month to reduce the risk of hyponatremia. We ask them to wear a medical alert and we educate them about symptoms of hyponatremia. So the last part, if there is still time, I'm not sure, has to do with what to expect after pituitary surgery. And you can expect poliurea from other reasons than AVPD. For example, patients with acromegaly whose growth hormone-secreting tumor was removed and then the poliurea occurs because these patients have an increased water volume before surgery. And then the other two things that can happen, usually in isolation but sometimes in sequence, are AVPD and the opposite, which is SIDH. In terms of prevalence, of course it depends where, who does surgery, but with expert neurosurgeons it's very rare to have permanent AVPD. That still can happen in patients with supracellular lesions such as rhabdosclerosis or craniopharyngomas. The diagnosis goes by the same principles that I mentioned before in terms of dilute urine associated with poliurea and hyponatremia is actually not necessary to make this diagnosis. And then SIDH, there was a presentation about SIDH in this room this morning, but SIDH is very important to consider postoperatively because it's the main reason for readmission after pituitary surgery. And you have the criteria that you can use for diagnosis listed there. And to prevent SIDH or hospitalization, most centers nowadays do fluid restriction, one liter per day at our center. We start on day three, postoperative day three, and do it for 10 days. And we always check the sodium level, typically on postoperative day seven. This rarely happens nowadays, a triphasic pattern by which initially patients develop AVPD for a couple of days, then SIDH due to the release of the preformed hormone from the posterior pituitary, and then because the stock was completely sectioned, there is no more AVP, so the AVPD returns. So this is a nice pathogenetic type of mechanism. We rarely see this anymore. It's just for those situations when there is complete surgical section proximally close to the hypothalamus. Risk factors for permanent AVPD, it's really where the tumor was and what happened in surgery. The rest of the criteria are there, but not in all studies. We manage these patients by monitoring them closely. And then when we administer desmopressing, we usually give it as a single dose, not as a scheduled every day or twice a day regimen, because we want to make sure that they still need it. And if we give overdue and make the sodium lower than normal, then we have to be careful when we correct for that, because central pontine myelinolysis, which is now called osmotic demyelination syndrome, can occur, and that has potentially disastrous neurological consequences. So we want to avoid shifts in sodium levels. And then we use DDAVP judiciously after discharge. Again, we try to avoid scheduled doses, and if a patient needs them, we want them to take it at night. And we follow up with the patient. There's a call on day three, usually postoperatively, and then labs and another call one week postoperatively. And the AVPD, if it happens, typically it goes away in the first six months. So that's important to discuss with the patient. And that's all I had for you, and I'm ready to take questions.

arginine vasopressin deficiency

central diabetes insipidus

diagnosis

desmopressin

nephrogenic diabetes insipidus

polyuria

treatment