Melanie Cole, MS (Host): From Brain to Liver, Advances in Wilson's Disease Management today on Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole, and we have two Northwestern Medicine physicians in a thought leader panel for you. We have Dr. Amanda Cheung. She's an Assistant Professor of Gastroenterology and Hepatology, and Dr. Danny Bega. He's an Associate Professor of Neurology.

Doctors, thank you so much for joining us today. And Dr. Bega, I'd like to start with you. Give us a little overview of Wilson's disease. What's the connection between the brain and the liver in this condition? And how common is it?

Danny Bega, MD: Thanks for the opportunity to speak. Wilson's disease is a rare genetic disease that is due to a mutation in a copper transporter. So, it leads to problems with metabolizing copper normally. And copper is really important for our cells to function. And both problems with having too much copper or too little copper can cause disease. And this mutation in the copper transporter makes it so that copper can't be normally eliminated or removed from liver cells. And so, they build up and they damage those cells and cause liver disease. And as the capacity of the liver to store that copper is exceeded, it spills over into other organs and vulnerable organs in particular include the brain. And areas of the brain involved in movement problems are a notorious problem with Wilson's disease. It can also lead to problems in other organs as well. But that's the typical problem, is the liver disease and the brain movement disorder neurological disease that we see in people who suffer from this genetic mutation.

Melanie Cole, MS: Thank you so much for that. And Dr. Cheung, what are some of the common symptoms that providers might notice for Wilson's disease? Why is it sometimes difficult to diagnose?

Amanda C. Cheung, MD: So, one of the issues with Wilson's disease is because the presentation often can mimic other disorders. And so, it can be misdiagnosed sometimes or missed in the diagnostic process. So the main organ systems that are involved that we think about are the liver, the neurologic system, and psychiatric system.

So from a liver standpoint, it really is a wide range. So some patients, a lot of the patients actually, initially will be completely asymptomatic. So, they may be detected or may be diagnosed through a workup for abnormal liver tests, for instance, which didn't cause any symptoms, just found incidentally on blood work. Sometimes it might just be a slightly enlarged liver or spleen. One of the large mimickers from the liver standpoint is fatty liver disease, which is actually quite common. And so, because fatty liver disease itself is common, it's often just chalked up to fatty liver disease, and there isn't further workup or evaluation from that standpoint. There can be a very extreme presentation of Wilson's disease from the liver standpoint, if you invest with acute liver failure or sometimes there's been too much damage already before the patient is recognized and they can develop cirrhosis and the complications of cirrhosis.

From a psychiatric standpoint, the patients can actually present with just your typical symptoms of depression, or bipolar disorder, or even personality changes. And then from a neurologic standpoint, well, maybe I'll let Dr. Bega cover the neurologic symptoms since he's the neurologist.

Danny Bega, MD: There's a spectrum of neurological conditions we'll see. And typically, it's related to involvement of the basal ganglia. It's an area of the brain that's particularly susceptible to damage from copper buildup. And it can lead to all sorts of movement problems from commonly tremors to abnormal movements we call dystonia, which are like contortions or overactive muscles, ataxia, or instability of gait or balance. Parkinsonism can even be mimicked with people who have Wilson's disease. And there can also be just generalized atrophy in the brain that can lead to cognitive and other psychiatric problems as well.

Amanda C. Cheung, MD: And then symptom-wise, the only other thing I would bring up, because every now and then we'll have patients where the initial diagnosis comes from them seeing an eye doctor and noticing these rings that we call Kayser-Fleischer rings. And sometimes that might be the first presentation where a patient goes to an eye doctor and the eye doctor says, "Oh, something's going on with your eyes." And then, that will lead ultimately to the diagnosis.

Melanie Cole, MS: Dr. Bega, as we're speaking about how Wilson's disease is typically diagnosed, expand and elaborate for us a little bit on the role of genetic testing in the diagnosis of Wilson's disease.

Danny Bega, MD: Sure. The most important thing in diagnosing Wilson's disease is suspecting it, which it's not always at the top of mind for everybody, because it's a rare disease and some people have never seen it before. So, it's really important to kind of have a high level of suspicion for it whenever someone has unexplained hepatic or neurological symptoms, particularly in people who are younger, let's say under age 60, who may have unexplained neurological or hepatic symptoms. And oftentimes it comes to diagnosis with blood work and urine tests that we can do. Oftentimes, we'll need a liver biopsy to actually confirm copper buildup in the liver.

But as you mentioned, genetic testing is available to us, and we can test for the genetic mutation in what's called the ATP7B gene. That is the gene for the copper transporter that is deficient and missing in people with Wilson's disease. And so, we can test for that gene. It's not usually the first test that we do for diagnosis, but it can help us in making a diagnosis. And it does have some potential drawbacks. It's not available to everybody at every hospital and every place. We do have it at Northwestern. We're able to test for. But it also, in isolation, is not used to make a diagnosis. It's just one tool that we'll use in our toolbox.

Melanie Cole, MS: I'd like you both to answer the next question. Dr. Cheung, starting with you, tell us about the Northwestern Medicine Wilson's disease Clinic, and as a neurologist and a hepatologist, how do you work together? Tell us a little bit about how the multidisciplinary approach works, where you collaborate with many different professionals.

Amanda C. Cheung, MD: Yeah. That's a great point to touch on because, I think, all caregivers for Wilson's disease recognize that the best care approach is actually a multidisciplinary approach. So, the three big organ systems that are involved is liver, neurology, and psychiatry. And so while not every patient has a manifestation in each of these categories, some of them will, and sometimes it will go undetected. So, that is one of the reasons why we have the clinic that we have at Northwestern.

So at our clinic, as far as clinicians, we have a neurologist, which is Dr. Bega, a hepatologist, which is me. We have a psychiatrist that's specifically for the Wilson's disease patients. You have a social worker, a dietitian, a geneticist, and a lot of support staff that helps to take care of these really complicated patients.

Danny Bega, MD: I'll just add that, because we have this big multidisciplinary team, sometimes for patients and families, they'll be seeing us, they'll be there for three hours sometimes, seeing multiple different providers. But the advantage is a one-stop shop for problems that are all interrelated, and also the ability for us to converse in real time about management plans, rather to, you know, catch each other at other times to run management plans, so we can collaborate a little bit easier. And it's, I think it's safer for patients too, that all of the providers are on the same page with the management. I do think that the social worker and the dietician have made a huge difference in our ability to improve people's quality of life. They meet with almost every patient in our clinic because there's almost always some needs there that they can find ways to assist with.

Melanie Cole, MS: Dr. Bega, can you discuss recent research that shapes our understanding of Wilson's disease with emerging therapeutic options, gene therapy, targeted molecular agents? How do you see the future landscape of Wilson's disease treatment and management evolving?

Danny Bega, MD: Well, Wilson's disease is thought of, as untreated, it's a fatal disease. And we're lucky to be dealing with disease where today we have treatments that can save people's lives, that keep them from progressing, that can keep them stable for their entire life on the right treatment. And so, that's fortunate compared to some other diseases. And that's one of the reasons it's really important too, to diagnose it and identify it early, is because we do have treatments. But the big areas for research right now are, um, Can we improve on the existing therapies that we have in terms of their ease of use, in terms of their tolerability, in terms of their accessibility to patients, and their ability to adequately remove copper from the body?

And so that's one area of active research is trying to improve on drugs that remove copper. and then the other really exciting area of research is gene therapy, because we know the gene responsible for the disease, is trying to, introduce the normal ATP7B gene, the normal copper transporter, into the liver cells so that they can then start to make the normal copper transporter and treat the disease, using replacement of the missing gene.

And so we're actively engaged in those trials, industry trials involved in, delivering that. Usually, the company is doing this right now are using viral vectors to deliver the normal ATP7B message, to the liver cells, so that they can then produce the normal protein,

Melanie Cole, MS (Host): Dr. Cheung, from your perspective, what's exciting in diagnostic methods or technologies to improve the detection of Wilson's disease? Speak about how recent developments in imaging modalities have helped you with monitoring of hepatic and neurological

Amanda C. Cheung, MD: So, current way of both diagnosing and then monitoring patients with Wilson's disease is based on blood work and a 24 hour urine copper. So that's collecting your own urine for 24 hours, and as it is, It probably sounds is quite cumbersome and annoying, but unfortunately is what we need to do to be able to monitor patients.

And in some patients, we may be asking them to do this once a month, every three months, but not infrequently that they need to do it. as Dr. Baker alluded to earlier, the time of diagnosis, some patients do ultimately get a liver biopsy so we can quantify the amount of copper in the liver. Usually we're not repeating that as part of the management strategy.

 the newer developments that are underway right now are really about how can we monitor these patients in, the most effective way, but in a less cumbersome way. And from a patient perspective, I think the most annoying part for them is having to actually collect that 24 hour urine, So it's having to be home for 24 hours and sticking it in the fridge, and these are just things that are difficult for them to complete sometimes. there is couple companies out there that are testing a serum, a blood marker, that can adequately quantify how much copper is effectively potentially causing damage in the body.

So, We can check a copper level right now in the blood, but that actually isn't, clinically significant as far as telling us how much copper is actually problematic in the body. So we need these other biomarkers. And I think probably within the next year or so, we'll probably have those available to us, which will, be a big game changer as far as management over time.

Melanie Cole, MS (Host): It's a very exciting time in your field. And Dr. Bega, are there any clinical trials that you'd like to speak about?

Danny Bega, MD: we do have trial called Cypress going on at Northwestern right now. And this is a, it's an industry trial. Ultragenyx is the company. and it's, really interesting design of a phase one, two, three trial, meaning they've designed it all under one protocol. and this is, the gene therapy trial that I alluded to where it's a single, uh, one time IV infusion of AAV9 vector that carries the normal ATP7B gene, message to hepatocytes, in hopes that it will then allow for the normal production of the protein, of the ATP7B protein.

 so that's an active study that's going on, throughout the country at a few sites, including ours. there's another company also working on a, gene therapy drug. we don't have that trial going on at Northwestern, but, it's nice to see that in the field there's more than one company working on this, given that it's a rare disease.

 but because of that, we really do need people to be aware of it. there's only so many people who are eligible and interested and willing to participate. given that it's a rare disease, we really need them to be aware of the trials that are going on.

Amanda C. Cheung, MD: And to be clear, just so it's, in case it's not, the gene therapy trials are really cool because what we're implying is that if it works, it's essentially a cure. So patients with Wilson's disease have to take medications for the rest of their lives and discontinuing medications can actually be fatal if, they discontinue it long enough before we catch wind of it.

 so the gene therapy trials, if they work and we're hopeful that they will, would be a huge change in the management of these patients.

Danny Bega, MD: And, to that point, actually, the trial is, the end point of the trial, in terms of how it's going to measure success, is going to be whether we can take people off of their standard of care therapy. And so if we're able to take people who are on stable standard of care therapy, and wean them off of it, then know trial is, that's the measure of success of this trial.

Amanda C. Cheung, MD: Right, so not only like being cured, but in not having to have the cumbersome task of doing labs and taking meds and whatnot, but these medications that we use to treat Wilson's disease are extremely expensive. So it could have a huge impact if we can. dose them with the gene therapy that essentially cures them.

They'll save them so much money long term.

Melanie Cole, MS (Host): This has been such an enlightening and informative episode, and I'd love to give you each a chance for a final thought here. Dr. Bega, understanding that this is a rare disease from the perspective of your specialty, what advice do you have for other physicians that suspect Wilson's disease in their practice, and if so, what would be their next step?

Danny Bega, MD: that's a great question. I think as a neurologist or a general practitioner, if you're seeing someone with neurological symptoms, generally, if they're under 60 years old and they're developing unexplained tremors, Parkinsonism that you think might be young onset Parkinsonism, um, other abnormal movements, gait ataxia, it is worth doing some simple screening tools to think about Wilson's disease.

Again, if you don't think about it, it won't be on your radar. You'll miss it. and 99 percent of the time you're going to screen and it'll be normal. Okay. but the low stakes tests that you can do in those patients are checking a 24 hour urine copper collection, a serum ceruloplasmin test, and potentially a slit lamp eye exam that Dr.

Cheung mentioned to look for kaiserfleischer rings, which is copper deposition, in a layer of the eye. those are simple, uh, tests. There are a couple fairly harmless things to level of suspicion. Um, and I think if you about doing it and you don't do it enough, um, even though most the time you'll do it, it'll be normal.

Um, I think you'll miss it. So, and then with any questions, definitely send them to a Wilson's disease expert. We're happy to see them, particularly the, confusion that I see comes up with people who see the serum copper tests and don't know how to interpret it. Again, as Dr. Cheung said, the serum copper test doesn't necessarily reflect the status of copper that we're interested in and can lead to a lot of confusion about whether people do or don't have Wilson's disease.

But the tests that I mentioned are pretty valuable and can be done even in advance of sending them to a Wilson's disease center to see if it's necessary to be seen by a specialist.

Melanie Cole, MS (Host): Cheung, last word to you.

Amanda C. Cheung, MD: Yeah, so I'll have to kind of echo what Dr. Bega said as far as just having a very high index of suspicion for these patients. So From a liver perspective, for instance, as we mentioned way early in the beginning of this podcast is that, sometimes the patients does present with abnormal liver tests like the transaminases, the AST and ALT are mildly elevated, or they may present with imaging that shows what we think is fatty liver at least.

So, for instance, fatty liver disease, quite common, a third of the population has metabolic associated fatty liver disease. But let's say you have a patient who comes in and they have imaging that shows fatty liver disease, but they have no metabolic, diagnoses. So for instance, the diabetes and being overweight and things like that.

 that should be a pretty high clinical suspicion that there's something else going on. Well, since being one of them, and because a lot of times patients may be asymptomatic leading up to the diagnosis, If patients, when they come in for cirrhosis or an abnormal liver test, it's often, most people would say it really should be considered one of the standard tests that you order in the very beginning, just looking.

And, as Dr. Baker mentioned, you may order so many and not have very many positives because it's relatively rare, but it's still worth it for that patient that you are going to diagnose earlier than you would have if you let them decompensate.

Melanie Cole, MS (Host): Thank you both so much for joining us today. To refer your patient or for more information, please visit our website at breakthroughsforphysicians. nm. org slash neuro to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.

Thanks so much for joining us today.