So, the topic for today's symposium is Every Reason to Continue Lithium, and I think there's a typo on the booklet, it said Elizabeth Moore, Every Reason to Continue Lithium, so I'm not sure who's Elizabeth Moore, but that's the talk, that's the talk. So I'm the chair for the session, my name is Dr. Balwinder Singh, I'm a psychiatrist at Mayo Clinic. I'm an assistant professor, and I have the honor of presenting the speakers for this session, Dr. or Professor Michael Gitlin, he's the world leader, one of the world leaders in lithium and bipolar disorders. I have the honor to introduce Dr. Lourdes Gonzales, she's a, oh, all right, I'm sorry. Hello? Can you hear me now? Okay, wow, I have to be really close to it, okay, all right. So my name is Dr. Balwinder Singh, I'm a psychiatrist and assistant professor of psychiatry at Mayo Clinic in Rochester, I hope you can hear me now, all right, perfect, thank you. And so the topic for our discussion today is Every Reason to Continue Lithium, and we'll have, we'll take questions at the end of the session so that, you know, because some of the talks may overlap a little bit. Our first presenter is Dr. Michael Gitlin, he's a professor of psychiatry at UCLA and a world expert in bipolar disorder and in lithium. Our second presenter is Dr. Lourdes Gonzales, she's a medical director of the Chronic Kidney Disease Clinic at Mayo Clinic in Rochester, Minnesota, she's a board-certified nephrologist, and our last speaker for the talk is Dr. Vishnu Sundaresh, he's a board-certified endocrinologist and associate professor of endocrinology at University of Utah. So I've been coming to APA, I think, for the last 10 years when I, or maybe a little bit more than, longer than that, but I don't recall a talk where there was an endocrinologist or a nephrologist on board, and every time I'll come to attend the sessions or give a talk the discussion would always be, okay, lithium causes kidney disease, it causes hypothyroidism, and it's the same thing again and again, but I never heard a talk where, okay, how do we manage, how can we solve this problem, okay? And I'll have just three slides to discuss from my standpoint, and this is the agenda. Here are my disclosures, none of them are related to this talk. So the objectives of this talk are to review the evidence of lithium in mood disorders, to review the clinical pearls, the effects of long-term lithium therapy in mood disorder, and understand its effect on renal and endocrine functioning, and to discuss how to effectively manage patients on long-term lithium therapy with renal and endocrine disorders, okay? All right. So this is a recently published study in JAMA Network Open, and this is, I think, one of the very well-done studies where they tried to minimize the confounding. So the trouble with a lot of the lithium studies is they are, even they can be prospective, but they don't account for the baseline confounding factors, okay? So in this study what they looked at, they have this active comparator design, and they, to minimize the confounding, they had used this inverse probability of treatment weights. So they had about 10,946 patients of those 5,308 initiated lithium and 5,638 initiated volproate, and they followed those patients longitudinally. Interestingly, the 10-year risk, or CKD risk, was very similar between lithium and volproate. There was no difference in the risk of developing albuminuria or decrease in the annual rate of EGFR decrease. So I think there is a bias in a lot of the lithium-related literature. If someone is on lithium and they ever end up developing chronic kidney disease, it will always be blamed on lithium. At least that's what we see. If you have a patient who even tried lithium for two, three months, and one year down the road they end up developing hypothyroidism, it's probably the lithium, it cannot be anything else. All right. Next is disparities in bipolar disorder. So we looked at, and we are working on this paper, it's not published yet, this is a data from 1.1 million patients with bipolar disorder from a database called Trinetics. So what we are looking here is the percentage or prevalence of medical comorbidities, the blue are people with bipolar disorder, pink are no psychiatric disorder. So the prevalence of most of the cardiovascular and metabolic disorder is extremely high in patients or people with bipolar disorder as compared to no psychiatric disorder. So hypertension almost three times, ischemic heart disease almost 4.2 versus 11%, and diabetes almost 300% higher rate, and CKD 2% with no psychiatric disorder, 7.6 if you have bipolar disorder. So how many of people think that it's due to lithium, or what would be the lithium prescription rate in this cohort? Any guesses? 10, 15, 20, 30? Okay. So when we look at this cohort, only 10% of patients with bipolar disorder are prescribed, 1.9% are on lithium, 55.8% or 56% were prescribed antipsychotics in a second generation, 58% antidepressants, 58% benzodiazepine, and 31.4% mood stabilizing. So only 10% of patients looking at, and we are looking at almost five or half a million patients with bipolar disorder. So very dismal prescription rates of lithium. Now let's look at patients who have bipolar disorder plus chronic kidney disease and no psychiatric disorder and chronic kidney disease. So still it seems like the medical comorbidity, those rates are higher. The hypertension, ischemic heart disease, heart failure, diabetes are still higher in patients who have bipolar disorder or CKD. So it seems like inherently patients with bipolar disorder, they have a higher prevalence rate of medical comorbidities, metabolic syndrome, which by themselves could predispose them to these conditions, not necessarily lithium. The interesting thing was when you look at the renal transplant rate, were much lower, even though the prevalence is higher, the transplant rate are much lower in patients with bipolar disorder who have CKD versus who do not have, versus no psychiatric disorder. And this is the last slide I have. So these are two case scenarios. So one, we published, I think around 2020, this is a patient I had when I was a second year resident at my residency program at University of North Dakota. A 66-year-old woman with a history of bipolar 1 disorder, you know, euthymic on lithium for 41 years. She had CKD stage 3, but she had diabetes along with that, and she had a history of recurrent UTI. And after one such episode, I got a message from a nephrologist, we need to stop lithium. I said, okay, we'll do it. And for next almost a year and a half, we tried every possible medication, on label, off-label, FDA-approved, non-FDA-approved, stimulant, antidepressant, including TCA. And what we are looking here are very simple, 1 to 10 scale, 10 being the best mood you ever had, 0 being the worst. And her mood will stay around 3, 3.5. And after one and a half years, she said, I don't want to live like this. It put me back on lithium. And this is where we restarted lithium, and within 30 days, we had to tweak the dose. We kept the dose pretty low, 0.4, 0.5, alternate day lithium. And she was back in remission, doing well, enjoying her life. And even at 12 months, her GFR kind of stayed in the same range. The second case, my mentor, Dr. Frye, who's here, so he published this case, I think in 2014, Every Reason to Discontinue Lithium, and I think that was one of the reason I chose to name this talk, Every Reason to Continue Lithium, because this patient, sort of a similar story, 60-year-old patient with a history of doing well on lithium, had every possible medical condition they can have. This patient even required nephrectomy due to sarcoma, but lithium is the only thing which kept the patient stable, and they ended up staying on that. All right. Now, with that, I would like to invite Dr. Gitlin to talk about lithium and its mood disorders. Thank you. Good afternoon. I'm thrilled to be here with colleagues and friends. So I've been wallowing in lithium for about 45 years, not personally, but with people I'm treating. And what I'd like to do is give you a slight overview of, a brief overview of what we know about lithium and its effects. That's going to be very brief, because really what I want to talk more about is how to think about the side effects from a psychiatrist's viewpoint. We'll get viewpoints from nephrologists and endocrinologists right after me, and I suspect there'll be some overlap and some disagreement. I guess after Balwinder's introduction, I should say that even though I am eternally grateful to lithium for a myriad of reasons, I do worry about lithium and its effect on renal disease. I have had numbers of patients who had no other risk factors who ended up on dialysis transplantation, essentially end-stage renal disease. But I think there are ways of managing this. So first, let's go over the brief overview of what we know about the efficacy of lithium. This is from one of the two meta-analyses that came out in the same year, within months of each other. And this goes over a meta-analysis of all the treatments for acute mania. And if you look on the left side, it may be hard to see, that's the primary outcome in terms of efficacy in changes in mania scores. And you can see lithium is about halfway down. It is not particularly better than a bunch of other meds. If you go back and look at the literature of lithium versus chlorpromazine, the early studies in the late 50s and 60s, chlorpromazine worked more quickly, was better at decreasing behavioral agitation, but didn't make people feel as normal as lithium did, which took a little longer. Just substitute the word olanzapine for chlorpromazine, same statement. It's true today. Nobody uses chlorpromazine much anymore. But olanzapine is the drug du jour at the UCLA inpatient unit, whatever ails you. As a maintenance treatment, we know that lithium has been the gold standard for decades. It is surprising how few good studies we have. The earlier studies, a number of them could no longer be used, because people were suddenly taken off lithium double blind, and there's this lithium discontinuation rebound mania, so it falsely raised the relapse rate among placebo patients assigned to placebo. Nonetheless, lithium clearly works. It works better against preventing highs than lows, manias than depressions, and that is unfortunately exactly what all of our patients tell us. They say, great, you got rid of all my manias about which I'm ambivalent, but I still get depressions about which I am not ambivalent. That's been one of the struggles in the long-term use of lithium. Not everybody is going to do well with lithium. There's a small subgroup, probably 20% people who have this magical light bulb response. They get all better, and it's just a spectacular result. Who are the people who are likely to get better? The people who resemble classic bipolars as in the textbook. Now, many of us see lots of patients who don't resemble that. But if you're asking who is most likely to do as well as possible with lithium, people with called the MDI pole sequence, which is mania followed by depression, followed by well interval, MDI, as opposed to DMI, where the biphasic mood swing starts with depression. For unclear reasons, those people do less well with maintenance lithium. And again, classic absence of rapid cycling, not too psychotic. A family history predicts it, actually a family history of lithium response. Lithium responsiveness does run in families. And again, fewer prior episodes. So the discrete episodes with complete resolution, not schizoaffective, not rapid cycling. Those are the people who do best on maintenance lithium. From a study from Germany from 14 years ago, showing it what they called atypical features, which are the features I was just describing. Rapid cycling, schizoaffective type states, mixed states, etc. And as you can see, the more atypical features that were present, the less well people did on lithium. Lithium, of course, is also used as an adjunctive treatment for depression. Used to be this, the first line of the slide said, best studied adjunctive agent. But the pharmaceutical firms of the second generation, antipsychotics, have done so many studies with such large numbers of subjects that from just a sheer volume of data, that's the largest database. There are, you know, 11 double-blind studies. The total N is in the hundreds, not in the thousands. Most with positive results, the meta-analyses are clearly positive. Surprisingly, there are no consistent patient predictors. Now again, we're talking about unipolar depressed people. Family history of bipolar disorder, none of it predicts, tells you who's going to get better from this. So it's a bit of a, just a guess. We used to think that this was better, that this adjunctive lithium for unipolars worked better with tricyclics, which we don't prescribe very much anymore, than with modern antidepressants. SSRIs, SNRIs, bupropion, et cetera. Probably not true. It may simply be that a number of the early studies, most of the early studies, were tricyclic studies. But from what we can see, this works with any and all antidepressants. How about for straight old unipolar depression? As an adjunct, we've already talked about how it clearly works. For acute unipolar depression, it is astonishing how few studies we have. Really, not enough to give you any sort of database that says, yes it works, no it doesn't work. There is a better literature, still not great, but a better one for lithium as a maintenance treatment with recurrent unipolar depression, as a preventer of, rather than as a treatment of acute depression. It is possible, there's one small study that indicates this, that it may be that the unipolar depressed people who do best on lithium are those who have discrete unipolar episodes. Not chronically depressed people, not double depression or chronic depression or dysthymia, but those people who have, it's as if they have bipolar disorder without the highs. They have an episodic cyclical mood disorder, but they don't have manias or hypomanias. That's speculative. One of the major uses of lithium that we've known to appreciate has been lithium in the prevention of suicidality. It's a very complicated area. Certainly, if you look at, if you do a meta-analysis and look at all the studies, I show you two of the better reviews on that, it is associated with decreased suicide and all-cause deaths, but not necessarily self-harm. If you compare it with active comparators, the way Dr. Singh was showing you a lithium valproate comparator study, it looks as if, not all studies, but many, that lithium is better at preventing suicidality than comparable agents like valproate. There's this remarkable, truly remarkable database on the inverse correlation between lithium levels in tap water and suicide or even violence rates. Remember, our reservoirs are surrounded by rocks, and rocks have different amounts of lithium in them. Communities that have reservoirs where there's more lithium in the rocks have lower rates of violence. Now, again, if you did lithium levels on people drinking that tap water, it would be non-detectable. These are teeny little amounts. It's a fascinating area that we need to understand better. The bullet one and two showing, yeah, yeah, yeah, all these studies showing that lithium prevents suicidality, that's wonderful. The single largest study, which is this slide and the next slide, was a negative one. This was a collaborative VA study in the United States, a very large N, 519 patients, and there was so little evidence that lithium was helpful that they actually, the DMSB, decided to stop the study early because there was no chance lithium could be better. These were mostly unipolar patients who were at high risk because they had a recent suicide event, added to treatment as usual, and treated for one year. This is what the pretty picture looks like, and it's an ugly pretty picture. As you can see, there's really no difference between lithium and placebo in the prevention of a suicidal event. However, look at the second bullet. The target lithium level was, correctly, 0.6 to 0.8. The mean level in the study was less than that. It's not clear whether the doctors didn't push it, whether patients decided, oh, the side effects, they didn't want to take more, but I think one way to describe this study is that low lithium levels do not prevent suicidal events. I don't think this study answers the question, if the mean level had been 0.7, would these results have been different? We can't know. Okay, so now let me spend the rest of my time talking about how a psychiatrist thinks about lithium and kidneys and thyroids and parathyroids. So first, we have known, I mean, Scow talked about this in the 60s, we have known that lithium affects renal function, primarily affects tubular function, less so glomerular function, and you can see it in rats as well as in people. This is an early rat study from 40-something years ago, in which there were three groups of rats. These were non-bipolar rats, by the way, and there was a control condition. We didn't get lithium in their crunchy things that rats eat. Those that had lithium in their food, that's the lithium fed, that's the bright pink, and the lithium intraperitoneally injected. That way, the rats had very high peaks and very low troughs, as if you took all of your lithium carbonate capsules once daily. That's the metaphor. And then you looked at water consumption, which is a measure of thirst, which is a measure of tubular function, and as you can see, steady lithium, the total amount of lithium ingested was the same in both groups, and what you can see is the steady lithium level rats had more polyurea, polydipsia. The first indication that maybe, if you want to protect the tubules, maybe the best way to prescribe lithium is all at once. That a measured BID-TID regimen is, in fact, worse for the kidneys. Similar results came from comparing the two lithium clinics again 40 years ago in Denmark, between Copenhagen and Aarhus, and they had one of the clinics, the Copenhagen clinic, did once daily lithium all at night, like the rats who were given intraperitoneal lithium, and the other clinic had BID-TID lithium, which probably reflected the personalities of the professors who ran the two clinics. And as you can see, the more measured way of giving lithium, two to three daily doses on the right side of the slide, look at the difference in 24-hour urine volume. 3,000 milliliters a day is diabetes insipidus. That's the arbitrary cutoff definition. So dramatically more tubular dysfunction, and in the subgroup who had renal biopsies, is a much smaller number, you can see that there were much greater abnormalities, interstitial nephritis, scarring of the interstitium, with relative preservation of the glomeruli, again, more in the two to three times daily. So again, consistent with the rat study. This is another study that shows the same thing, that the correlation of urine volume with serum lithium concentration is on the right side of the slide, and it correlates not with the peak, not with the 12-hour level, but with the minimum lithium level. What does that mean? What that means is that renal cells probably need some time in a 24-hour cycle with very low lithium levels to regenerate, and when you do TID lithium, you don't have that. You avoid peaks, but you also avoid troughs, and it may be the trough is what you need to protect the poor little tubuli. Okay, so a summary of this is, as I said, the lithium we know affects tubular function, and some group go on to interstitial nephritis. The glomerular effects are much less common and less consistent. By the way, the tubular effects initially are functional. We all know that when we drink alcohol, we urinate a lot. The alcohol interferes with ADH mechanisms. So does lithium, and initially it's just functional, like alcohol. Later, if you take lithium regularly, you start seeing these structural inflammatory scarring changes. It correlates with how long you've been on lithium, and that's the primary well-documented effect. The glomerular effects, which are frankly more important, when people go into end-stage renal disease for dialysis or transplantation, that's because the filtering function, the glomeruli, are adversely affected. Lithium does affect creatinine clearance, or EGFR, but it is not as inherently progressive as the tubular dysfunction. We also have some evidence, or obviously not a lot of studies on it, that the lower, the worse your renal function is when you stop the lithium, the greater the chance is that the renal function will progress beyond the age-related decline. So the single most recent study showed that people who had an EGFR of 32 or less, which is reasonably low, at the time they stopped lithium had a much worse course than those whose EGFR was, let's say, in the high 40s or 50s. So you don't want to wait too long, and I suspect we will all talk about this. There are rare cases of end-stage renal disease or renal failure where the only obvious risk factor was lithium, but these are really very infrequent. And as Dr. Singh said, most studies find, but not all studies, that lithium affects renal function more than other mood stabilizers. The study he showed was one of those that did not. So just so you know, this is, you know, renal function for psychiatrists. CKD, chronic kidney disease stage 3, is defined as an EGFR, estimated GFR of 60 or less, stage 4 is 30, end-stage renal disease of 15. And again, it does correlate some with duration of exposure, and I show you two studies that demonstrated that stage 3 CKD was indeed higher, despite the study that Dr. Singh showed, compared to either other mood stabilizers or the population at large. So I do think there's something about lithium and renal disease. It doesn't mean you shouldn't prescribe it. It doesn't mean if the EGFR goes to 59 that you should stop the lithium. That's an unwise way to practice, but I think we have to acknowledge this is something we do need to monitor and pay attention to. This is a study from a year and a half in which they looked at a large number of people and looked at the changes in EGFR, and the real key is the fifth column to the right that says greater than 10 years of lithium exposure. That is the group where the annual decline in EGFR was dramatically higher, meaning the first few years of lithium, terrible things are not going to happen. There's one study from Sweden showing that everybody who ended up in end-stage renal disease had been on lithium for at least 25 years. This is a slow-moving problem. So even if you notice a decrease in the EGFR, you don't need to panic. You don't need to suddenly stop the lithium. What you need to do is get in a consult. If you're going to change medicines, add the second mood stabilizer and then slowly stop the lithium. This is not an emergency. This is a slow-moving problem, and this shows the same thing. As you can see on the far right, you can see the difference in slope for patients who had been on lithium for more than 10 years. So that's the key, is don't get worried, especially early on. But people who've been on lithium for decades, you've got to at least monitor and be thoughtful. So this is how a psychiatrist thinks about it. We'll hear from a nephrologist soon. I would urge you to consider a renal consult if the EGFR is less than 60 milliliters per minute. If the EGFR goes below 45, I can tell you I get nervous, and you might get nervous too. We all have different capacity for tolerating risk, but I think under 45 we should think hard about it. And there's no reason to stop lithium suddenly because this is not an emergency. And there's a study actually from my colleagues at Mayo showing that after you discontinue lithium in people because of renal issues, a number of them really have trouble. Because these are people have been on lithium for a while, we're good responders, you take it away, and boy is it sometimes hard to find a drug or really frankly a combination of medications that can do anywhere near as well as lithium did. So now let me switch to thyroid because we're gonna hear more about thyroid. Also the rate of hypothyroidism varies across studies, partly because the definition of hypothyroidism varies across studies. From florid hypothyroidism to chemical hypothyroidism, low T4 low T3 high TSH, to people who have subclinical hypothyroidism, a high TSH, but all other parameters are normal. We know, and again Scow talked about this in the 60s, that lithium clearly affects thyroid hormone release. It reduces iodine uptake into the thyroid gland, which obviously you need to do to make T3 and T4. Women who have a higher rate of autoimmune thyroiditis are at higher risk, probably because they have antibodies but don't have symptoms yet, and age and maybe antithyroid antibodies, maybe. What do you do? Well this too is there's more kind of wisdom and a clinical experience than great data. If the TSH is greater than 10, you really should treat it, or if you're not comfortable, have the primary care doc, the endocrinologist treat it. TSH greater than 10 means the TSH, the pituitary is really pushing the thyroid gland to make more hormone, and the thyroid gland is not responding. If the TSH is subtly high, top normal for most labs is like 4.8 or so, like 5 to 10, it's a gray zone as to whether at that rate, with that TSH, assuming no other symptoms, do you still need to give them exogenous L-thyroxin? So different practitioners practice differently in that sense. If your patient is doing well on lithium, there is no reason to stop it if they develop hypothyroidism. Renal disease is different. It's hard to treat renal failure. Thyroid disease is relatively easy to treat, so a robust respond to lithium should be kept on lithium, and you just, you or a colleague, treat them with L-thyroxin. And the last part is that of parathyroidism, this is the only recent side effect, something that Scow didn't talk about in the 60s. We realized about 10 years ago that lithium really did affect parathyroid and calcium function and metabolism, and it's both hyperparathyroidism and hypercalcemia. The predictors are how long you've been on the lithium, comorbid thyroid dysfunction, and possibly mild renal insufficiency. Mild. And again, there are biological reasons, which we'll hear about in a few minutes, as to how lithium does this. Most practice guidelines were written prior to the last, whatever it is, seven or eight years, so if you look at most of them, they're not going to tell you to routinely check calcium and PTH levels. I think it's inevitable that one of these days, that will be a part of the standard of practice for those of us who prescribe lithium. We're going to hear more about treatment, not from me, if somebody actually does it. At least my reading of the literature as a psychiatrist is that surgery is not something you rush to. Surgery is seemingly a good thing if you have a parathyroid adenoma. You can take it out. But lithium seems to generally cause hyperplasia of all the four glands, so it becomes a little trickier than a single adenoma. That's a soft call, and I'll be very interested to hear what my colleagues say about that. So let me finish by just summarizing. It is still somewhere between A and V. Central medication in treating mood disorders, Lord knows in bipolar disorder, and substantially in unipolar disorder, with the best data being for adjunctive treatment, and I still think for suicide prevention, despite that negative VA study. There's no doubt that lithium affects renal function, thyroid function, and parathyroid function. That should not put any of us into a panic. These are, with rare cases as exceptions, very manageable side effects and risks. And remember, inadequate treatment of bipolar disorder has its own profound risks to life, to health, to quality of life, to function, all those things that are very important. But this does tell us that we absolutely do need to monitor for all these parameters, lithium levels, thyroid, calcium, renal effects, on a regular basis to optimize treatment for our patients. So let me stop at that point, and my colleagues will go on, and then we'll do Q&A later. Thank you. I'd like to invite Dr. Gonzalez. Good afternoon, everyone. Can you hear me well? Great. I'm very happy to be here. Thank you so much for the invitation. This is my first psychiatry meeting that I'm attending, and I may became a regular because I really like the ambience that you guys have. Everybody's very relaxed and very friendly. I love it, actually. Thank you for the invitation. Okay, so let's go and start. We have heard a very good introduction about the renal aspect of the use of lithium. So you may hear some things that are very similar with my talk and the prior one, and some things that will be a tiny bit different. So these are my disclosures, and this is the usual questions that we hear, whether if there is a association with a long-term lithium therapy and nephrotoxicity, if there are no episodes of acute intoxication. So how much the acute intoxication of lithium will have an effect on how the kidney will function afterwards, and if there is a role of an accumulative dose in the toxicity for the kidneys. Unfortunately, the answer to both of these questions is usually yes, but we're going to go over it in detail. So we know that lithium will be affecting the kidneys, and as it has been mentioned before, the most common side effect in the kidneys is the nephrogenic DEI. That was a previous term. Nowadays, we call it ABP resistance, so arginine base suppressing resistance. There is also tubular interstitial nephropathy. What happens is that the lithium itself will be attacking the tubules in the kidneys, and this will cause the inflammatory response in the interstitium, and if that inflammatory response in the interstitium is not well treated, then that inflammation in the tissue will tend to cause fibrosis over time, and the problem with that is that fibrosis is irreversible. So if we're able to see these patients and treat them on time, then that may be a better case on what to do with the specific situations. There's also some reports of nephrotic syndrome, and that's due to the lithium toxicity to the glomeruli. The glomeruli, as you may remember, is the filtration unit, and that is more rare than the specific attack to the tubules. We also have this distal RTA, which is the renal tubular acidosis, and hypercalcemia. Now, I will not talk about hypercalcemia, as my colleague in the crinology will be discussing that later. I'm going to move to a side because I'm not able to see everyone. I'm a little bit shorter. Okay, so from the first side effects that we can see in terms of the lithium exposures in the kidneys is that the development of these microcysts, and this is one of the first things that we can actually see even before we see any changes in the kidney function. So if patients that have been on lithium get just a regular imaging study for something completely unrelated, we may incidentally find these microcysts, and those microcysts are very small. We're talking about one millimeter to two millimeter in size. It can be up to three millimeters, but they usually don't grow very much. The problem with those is that if there were to be many of them, they will be taking over the healthy tissue of the kidneys, and those kidneys will no longer be able to function well. Yes, so these like very rounded small areas, so there's one here, one here, this one, this one, here we have few of them. They're small and round, and they're usually in the cortex, which is the outer area of the kidneys. The same for the other side. There is one here. This is one of the patients that we have from our consults at Mayo. So they're tiny, they're small. This patient hasn't actually developed chronic kidney disease, which is the cutoff that we have of less than 60 for the GFR, the estimated GFR, but the presence of those cysts is what trigger the consult to come and see us. So how does the lithium will cause this problem? So we know that the chronic lithium exposure will cause resistance to the ADH, and that will cause the symptoms that we usually see for the nephrogenic DI, the polyuria, the polydipsia. What happens is that lithium can get into the principal cells, and those principal cells are located in the collective duct. So this is just as a reminder of how a nephron looks. This is where the glomeruli will be located in the Bowman capsule, and then we have the proximal tubule, and then it goes into the loop of Henle, the distal tubule in the collecting duct, and then the urine will flow. So we are born with about one million of these nephrons, and as we receive nephrotoxins through our life, then many of these nephrons will not be longer available. And lithium, unfortunately, is one of those medications that may cause this. So lithium will enter to those principal cells in the collecting duct, and it has several mechanism of action that has been proposed. And these are theoretical, and sometimes in theory is not necessarily how it really works, but for the most part, we think that once the lithium enters into those principal cells, will cause the destruction of those cells, or another theory is that it doesn't actually destroy it just initially, but it will cause those cells to continue to proliferate, but then they go into a cycle arrest, and they are not able to work anymore. And that will lead to that inflammation, which is the interstitial nephritis, and eventually to fibrosis. And another theory is that the lithium itself will cause the aquaporin gene transcription to have a mutation on it. So the aquaporins are needed for the water to be transported across the membrane, and that what is helping us actually to produce the water that is needed for the urine. And as the lithium causes that transcription mutation of that gene, then those patients no longer have the ability to concentrate the urine. And that's why we have a very diluted urine for those patients that have nephrogenic GI. So if we are unaware that this problem is ongoing, it can become irreversible. And for that same reason, we want to make sure that we catch it on time, because in many cases, if it is only mild, it will be irreversible. However, if it is severe, after prolonged therapy, the most common recommendation will be to discontinue the drug. So again, if we're able to catch this on time, it will be better for the patient. The main symptom is nocturia. They will have polyuria, as defined more than three liters, as mentioned before. But now it's important to remember that not all the patients that come to our consult with polyuria is related to nephrogenic GI. We can also have central diabetes insipidus that is related to the deficiency of the AVP. Or we can have primary polydipsia that is also very common in this patient population, as they are usually very thirsty. Many of the antipsychiatric medication will cause them a dry mouth, and for them to feel very thirsty. And with this alone, they will keep on drinking a lot of water. So the more water they drink, the more urine they will produce, and it's just a repetitive cycle. And it's unfortunately common to see. So the patient comes with polyuria, they're on lithium, and we just make the assumption that it's related to the lithium. And for those patients, we need to do a water deprivation test. The test will help us to determine the cause in the majority of the cases. So the water deprivation test will bring the patients, will ask them not to drink anything overnight. We measure the plasma osmolality and the urinose molality. We measure the serum sodium, and then we measure those again the next morning. Ideally, in a patient that has primary polydipsia, because they haven't been drinking overnight, the physiologic effect is for us to see that the urine is able to be concentrated. And that urinose molality will be higher the next morning. And it's usually as high in the 700 milliosmoles. And that gave us a good idea that that was related to primary polydipsia, rather to think that it was related to diabetes insipidus. Now if we don't see too much of a concentration in the urine the next morning, then those patients may be having diabetes insipidus. And in order to figure out which one is, then that's when we use the Desmopressin. And the Desmopressin will help us to differentiate between central diabetes insipidus, or a deficiency of the ABP, and the resistance of the ABP or nephrogenic DI. Again, lithium has been associated with nephrogenic DI. So those patients, even if we give the Desmopressin, we don't see that they're able to concentrate the urine. And that is due to the effect of the lithium on those principal cells. So what do we do? We do have some tricks trying to help these patients with nephrogenic DI. But this is only when we see that the problem has not been severe. When the patients have had nephrogenic DI for a while, unfortunately this can just proceed and they won't be able to concentrate the urine. So for those patients that only have a mild to moderate presentation of nephrogenic DI, we may use amylorite. Amylorite is a diuretic and may be contraintuitive to try to prescribe a patient that is having a lot of urine output a diuretic. But it has to do with the effect on the electrolytes and how it will be affecting the electrolytes in the urine. So overall, amylorite will block the ENAC channels. So there won't be able to be sodium reabsorption. And then the sodium will go in the urine and that will drag some of the water. But over time, that cause some volume depletion and the urine output starts decreasing. So there's been studies that shows that after three, four weeks of giving the amylorite along with the lithium, and those patients that have moderate diabetes insipidus, they're able to see that the volume of the urine decreases and that they're able to concentrate better the urinose molality. We just need to be cautious of keep on checking the lithium because there may be more reabsorption of lithium. And then that can create a problem of toxicity if we're not careful with checking that as we are giving the amylorite. Now if there is a severe disease of a nephrogenic DI, unfortunately those patients, they're no longer able to concentrate. And the urine will be very diluted. So even if we try to give the amylorite, we won't be able to achieve what we need. And they wouldn't be ideal candidates to use this therapy. So for that reason, it's important as you are following those patients that are on chronic lithium use, one of the main symptoms to think about is nocturia because that's how it starts. And trying to figure out the rest of that, they usually get referred to nephrology. We do those water deprivation tests to determine where the cause is and to determine which patients will be an ideal candidate for the use of amylorite. Another diuretic that has been very much in use for these patients are the thiazides. They work a little bit different, but they also work in the same area in the distal tubule. And also cause a little bit of myosodium depletion, similar to amylorite. We also need to monitor lithium levels for the same reason, that the level can be increased over time with the prolonged use of the diuretic along with the lithium. It works. In general, there has not been a comparison between the two diuretics, which one is better. But nowadays, we see that we tend to use more amylorite first rather than the thiazide. Another rare side effect in the kidney, as it has been mentioned before, nephrotic syndrome. What does it mean, nephrotic syndrome? The glomerulide will be affected by, in this case, the lithium. And that glomerulide is in charge of filtering all the blood that is coming in circulation. Protein is also coming in circulation. In general, the glomerulide should be able to hold on to protein. We need the protein inside of us. It shouldn't be coming out in the urine. But if the glomerulide is affected or injured, there will be created sort of holes that will allow the protein to leak out. And in those cases, we're going to see a lot of protein in the urine that shouldn't be there. And the usual definition for nephrotic is more than three grams. We kind of like the number three for a lot of things. Three grams of protein in 24 hours, that will be an indicator of a nephrotic range of protein urea. Those patients tend to also have high cholesterol. They also have lipids in the urine. They have swelling. So when we have the constellation of symptoms, we call it nephrotic syndrome. And this nephrotic syndrome, the usual characteristics, when we biopsy these patients, we can see different diseases. The most common one being minimal change disease of FSGS, that's another one. And then there will be a specific treatment for those. Now when it is related to a medication, again, the usual indication for that will be to stop the affecting agent, and in this case will be lithium, if we think that's what it is. We need to do a very good workup to make sure that we're not dealing with an autoimmune process or any other source of possible culprits, rather than just go directly and say, yes, it's the lithium. In general, we do a very complete serologic workup to rule out any autoimmune disorder that may be concomitant in any patient that comes to our clinic. Now when the patients only have swelling, it's difficult to determine. This is a very old term that was described more than 30, 40 years ago, and it was related to the manic phase, that those patients tend to swell up, apparently. And there is not good correlation on really what was the cause of that. And they think, well, maybe they're just because they're just eating more sodium during the manic phase, and the sodium will come and drag the water along, and that will cause the swelling. There is not much described. It has been described in the past, so I'm not quite sure about that one. I have not personally seen it, and I don't think it is a real thing that we see prevalently in those patients. So unfortunately, the lithium dose tends to cause toxicity, and that's because it's very rapidly absorbed in the GI tract, and it can distribute across the body. It's a very small molecule, and it doesn't bind to protein, which is very good for us, because those molecules that bind to protein, we cannot clear. We cannot clean it from the blood as easily. But this one, we can. And those patients that have lithium toxicity, we can dialyze them. With dialysis, we put the blood through the filter, and anything that is not protein-bound will be coming out, because the pore of those filters are small enough, but all small molecules that are not attached to a huge protein molecule will be able to be clear. So dialysis works for those patients, as you know very well. And in general, the physiological way of eliminating the lithium is through the kidneys. So it is excreted in the urine, if they are able to make urine. The main symptoms for the toxicity, nausea, vomiting, and diarrhea, GI symptoms. The ones that we're worried about, from the nephrologist's standpoint, to decide if a patient will require dialysis or not, is a neurological symptom, specifically associated with confusion, seizures, encephalopathy. Those are the patients that will try to pull the trigger sooner and dialyze them. If we need to dialyze them, we usually do it very slowly, so we can be able to clear the majority of those small molecules of lithium. In general, a patient that requires dialysis non-related to lithium will have a dialysis length of three and a half to four hours. Those patients that are having an acute lithium intoxication, we need to dialyze for longer, and we may need to do it more frequently. So it's not uncommon to see that we dialyze them twice in the same day, or on a daily basis until we're able to see an improvement on their clinical scenario. For those patients that are making very good urine, then the treatment with IV fluid hydration may be just enough. If those kidneys are able to clear, then just that hydration will keep those kidneys flushing that lithium out of the system. So it depends on the level of the lithium and the characteristics of the patients for us to decide that if we can just use a conservative measure of IV hydration versus using dialysis. There are major risk factors for the nephrotoxicity associated to the duration of the exposure, the accumulation of that dose of lithium. Patients that are older, they tend to get more frequently nephrotoxicity if they're using other antipsychotics, and the comorbidities. So the comorbidities is a big one. And please don't pay attention to the percentage, because I added up this morning, and I saw it was 103. What you can see, and what it is true of this slide, is that the diabetes is the number one cause of chronic kidney disease in general. And if your patient that is needing lithium are also having a diagnosis of diabetes, then the chances of them having chronic kidney disease will be higher with or without lithium because of the diabetes. The same for hypertension, and they're very common. So those are the patients that you want to keep an eye on, a close eye on, to see if they're having problems, if they're having a progression on a decline of the GFR. And as it has been mentioned before, the chronic kidney disease is divided in five stages, one through five. Stage five is when we start people on dialysis. Stage three is when we want you to start referring patients to the nephrologist. Stage three starts when the GFR is less than 60. We get concerned about stopping lithium when the GFR is less than 30. So less than 45, I'll say, if they have comorbidities, yes. It's something that I will consider, or at least a very close monitoring on how the function goes. It advanced very slowly, so it's not a very rapid track, but it is important to have an idea on how is it moving through every three, six months to see where the function is at. But we do that follow-up for you, so as you refer them to us, we'll continue to monitor. We are in communication with a psychiatrist to figure out what other things can be done, or if we find that it's another possible risk of that. Remember, the presence of the microcyst is even before they have any changes in their GFR, so it is important to keep an eye on that, along with the amount of protein in the urine. So which path should we take for those patients that are having a fast trajectory? Should we discontinue the lithium? Should we continue? It's a hard decision to make, and I think it's on a day-to-day basis to decide. We don't have strict guidelines or cut-offs on saying, oh, after this GFR we should stop it, but having an idea that if the GFR is already approaching 30, for sure it will be a determinant that they have been progressing faster. But it has to do with age as well, because we have an aging process, and if the patients are younger and their GFR is very stable, it may be something that we just continue to monitor for longer before deciding that we need to stop. So don't panic, refer, and we will have a good interaction with the psychiatrist to try to figure out what to do next. Managing the comorbidities will be a plus. We need to have patients that have good control on their blood pressure, good control of their glucose if they have diabetes, that are exercising, that they're having a healthy diet. Specifically, the tobacco and alcohol may be a major determinant also of problems with the progression of the chronic disease on their own, and if we add the lithium to it, then the risk may be higher. So we do need a multidisciplinary management for that, and as I mentioned, we need the psychiatrists, we need the primary care doctors, nephrologists, endocrinologists, everybody on board to treat these patients and to make the best decision for them. These are the usual routine labs. This is why everybody does that in their clinic. So if they notice any, if you notice any changes in the GFR, any protein in the urine, then those are the patients that you will want to refer. We have other tests to use, creatinine or cystatin C. Creatinine has to do more with muscle mass. Cystatin C doesn't, so it tends to be a little bit more accurate, but we usually use a correlation of those two to decide exactly where the GFRs are. And for us, the urine becomes very important because there is a direct correlation of the protein in the urine and the progression of the GFR. So patients that have higher protein in the urine progress faster towards dialysis, and those that have less protein in the urine progress more slowly. Thankfully, the majority of patients with lithium, they don't have usually high amount of protein in the urine, so that will be helpful. And managing that proteinuria is super important for us. Nowadays, we have medications that we can use for that, such as the SGLT2 inhibitors, the GLP-1 agonists. So those are the ones that are now very involved for weight control, but they also have an effect on protein in the urine. And the mineralocorticoid receptor antagonists, such as finerenone. From this, the ones that we are trying to use more and more, and we use it on a daily basis, are the SGLT2 inhibitors for proteinuria. They have not been checked in lithium yet, so that's something that will be interesting to see for the future for these patients. Because any patient with CKD, nowadays they have the FDA approval for the SGLT2 inhibitors, because we know that these medications help to delay progression of the chronic kidney disease. Okay, thank you. I'll invite Dr. Sundaresh now. Thank you. Thank you, Dr. Singh, for inviting me to this excellent symposium. And this is my third time attending and talking at one of the psychiatry conferences, and I love the ambience and interactions, and I continue to do so. Okay, let's jump on. Now? Perfect. Okay, no disclosures for this topic. My interests in clinical practice, and also for today, is thyroid and parathyroid. All of us know the thyroid gland is a butterfly-shaped gland in the front of the neck. Pretty much controls all organ systems. Some of you might be wondering what's the rhino doing there, but Dr. Owens was the first surgeon who dissected and found a parathyroid gland from the Zoo of London a few centuries ago. So if you see a rhino with a surgeon or a doctor, that means they are interested in the parathyroid. So patient one, I'm gonna read this, but at the end of 20 seconds, please let's do a show of hands and see what people are thinking. 34-year-old young female with bipolar 1 disorder, euthymic on lithium for four years. No known family history of autoimmune thyroid disease or any other autoimmunity. Somebody checked her thyroid function prior to starting lithium, which was perfectly normal. She comes in complaining of muscle cramps and fatigue. Her TSH is 18, which is high. Free T4 is borderline low normal, 0.9. Her antibodies are negative and repeat labs have shown similar results. Which of the below options are correct? A. Anybody for A? One person for A. Okay, let's keep going. B. Stop the lithium and check TSH free T4 in two months. Nobody wants to stop lithium. Okay. Initiate levothyroxine. Okay, excellent. Initiate cytomel or try erdothyronine. Okay, a few. Okay, excellent. So I guess my job is easy. I can fly through the slides. That is the correct answer. All of you got it right. So, you know, although thyroid gland affects so many organ systems, lithium is like, you know, targeting the thyroid gland, pretty much affecting all of thyroid functions. It increases the iodine content in the thyroid gland. It reduces the thyroid gland's ability to produce thyroid hormones, and it also alters the structure of the thyroglobulin, which is a protein inside the thyroid gland, and blocks the release of thyroid hormones from the thyroid gland itself. So all of these, including, you know, blocking the D-iodinase 1 in the thyroid and liver and kidney, and the D-iodinase 2 in CNS, cardiomyocytes, skeletal muscles, and brown adipose tissue, it causes hypothyroidism. So this is a cohort study which was published last year at the Mayo Clinic, and cohort study where they evaluated survival-free of thyroid disorders, and the median time for being diagnosed with any thyroid disorder was 17.5 years for females as compared to 42.5 years for men, okay? And the risk was significantly clinically statistically increased in females with a hazard ratio of 2. And this is the frequency distribution of diagnosis of new thyroid abnormality during lithium treatment. Within first year, seven percent of them were diagnosed with a thyroid disorder, and within five years, about 60.5 percent were diagnosed. The challenge here is, after five years also, almost 39.5 percent were continuing to be diagnosed with any thyroid disorder. This implies or makes the point that long-term screening for abnormal thyroid disease is important. So screening is pretty easy. A serum TSH with a reflex to free T4, and it's always good to get a baseline TSH and a T4 prior to initiating lithium so that later on we are not confused whether it's a chicken or the egg. And every year after initiating lithium, also it's good to keep screening because many times the symptoms are non-specific and subtle, which brings us to the next point where I say PRN in red, symptoms after initiating lithium, because who does not have symptoms of hypothyroidism? Fatigue, brain fog, you know, feeling cold, weight gain, constipation, all of us have it, right? So that's why we need to have a good clinical acumen before checking the TSH, but whenever I see a patient, usually at least like everybody has a TSH check four to five times a year. It's simple, it's done, it's normal most of the time. Consider a TPO antibody also to see if they have any autoimmunity, you know, you know, because that poses them at a higher risk for getting hypothyroidism or hypothyroidism. And below is the reference range for non-pregnant adults. Most of it, most of the labs in the USA is pretty much in this frame, the TSH 0.27 to 4.2 and the free TFO is 0.1.7. So diagnosis could be subclinical hypothyroidism, where the TSH is high, above the upper limit of reference range, and the free TFO is normal, okay? And or it could be overt hypothyroidism, where the TSH is high and the free TFO is frankly below the normal range, okay? So one more thing which all of us need to be very cautious about and, you know, we have been doing this in the last almost eight years. Biotin is a vitamin which is present in skin, nail, and hair supplements. If a person is taking biotin, you know, like high doses like 5 milligrams, 10 milligrams as present in these supplements, it can cause low TSH and a high free TFO. And let us say a person on lithium TSH is actually 8 or 10 or 11 and because of biotin it could still be appearing normal, so it could lead to a false or no diagnosis. So always make sure that they have stopped any supplements containing biotin three days prior to having a blood drop. Biotin is also present in multivitamins, but they are present in micrograms, so it does not make a big difference, but the separate biotin supplement can cause false values. Now when to treat, when to refer, that's the, you know, discussion here. Treatment of hypothyroidism is very simple and I'm sure most of you are comfortable or will be comfortable in the next 20 minutes to treat hypothyroidism, okay? So overt is very easy, you know, everybody gets a treatment. Subclinical is always a question, especially when the TSH is between 5 and 10, there are not many guidelines for us to treat, but if they have, if the number is above 8, if they have a TPO antibody present and if you feel that they have a goiter or if they have like symptoms of hypothyroidism, which most of us do, we can proceed with treatment, okay? And if there is any confusion about this, you know, we are always there, primary care is always there, every person, every psychiatrist practices in a different way, so feel free to refer to any of these two specialties. Management again, right? Levothyroxine monotherapy has been the standard of care from several years and recently the combination therapy of levothyroxine and T3 has, you know, becoming, become popular. They are available in various combinations, we have a fixed combination where the T3 is slightly higher than what we want compared to T4 or you can prescribe a separate levothyroxine and a separate T3 prescription. T3 monotherapy is definitely not recommended for long-term replacement of hypothyroidism, okay? So either T4 or T4 and T3. Levothyroxine is easy, it is not expensive, available everywhere, never in backlog, tablet, capsule, liquid formulation and the dose in non-pregnant adults is 1.6 mics per kg body weight and those in elderly patients would be around 1 mic per kg body weight for obvious reasons of cardiac and neuro risk in susceptible individuals, so we can gradually increase the dose based on the TSH, which we'll check later on. Now I mentioned T3 monotherapy is not recommended for long-term replacement, but I'm sure many of us have used T3, which is one of, one of really good antidepressants, so I have learned in the last few years after collaborating with Dr. Singh and, and you know, T3 itself has been used for high doses, 25 mics at twice a day for acceleration or augmentation effects, but that's a paper there, but for me from a hypothyroid perspective, long-term would be T4. Timing of dose is very important, right, they could be, it's very patient, education is really important and on empty stomach with water is ideally the time to take it, about 60 to, 30 to 60 minutes before breakfast. Should not be taken with meds like calcium, multivitamin, iron or bilacid resins, which are very rare now, given that we have a lot of good cholesterol medications, but most of patients take multivitamin, calcium, iron, make sure they are taking it four hours apart. Some of my patients just take it at bedtime, two to three hours after a meal, that's also acceptable. Target DSH has always been a challenging moving target in the last decade with multiple papers producing different results, but in general, I would say in the young population, let's keep it less than 2.5 and in the elderly above 65, 70, we could maintain it within the normal reference range. Monitoring, again, opposite symptoms of hypothyroidism. Symptoms could be palpitations, jitteriness, hand tremors, usually if we start in the weight-based dose, which I mentioned before, symptoms should not happen in majority of the patients and the lab is always a simple serum TSH, checked five to six weeks after initiating a dose or after changing a dose, okay. A free T4 or T3 is not recommended. Free T4 can vary based on when the blood is drawn as compared to when the levothyroxine tablet is taken, and T4 will be pretty much low and also it's an intra glandular hormone, it won't be floating around in the serum, so it's not useful to check T3. And, of course, we are going to change the levothyroxine dose based on TSH levels to achieve our target. So that's about hypothyroidism. Goiter is also, you know, common abnormality in lithium treated patients and as Dr. Gitlin alluded to several minutes ago, you know, the percentage varies on, you know, what the parameters are for diagnosis and individual studies, but it's about 40 to 50 percent. So this is pretty simple, right. So the lithium is the pathogenesis. The lithium is attacking the thyroid thyroid sites. T4, T3 goes low. There's a negative feedback to the positive feedback to the pituitary. Pituitary produces excess TSH and tries to stimulate the thyroid gland to produce more hormone. During this time, the thyroid gland, there is hyperplasia. That's how we get a goiter. Usually twice the normal, not very big like a multinodular goiter, and that we see in Graves' disease. And usually it's a diffuse goiter. Very rarely we see nodules. And, you know, most studies mention that they found the goiter within two years of starting lithium treatment. Of course, ultrasound of the neck thyroid is a good way to start off. And if there is significant enlargement or nodules, then refer to primary care or endocrinology. And when I say two times, you know, the thyroid gland is about 15 to 20 grams in size. And usually two times is not going to cause any dysphagia or dysphonia. We refer to surgery if it is more than 90 or 100 grams. So 40 gram, 50 gram thyroid is not going to kill me. Okay. So no stopping lithium. Okay. And two more things which the lithium can cause is Graves' disease, which is an autoimmune hyperthyroidism, the opposite spectrum. Apparently lithium can induce some autoimmunity and cause overactive thyroid. And it can also have a direct toxic effect on the thyroid cells, destroying them. So there is a painless silent thyroiditis with leaking of thyroid hormones causing a transient overactive thyroid, which will resolve by itself in a few weeks. But best to monitor for a few months to make sure after becoming normal they don't become hypothyroid. Okay. And on the right side, again, no systematic lithium discontinuation is necessary. All of the thyroid gland dysfunction can easily be treated. Not a problem. Okay. So going to patient number two. 56. You're a young male with bipolar disorder. Euthymic on lithium for 10 years. And complaints of mild polydipsia, no polyuria. Calcium is 9.9. The reference ranges are there in the parentheses. Parathyroid hormone is high. GFR is normal. Vitamin D is low. 24-hour urine calcium is low. What is the diagnosis? Anybody with A? B? C? D? Okay. Somebody is going with the D also. OK, excellent. Let's see what's happening. So secondary hyperparathyroidism. It was tempting to go with B, I assume, but that's why the question is there, to keep us awake at 5 o'clock. So low vitamin D, when the calcium is normal and the parathyroid hormone is high, always think why the calcium is not high. Maybe is it a secondary mediated hyperparathyroidism? The most common causes are low vitamin D, low calcium, intake or absorption, and chronic kidney disease. So lithium increases serum calcium and PTH levels within weeks, but most of them remain in the normal reference range, and gradually they may go up. And this is a simple study with 313 subjects where lithium, this is bipolar disorder on lithium. 26% had hyperpara, whereas not on lithium and controls, there was no significant difference at all. And I will stress the importance of this quickly. This is a defense mechanism of how the calcium is maintained in the blood. So when there is a decrease in the blood calcium, it acts on the calcium-sensing receptors on the parathyroid gland and tells the parathyroid, hey, we got no calcium. And then parathyroid hormone will act on the kidney, the bone, and the intestine and bring the calcium back to normal. It happens within seconds to minutes when you check the blood test, the calcium and PTH is normal. What lithium does is it goes and sits on the calcium-sensing receptor and then inhibits it. And the parathyroid thinks there is no calcium, so it overworks, and then that leads to high PTH and high calcium. So again, representing the same thing. And it can also inhibit renal camp and GSK-3b. These are all plausible mechanisms. 2 thirds, Dr. Gilden asked me this question. Hyperplasia happens in 2 thirds, and adenoma happens in about 1 third of the patients. I mean, the renal stones, bones, abdominal groans, and psychic moans are all older terminologies. Usually in lithium, it is protective of kidney stones. It does not actually cause stones. This is stolen from the primary hyperpara. But all these symptoms and advanced symptoms used to occur before 1970, when calcium was not part of the BMP. Nowadays, calcium comes in a BMP, RFP, and CMP and easily diagnosed very early on. And screening is pretty easy. You get a PTH and a calcium before we start lithium, and maybe three to six months after starting it. And if the PTH is high, make sure you ruled out the secondary causes. But if both PTH and calcium are high, repeat it in a good lab. And if it is still high, we should start thinking about lithium-associated primary hyperpara. And this is a table. I think the slides will be available later on. But quickly going through, serum calcium is high in primary and lithium, normal to high in both of them. But the disclaimer, of course, is here. In 24-hour, urine calcium is normal to high. But the lithium-induced hyperparathyroidism, because lithium increases reabsorption of calcium, the urine calcium is low. Diagnosis is easy. PTH normal to high. Calcium is high. 24-hour, urine calcium is low. And go for imaging only if you are planning for surgery. Let us say the calcium is 10.7. Patient is 75 years. We are not going to go for surgery. We can just monitor. So imaging is important only when we go for surgery. 2 3rds of them have foregland hyperplasia. This is a nuclear medicine system we scan. And then this is neck ultrasounds. About 10% of US institutions have adopted neck ultrasound as a less expensive mechanism. You can see the adenoma. Somebody was going for FHH in the multiple choice questions. FHH is a familial hypocalciuric hypercalcemia, high calcium in the blood, low calcium in the urine. And it is a familial thing. Surgery is not helpful. And we usually try to think about this when the scans are not localizing to any foreglands or particular gland. And monitoring, of course, in mild cases. If there is an acute increase in the calcium, IV hydration will bring it down. We can also use zoledronic acid or denosumab for very high symptomatic high calcium. Sinocalcite is a calcium mimetic. It's a tablet. Again, non-surgical management. It has been used in a few cases of lithium-associated hyperparathyroidism. Percutaneous ethanol ablation or injection is also a new thing. Probably a handful of physicians do this in the US. It's more commonly done in the Europe and Asian countries. If there is a single adenoma, just inject alcohol. It's going to cause denaturation and help us. And ultimately, parathyroid surgery is the only way if it is significantly symptomatic and not resolving to other options. And let us say we do surgery and everything is done. Don't relax. Even if I remove one gland, the other three are there and lithium can affect them. That's one thing. And if we do, if it's a parathyroid hyperplasia, let us say the surgeon decides we'll only do three and a half parathyroidectomy, then the half a gland is still there. So we may have to continue to monitor. If the surgeon decides on a four gland parathyroidectomy, then the person has to be on calcium and high doses vitamin D for a long time. That itself can cause a lot of problems with hypocalcemia. That's why three and a half is a little bit safer. And again, one of the papers says discontinuation of lithium can be discussed if possible, but I still feel that we can handle the thyroid and parathyroid easily without stopping the lithium. So this is our final slide. Thank you so much for your patience. Thank you. Thank you. So we have eight minutes, so we are up for questions. How do we get the slides? We'll upload after this. I was taught by an endocrinologist probably 25 or 30 years ago. It's working, I think. I was taught by an endocrinologist a long time ago to be much more aggressive in treating what you would consider borderline high TSHs in patients who I had on lithium. Now, I have an ECT practice. I have really fragile, depressive patients. And I think maybe that's why she discouraged me to almost use T4 as a prophylactic agent with people on lithium, rather than waiting until they had really high TSHs or were symptomatic. Am I being overly aggressive? Am I endangering my patients in any way by being aggressive at using T4? So question is, before on lithium patients, is it important to use levothyroxine even before they become hypothyroid, right? So as long as the TSH is above 0.3, we are safe. It's not going to cause any harm. That's one thing. But we need to understand the fact that they may never become hypothyroid. And if the TSH is less than 2 and 1 half, they still have a good reserve of thyroid hormones. And we are committing them to a lifelong use of a tablet in the morning, half an hour before breakfast. So if we understand that, that helps us. But again, if the TSH even is like 4.55, and if you want to try it, and then if it helps their mood, then I guess that's a good choice to go. Yep. Again, gray zone area. And even within the bipolar maven world, there are differences in opinion in that regard. Not only what do you do with a TSH that's, let's say, 5, but I have some unnamed colleagues who will treat with a TSH of 3.5, still within normal but the high normal range. The data in support of that is minimal, shall we say? So it's more heat than light. I have two quick questions. One is, why can't you use T3 long term for people? Because I guess some of us might do that for depression. T3 is, again, a rapid acting and a short acting hormone. And what I tell my patients or my students is like it's a very high dose caffeine. So when we take a tablet, it goes up pretty high and then goes away. It leaves the body in about six to eight hours. And in patients, it can cause cardiac side effects and also long term bone side effects. Whereas T4 has a half life of seven days. It is more stable and more safe with respect to bone and cardiac health. Thank you. My other question is, isn't there some kind of controversy about whether TSH actually accurately measures thyroid in people who have inflammation and other conditions? And aren't there some people who still have a low T3, even though their TSH and T4 might be normal and don't actually convert T4 to T3? And should we be monitoring that as well? Yeah, great question. So I have two answers for that, but on similar lines. Many years ago, before 2000, the assay for the TSH was not very good. That's why many of you may have seen TSH, T4, T3, T3, T4, resin uptake, and all those things, which I have never used in the last 10 years. Now the TSH is third generation, fourth generation. And if I get a value of 2.4 from a good lab, we can repeat it, it's going to be in the similar range, like 2.1 to 2.6 range at the same time. Of course, there are diurnal variations and seasonal variations. That's one thing why we believe in the TSH. Now the second thing is T4, again, can fluctuate a lot. And T3 is the thyroid gland produces 80% T4 and only 20% T3. So T4 is a prohormone, and T3 is an active ingredient. And every organ system, like the muscle, or the heart, or the kidney, or the liver, or the brain, they will have different rates of conversion of T4 to T3, depending on what exercise. Let us say I'm exercising, my muscles convert more. If I'm not, it will convert less. And extremely rarely, deiodinase deficiency may be there. But even then, the TSH will get a feedback from both T4 and more so T3. So T3 is supposed to have been converted. Unless we do genetic testing for everybody, there's no way to actually diagnose them with deiodinase enzyme defect. But what we do in clinical practice is we optimize the TSH to around 1, or 1 and 1 1, or even less than 1. With T4, if they still have persistent symptoms of brain fog, fatigue, such symptoms, we try to make sure we evaluate everything else, like diabetes, high calcium, or low testosterone, B12 deficiency, vitamin D deficiency, iron deficiency, sleep apnea. If everything is ruled out, then most endocrinologists would add a T3, 5 in the morning and 5 in the afternoon. That will help them most of the times. Thanks for a very, very informative panel. I read that two years ago, there was a study showing that since there's an age-related reduction in your EGFR, having a standard of what's chronic kidney disease type 3 of 60 is inappropriate for people over 65. And that there should be a lower definition of CKD if you're over 65, like maybe 0.45 to 0.6, I mean 45 to 60, could be OK. So my question is, who should we refer for kidney evaluation? Oh, the reason they found that is that these elderly people who have this lower for CKD had no proteinuria or any other signs and symptoms suggesting kidney problems. So that it would be reasonable to start them on lithium, one would think. So when do we need to do endocrine evaluation? And is it OK, in fact, to start lithium in an older person with a 45-year-old kidney disease? In an older person with a 45 as their EGFR. Excellent question. Dr. Gonzalez, do you want to take that? Yes. So I agree with you. The GFR has a lot of flaws. And the way that we're measuring it in blood is just an estimation. Remember, the E is an estimate. And what we're doing is actually gathering information from the population, I'm sorry, and trying to see what is more commonly seen, not necessarily truly defining the real filtration rate. And in those scenarios, the aging process will have a major role. It is expected that maybe up to one point of decline in the EGFR just by aging, normal aging process, we all go. So an 80-year-old with no medical problems will have an estimated GFR lower than 60. And by definition, will fall into chronic kidney disease. Even it's not the case, because it's aging. And we all age. And the same way we wrinkle outside, we wrinkle inside. And that aging process has not been really determined on what is going to be the role for the future. We're aging more and more. And we are able to reach, thankfully, an elderly population that now has moved to, say, well, maybe 85 and older. And before that, we still considered them very young. And it's great, because we're able to have very functional patients that may or may not fall into that definition. So having said that, if we have an elderly patient that has an estimated GFR of 45, I think it will be reasonable to consider a consultation with a nephrologist to determine accurately what the GFR is. Because it may be even higher than that 45 to start with. And even if it is 45, but it doesn't have any other risk factors, that's a patient that we can closely monitor and to decide if it is going to be a rapid decline on the function after starting lithium versus not. Unfortunately, we don't have guidelines on that. We don't know too much about it, although the medication has been there for many, many, many years. And the data, unfortunately, is very deficient. But having a case-by-case basis and monitoring closely those patients, especially those that don't have proteinuria, as proteinuria is the number one risk factor for progression, will be ideal. So we can determine safely to continue it. Thank you. Thank you. Yes. In fact, the whole community in nephrology, we are having that problem to determine the GFR for the elderly population. So we are trying to change the guidelines on it, because we agree it's not accurate at all. Thank you, everyone. So we are above 515, but we are here if you have questions. But thank you, everyone, for coming. Appreciate it. Thank you. Thank you. Sometimes I'll see a battery of blood work that'll have the creatinine, TSH, et cetera, which I'm looking for, but not the GFR. If I see a normal creatinine level, can I assume that the GFR is normal? Or what is a broader question? What is the proportionality between the creatinine and the GFR, if it is one? So it's usually creatinine of one. Anything that is one or lower is considered normal. But there are calculators. So if you Google GFR calculator, you put there your creatinine, the age of your patient, and it will calculate the estimated GFR. But generally, it is 10 to the 15th of that. So normally, it isn't likely the GFR will be normal. Yes. But it is also important to see, because we consider anything that is less than one normal. So it's important to see how the trend. But the trend, because if they had, let's say, a baseline a year ago of 0.6, and now it's 0.9, the trend went up quickly. And we will need to determine that. Oh, OK. Sorry.

Lithium

Mood disorders

Kidney health

Thyroid function

Bipolar disorder

Renal monitoring

Endocrine impact

Nephrogenic diabetes insipidus

Chronic interstitial nephritis

Hypothyroidism

Interdisciplinary management

Therapeutic benefits

Side effects