Activity Transcript

Caitlin Mulligan, MD: Hello, I'm Caitlin Mulligan, assistant clinical professor at the University of California, San Diego. Welcome to this program titled "Watching Out for Wilson Disease: Overcoming Diagnostic Challenges." Joining me today are Michael Schilsky, who is a professor of medicine and surgery and director at the Center of Excellence in Wilson's Disease at Yale University, and Nadia Ovchinsky, who is professor of pediatrics at Albert Einstein College of Medicine and medical director of pediatric hepatology and medical director, pediatric liver transplant, at Children's Hospital, Montefiore. Welcome.

Over the next half hour or so, we will discuss what is Wilson's Disease (WD), when to suspect it, challenges in diagnosis, establishing a diagnosis, and briefly, we will touch on treatment.

So what is WD? WD is a rare autosomal recessive genetic condition caused by 2 mutations in the ATP7B gene. The ATP7B gene encodes an ATPase that mediates excretion of copper into the bile and also allows for copper to be loaded onto ceruloplasmin to be transported to other tissues. In WD the absence of this ATP7B gene leads to copper excess in both the hepatocyte, as well as organs around the body, including the brain.

Its estimated prevalence is one in 30,000 to one in 50,000, depending on which study you look at. In terms of the clinical presentation of WD, most patients with WD will present between the ages of 5 and 35 years.

As I mentioned, copper excess can build up in many organs and this can lead to various presentations. You can have a liver presentation of WD, but also with copper buildup in the brain, neuropsychiatric disturbances are also present. In pediatric patients they can be asymptomatic or have hepatic symptoms. They can also have neurologic symptoms. However, it is more common for adult patients to present with neuropsychiatric symptoms, as opposed to children. In the adult patients, the neuropsychiatric symptoms can be predominant or lead before hepatic symptoms. Asymptomatic patients are usually identified by family screening.

Now in terms of prognosis of WD, if WD is left untreated, it can be fatal. Most patients will go on to die from liver disease if WD is not treated. In addition, some complications of neurologic disease can lead to death as well. The prognosis for WD really depends on the severity of liver and neurologic disease, but also the importance of adherence to treatment. It’s really key for the prognosis of patients with WD. WD is one of the few genetic diseases that can be managed successfully if diagnosed early and treated correctly.

But the trick is diagnosing WD. Michael, what are some of the challenges we face diagnostically with WD and what are some of the red flags you look for?

Michael L. Schilsky, MD, FAASLD: Thanks, Caitlin. WD has a really varied phenotype, and this really makes it very challenging because patients have very different clinical presentations and manifestations of the disease. As you mentioned, there are asymptomatic patients and many of these are usually only identified by family screening or by good luck. And many of the hepatic symptoms that patients have overlap with other liver diseases, for example in children, autoimmune hepatitis and in our adult population often with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. When there is neuropsychiatric symptoms as the dominant feature, it's often hard to actually get to the diagnosis in a rapid time. And the liver disease is often hidden in the background. So these patients often are misdiagnosed as having either behavioral problems [or] other psychiatric illnesses, which may range from simple depression to even psychotic disorders of schizophrenia, schizoaffective and delusional disorders. And this results often in a 1- to 2-year delay from the time of symptom manifestation to the time of diagnosis of the disease.

Now there may also be very atypical late presentations of WD. As you mentioned, it's often found earlier on in life, but some patients can be found even into their seventh or eighth decade. And these can be mistaken for other age-related diseases as well. The genetic diagnosis can be challenging too, as there are more than 500 possible disease specific mutations and many others that are variants of uncertain significance. Patients can have either 2 copies of the same mutation, disease specific, and those are homozygotes. Or they may have one copy of 2 different mutations on each allele. In other words, each allele has one of the 2 mutations, and these are compound heterozygotes. And this I'm referring to as the ATP7B gene or the gene that encodes the WD gene protein.

And so some of the other red flags that raise the index of suspicion for considering WD include those patients who may have been given a diagnosis of autoimmune hepatitis, but failed to respond in a predictable manner and show improvement. And when we see fatty liver disease, in particular, in younger patients, that may be a tip off to look for it. In particular, when we have overlapping neuropsychiatric symptoms and the presence of liver disease simultaneously, WD must be excluded. Now, infrequently, we do have patients who have severe acute hepatitis that have rapid onset of jaundice associated with a non-immune hemolytic anemia. And this is about 5% of patients. And this can be an onset of, and a harbinger of acute liver failure due to WD. And there may be others who have liver biopsy to seek the etiology of the liver disease. And they may have certain histologic features, such as fatty change, which can be macrocytic and even microcytic, and also have changes with glycogenated nuclei that may tip people off to then go back and look for WD.

Caitlin, what red flags do you look at from a neurologic standpoint?

Dr Mulligan: Thanks Michael. So from a neurological standpoint, again, the symptoms of WD are actually very varied. Dysarthria is the most common neurological symptom in WD, but this is a very nonspecific symptom and there are many neurological conditions which can cause dysarthria. So dysarthria for me is not so much of a red flag, for WD, as much as a movement disorder. So that means dystonia, tremor, parkinsonism. These are common features of WD, and any young person with these symptoms-- dystonia, tremor or parkinsonism should really prompt an evaluation for WD, especially if they have a history of psychiatric or hepatic disease. Another red flag is the psychiatric manifestations. Mood disturbances, declines in school performance or inappropriate behavior may also be tip offs to WD as well.

Regardless of the presentation, the diagnosis requires a thorough evaluation of clinical and laboratory studies. We use various laboratory measures to evaluate WD, including serum ceruloplasmin, the total serum copper, 24-hour copper excretion, liver function tests. And sometimes, if needed, liver biopsy or hepatic copper measures. And then as mentioned, there is genetic testing, which can be helpful in establishing the diagnosis of WD.

In addition, with neurological conditions, the MRI is an important tool as well. There are many different findings that you could have in MRI imaging for WD. You can get symmetric hyperintense changes in the basal ganglia, as well as other deep gray matter, including the thalami, the midbrain, and the pons. However, these are also not necessarily specific to WD. The MRI though is helpful for differentiating other causes of neurologic symptoms with WD. And it's still an important tool that we use.

An additional tool in neurologic presentations is the ophthalmologic exam. Using a slit lamp to look for Kayser Fleischer rings. This is an important diagnostic feature, especially if there's neurologic involvement. We know that almost all patients with neurological manifestations do have Kayser Fleischer rings present with their slit lamp exam. This is less important for patients with hepatic disease or patients who are presymptomatic. But with patients with neurological symptoms, it certainly is helpful.

A few other things to note in terms of the differential diagnosis. As I mentioned, the dysarthria is not specific to WD. There's many things that can cause dysarthria, including cerebellar ataxia, neuromuscular diseases, other types of movement disorders, including Parkinson's disease. In addition, ataxia has many causes, including genetic ataxias, multiple sclerosis, Creutzfeldt-Jakob disease. Parkinsonism has a separate differential diagnosis. There may be a genetic condition, such as Fahr's disease, or iron accumulation disorders, which would be in the differential diagnosis as well. And then in terms of dystonia and chorea, Huntington's disease or other genetic dystonia syndromes may be considered for those types of symptoms.

Nadia, what about the diagnosis from a hepatic standpoint?

Nadia Ovchinsky, MD, MBA, FAASLD: Yeah. Thank you, Caitlin. So we all know that WD is a great masquerader in the field of liver diseases, so we really need to consider Wilson's for anyone with unexplained liver disease or persistently elevated aminotransferases. Nobody can be excluded just based on their age, for example.

In addition to doing all our regular biochemical investigations and imaging for other etiologies of liver disease, we must remember to get the serum ceruloplasmin, the 24-hour urinary copper. And then if we have further suspicion again, just like you said, Caitlin, an exam, a slit lamp exam is important for detection of KF rings. In fact, if a patient has a low ceruloplasmin and elevated urine copper and positive KF rings, then we can establish the diagnosis of WD. However, it's an exception in hepatic presentation. So most patients do require a liver biopsy for histology, and also very important for copper quantification, because this really helps us establish the diagnosis.

Mutation analysis by sequencing the entire ATP7B gene is available and should be used for patients where diagnosis is difficult based on our clinical and biochemical evaluations. And then we can look for a specific testing of known mutations in order to screen the family for first-degree relatives of patients with WD, because we know the exact mutations that the patient has been identified with. To me, it's always helpful to have a clinical geneticist involved, because they can help us interpret the testing. And also even more importantly, provide important counseling for families of patients.

So the great masquerader has a very wide differential diagnosis. As Dr Schilsky said, autoimmune hepatitis should be considered as one of the top differential diagnoses for WD. In fact, patients’ biopsies can sometimes look identical to those with autoimmune hepatitis and they're even certain biomarkers in the blood, autoimmune markers that can be picked up in a good percentage of patients. Because Wilson's causes steatosis or steatohepatitis in the liver, certainly fatty liver disease should be considered in adults and pediatric patients, especially in younger ones and those who are non-obese. Chronic hepatitis such as hepatitis B or C needs to be in a differential and especially important for your younger population, inherited disorders of cholestasis and other rare genetic liver diseases need to be thought of. So alpha 1 antitrypsin deficiency, a group of diseases that result in progressive familial intrahepatic cholestasis. Again, interestingly, these cholestatic patients can have not just the clinical presentation, that's similar to WD, but can also have elevated quantitative copper in the liver. Patients with Niemann-Pick disease type C and patients with lysosomal acid lipase deficiency among other metabolic disorders. Patients who have LAL-D actually have steatosis in the liver as well. So Wilson's is not the only genetic diagnosis that we're going to consider in this group of patients.

WD should be considered in any patient with acute liver failure presentation. Although predominantly it appears in young females. It's very important to make this diagnosis, to make it rapidly because there's a fast progression and it's fatal without liver transplantation. These patients do have some specific clinical presentation. This Coombs-negative or non-immune hemolytic anemia is one of the main ones that's easily recognized. There's also rapid progression to renal failure, and then biochemically the AST and ALT elevation is usually only modest, and AST is higher than ALT because of hemolysis. And sometimes rhabdomyolysis as well. Patients have this typical, lower alkaline phosphatase, which is out of proportion to their cholestasis. And the total bilirubin level is actually atypically high, because it's contributed to [by] not just cholestasis, but by hemolysis as well. So we often will look at the ratio of alkaline phosphatase to bilirubin levels. And if this ratio is less than four, then this is highly suspicious for WD as an etiology of acute liver failure. Again, these patients need an urgent evaluation for liver transplantation.

It's also important to remember this hemolytic anemia presentation. So although most of the time it's associated with acute liver failure or acute liver injury presentation, sometimes it can occur sporadically in patients with untreated WD without the acute liver failure presentation. So evaluation for WD is critical in this group of patients who continue to have this recurrent non-immune hemolysis that's unexplained. And these patients don't usually present to liver doctors or neurologists. They usually present to hematologists. It's just an example of how WD can span many systems.

There have been some diagnostic scoring systems that were developed to facilitate diagnosis of liver disease. So the Leipzig score is probably the most common used diagnostic score. And it's been validated in both adult and pediatric populations. It can be especially helpful for patients with non-classic Wilson disease presentation. So take certain clinical points and biochemical points and assign 0, 1, or 2 to many of these. It's easily found on any online medical calculator and can be very useful for us to identify certain patients who have high risk of Wilson's, who are unlikely to have Wilson's, and then those who are intermediate, where we know we need to do further investigational studies.

Dr Mulligan: Thank you, Nadia. So when it comes to best strategies, as far as recognizing WD, it's really about knowing those red flags and ordering the right tests.

Let's talk briefly about treatment. Michael, what are some things to keep in mind?

Dr Schilsky: Well, once the diagnosis of WD is established, it's very important to think about the medical therapy, and we'll come back to the options for that. Because it's a lifelong medical therapy. Now, in addition to treatment that's directed at the copper accumulation, we also consider dietary restriction for copper and in particular, in patients who have advanced liver disease with portal hypertension and cirrhosis. Screening for and surveillance for esophageal and gastric varices is helpful, as well as screening and surveillance for hepatocellular carcinoma on an ongoing basis as well.

Now, the approach to medical therapy is really dependent on whether or not there is symptomatic or asymptomatic disease. And that incorporates as well, clinically evident disease and whether or not there's tissue injury and evidence of inflammation in the individual. Now, in those who are symptomatic, we consider first line therapy, chelators. In the currently available chelation therapy for binding and removing copper includes D-penicillamine and trientine. And zinc salts may be used as well, more often in maintenance therapy for patients. And in that instance, the zinc prevents the absorption of the copper through the gut and thereby reduces the copper burden in the body over time. Now rarely, dual therapy may be indicated for patients with very advanced disease. And here the chelation may be given administered separate from the zinc, so that 2 don't bind each other. And you may still have the effect of both's action.

Now with medical therapy, liver function improves in the vast majority and up to about 90% of patients usually do show some signs of improvement within 2 to 6 months with more of the synthetic function, whether it's albumin or clotting factors such as measured in INR showing larger degrees of improvement, more along the lines of 6 to 18 months. Now medical therapy is rarely effective in patients with acute liver failure, and those patients may need to be considered for transplantation. Now treatment is lifelong and therefore adherence is extremely important and in up to about half of patients really show some period of non-adherence during their lifetime. However, those with more significant non-adherence and less well controlled disease may exhibit progressive liver failure or acute liver failure in some as well.

Nadia, tell us a little bit more about liver transplant for WD.

Dr Ovchinsky: Yeah, so we already have learned that liver transplant is the only curative therapy for patients with acute liver failure or those who present with acute liver injury rapidly progressing to failure. Although this group of patients can be stabilized by using certain pheresis techniques, they really need to be evaluated for liver transplantation. What about patients with chronic liver disease and decompensated cirrhosis? Well, they might respond to a very aggressive and intense medical regimen, but it needs to be recognized that liver transplant evaluation should be done as a backup. And for those patients who fail to respond or some who fail to tolerate medical treatment, a rapid progression to transplant should be considered as well. There are certain patients with cirrhosis and hepatocellular carcinoma who can also be candidates for liver transplant. On the other hand, liver transplant has a controversial role for those patients who have significant neuropsychiatric presentation, and these patients may not improve.

So Caitlin, how would you manage patients with neuropsychiatric symptoms?

Dr Mulligan: So in terms of the neurologic manifestations of WD, we really turn to some of the same anti-copper therapies that the hepatologists turn to. So we're using the trientine and penicillamine as well as zinc therapy and dietary changes. And neurologic symptoms can improve with anti-copper therapy. Sometimes this takes a prolonged period of time, up to 1 year or 2 years to see neurologic improvement. Symptoms don't always go away completely, but certainly there can be some improvement in symptoms. One of the things that I worry about, however, is that with the chelation therapy, there is a chance for neurological deterioration. This is well known amongst neurologists and other doctors who treat WD, and one of the concerns about chelation therapy.

In terms of the symptomatic therapies we do sometimes try to manage some of the symptoms of WD with symptomatic treatment. So for parkinsonism, that may mean trialing a medication such as levodopa. However, this is rarely effective in Wilson's patients. Dystonia can be managed with certain medications, including medications that work on acetylcholine, as well as muscle relaxant medications, or sometimes botulinum toxin injections to target the dystonia. And then there's also management of psychiatric symptoms such as depression, anxiety, psychosis, oftentimes we're using medications like SSRIs to manage those symptoms. There is some evidence that perhaps the dopamine blocking medications, antipsychotic medications may be less well tolerated in Wilson's patients. So in general, we try to avoid those if possible, though, for some patients with psychosis, they may be necessary. Supportive treatments, such as physical therapy, occupational therapy, speech therapy can be very helpful for patients with WD to manage their day-to-day functions.

I wanted to briefly note some emerging therapies for WD. There's a compound called bis-choline tetrathiomolybdate that's in a phase 3 clinical trial, currently. This is an exciting prospect, especially for patients with neurological dysfunction because of the mechanism. It is thought to have possibly a decreased risk for worsening of neurologic symptoms. However, the studies are still in process, and so we're still waiting to see what those studies are showing. The previous studies have showed some improved liver function and neurologic symptoms in the phase 2 trial.

There's also some gene therapy trials, which are in development in phase 1 and 2 trials. Two different compounds there. And at least one of them in animal studies has shown to reduce hepatic copper and also prevent liver injury. And clearly WD being a genetic condition, I think everybody's excited about the prospective gene replacement therapy being one of the exciting ways forward in terms of WD treatment.

So to summarize, WD is a rare disorder of abnormal copper metabolism and copper accumulation in organs, particularly in the liver and brain. WD can be managed successfully if diagnosed early and treated correctly. And this makes it really important to know the red flags for WD, and also how to evaluate for WD and knowing which laboratory test will be helpful in establishing that diagnosis.

As we spoke about diagnosis requires clinical and laboratory measures. Some of the key clinical hallmarks of WD are what we discussed in terms of the varied hepatic presentation of WD, as well as the varied neurologic presentations for WD. The laboratory tests might include evaluation of the serum ceruloplasmin, the serum copper, the 24-hour urinary copper excretion, as well as liver function tests, liver biopsy, MRI, and possibly genetic testing as well. The treatment for WD is lifelong. Recall that we mentioned that the prognosis for WD is good with good treatment for WD. However, this is a lifelong condition in adherence is extremely important for prognosis of WD patients. We also touched on the emerging agents that are under study, including some of the genetic compounds under study for WD.

Michael, Nadia, thank you so much for this great discussion and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.