Wilson's Disease–History and Metabolic Context

The History of Discovering and Defining the Symptoms and Underlying Causes of Wilson’s Disease

In 1912 Kinnier Wilson published a portion of his thesis for his Medical Degree in Brain characterizing, for the first time, several cases of what he referred to as “Progressive Lenticular Degeneration: A Family Nervous System Disease associated with Cirrhosis of the Liver” in six of his own patients and six patient records from other physicians that had documented similar symptoms. (Wilson 1912) This was the first characterization of what is known today as Wilson’s Disease or hepatolenticular degeneration. Images of some of his first patients can be seen in Figure 1.

Wilson studied the patient cases looking specifically for a connection between changes in the liver, such as cirrhosis, and softening of the lenticular nucleus due to inflammation. (Wilson 1912) Based on these cases, Wilson described the disease as progressive, fatal, occurring in young people, and as, “often familial but not congenital or hereditary; it is essentially and chiefly a disease of the extrapyramidal motor system.” (Wilson 1912) Wilson also correctly identified the presentation of many of the disease signs including tremors, muscle weakness, spasticity, progressive emaciation, dysarthria, dysphagia, emotionalism, and mental symptoms seen in his patients. (Wilson 1912) Wilson was correct that the disease does usually present for the first time in young people and that it is progressive and was often fatal in his time because there were no effective treatments available for Wilson’s Disease in 1912. Based on the signs that Wilson was observing in his patients, it also made sense to link the disease to the extrapyramidal motor system which controls initiation, rate, force, coordination and activation or suppression of movement. (Wilson 1912) However, he would later be disproved in regards to the hereditary nature of the disease. Wilson also characterized the pathology of the disease via brain and liver slices of patients post mortem. (Wilson 1912) He noted the degeneration of the lenticular nucleus in the brain and the presence of liver cirrhosis, but he emphasized that the cirrhosis was not the cause of the patients’ symptoms. (Wilson 1912)

Above are photos of three of Dr. Kinnier Wilson's original patient case studies for Wilson's Disease. The images depict some of the classic symptoms of untreated Wilson's Disease with copper accumulation in the brain causing neurological damage such as muscle tremors and rigors, slack jaw, and vacant stares. (Wilson 1912)
Figure 1: Above are photos of three of Dr. Kinnier Wilson’s original patient case studies for Wilson’s Disease. The images depict some of the classic symptoms of untreated Wilson’s Disease with copper accumulation in the brain causing neurological damage, such as muscle tremors and rigors, slack jaw, and vacant stares. (Wilson 1912)

There was suspicion in the scientific community that Wilson’s Disease was an inherited disorder, despite Wilson’s original assertion that it was not hereditary. In 1921 Hall reviewed Wilson’s patient cases and an additional seven cases and stated that the disease was likely inherited in a recessive pattern. Later studies also lent support to the idea that Wilson’s Disease was an inherited, recessive disorder, but up until this point all genetic analysis had been done using old patient case reports. This methodology left a lot of room for error if everything hadn’t been properly recorded in the initial case report. Finally in 1953 A.G. Bearn used genetic ratio analysis calculations, instead of patient case reports, to confirm that Wilson’s Disease is inherited in an autosomal recessive pattern. (Bearn 1953)

Despite Wilson’s strong characterization and identification of the disease, he was unable to determine its underlying cause. In 1948 Uzman and Denny-Brown observed amino aciduria in Wilson’s Disease patients (later found to be as a result of the accumulation of copper’s toxic effect on the renal tubule) and hypothesized for the first time that Wilson’s disease may be linked to an underlying metabolic problem; however, they were unable to determine what the specific metabolic problem was. (Uzman et al. 1948) In that same year, J.N. Cummings indicated that the issue with Wilson’s disease may be linked to copper metabolism when he found increased copper content Wilson’s Disease patients’ liver and brain when compared the copper content of brain and liver in patients without Wilson’s Disease. (Cummings 1948) In 1952 Scheinberg and Gitlin finally identified that Wilson’s Disease patients have a deficiency in ceroplasmin, the protein needed to bind free copper in serum plasma in a healthy individual. (Scheinberg and Gitlin 1952)

Finally in 1993, some light was shed on the genetic basis of Wilson’s Disease when a suite of Nature Genetics papers were published which mapped the Wilson’s Disease gene to chromosome 13q14.3 and found that the gene codes for ATP7B, a copper-transporting ATPase that transports copper out of the cell and into the circulatory system. (Bull et. al. 1993) (Petrukhin et. al. 1993) (Tanzi et. al. 1993) Case studies have uncovered a wide variety of kinds of mutations in the Wilson’s Disease gene can disrupt the gene enough to disrupt ATP7B enough to cause Wilson’s Disease. (Bull et. al. 1993) (Petrukhin et. al. 1993) (Tanzi et. al. 1993) Much of this work was made possible due to the similarity of ATP7B to ATP7A, another copper-transporting ATPase which is linked with Menkes Disease, another copper transport disorder. (Tanzi et. al. 1993)

This genetic confirmation provided the final piece of the puzzle. Wilson’s Disease is a copper transport disorder. It is characterized by disruption of the body’s ability to incorporate copper into ceruloplasmin via ATP7B and a reduction of copper excretion from the liver into bile via ATP7B. When copper transport is disrupted, copper accumulates in vital organs and the signs and symptoms of Wilson’s Disease are triggered.

Research is still ongoing in the field of Wilson’s Disease. In 2014 Kalita et al linked Wilson’s Disease to oxidative stress. They studied Wilson’s Disease patients and observed reduced glutathionine levels, reduced total antioxidant capacity, increased cytokine levels, and increased malinodialdehyde levels when compared with their non-Wilson’s Disease carrying siblings. (Kalita et. al. 2014) They concluded that increases in these oxidative stress markers are indicative of an environment with reduced antioxidants which they propose is caused by the presence of free copper in Wilson’s Disease patients. (Kalita et. al. 2014)

Symptoms of Wilson’s Disease

This figure displays the majority of the symptoms associated with Wilson's Disease and the organ from which the symptom originates (Original Composite Figure, Images used are from Google Images)
Figure 2: This figure displays the majority of the symptoms associated with Wilson’s Disease and the organ from which the symptom originates (Original Composite Figure made by KC, Images used are from Google Images)

Because Wilson’s Disease results in copper deposition in vital organs as well as increased free copper circulating the blood stream, it impacts many parts of the body and causes a wide variety of symptoms. These symptoms are presented in a visual manner above in Figure 2.

Deposition of copper in the liver causes inflammation. When the inflammation is prolonged and uncontrolled, patients can develop cirrhosis, hepatitis, and nonalcoholic fatty liver disease in response to the inflammation. (Wilson 1912) This can also result in hepatomegaly (an enlarged liver) and acute liver failure. Liver failure can cause jaundice which often manifests itself as yellowing of the skin and the whites of the eyes. It is important to note that it is not the mutation in the Wilson’s Disease gene that causes these liver symptoms, but rather that the mutation causes a dysfunctional ATP7B protein which leads to the accumulation of copper in the liver. The accumulation of the copper causes an inflammatory response which results in the above liver symptoms.

Accumulation of Copper in the eyes results in brown, Kayser-Fleischer rings around the irises. (Wilson 1912) Accumulation of copper is also toxic to the renal tubule and can cause Amino-Aciduria and patients can excrete high levels of amino acids in their urine. (Uzman et al. 1948) Patients with Wilson’s Disease typically excrete higher concentrations of copper in their urine as well.

Blood tests typically also reveal increased levels of free copper in the serum and decreased levels of ceruloplasmin. Wilson’s Disease patients can also exhibit low white blood cell count, anemia, and low platelet count.

Deposition of copper in the brain results in a slew of neurological symptoms including migraines, psychosis, depression, anxiety, nervousness, memory impairment, and personality changes. The neurological symptoms extend to include an altered gait, muscle tremors, muscle weakness, uncontrolled movement, and problems with physical coordination. (Wilson 1912) Many patients also experience trouble speaking and swallowing. (Wilson 1912)

Patients with Wilson’s Disease can also experience arthritis, osteoporosis, nausea, and vomiting as a result of their disease.

Disease Identification for Wilson’s Disease

In 1912 when Wilson first characterized instances of Wilson’s Disease, the only means of identification at his disposal was to observe the signs patients presented, such as neurological symptoms and muscle tremmors. These usually occurred in advanced stages of Wilson’s Disease. Then, if the patient died, Wilson was able to look at cross sections of their liver and their brain for signs of inflammation, likely due to copper deposition, and then he was able to make a conclusive diagnosis. This system was less than ideal.

In today’s world, we have more knowledge about Wilson’s Disease and more sensitive and specific testing has been developed to detect Wilson’s Disease before it gets to the advanced stage that Wilson was detecting it in. Of course, these diagnostic tests are coupled with a patient’s exam and disease signs and symptoms.

Blood Testing: Blood testing is used to check for the amount of copper in the patient’s blood stream. (labtestsonline.org) Often copper levels in the blood are normal in patients with Wilson’s Disease. (labtestsonline.org) However, excess free copper (copper not bound to ceruloplasmin) in the serum is indicative but not diagnostic of Wilson’s Disease. (labtestsonline.org) Excess free copper can lead to symptoms synonymous with copper poisoning. Blood tests will also look at the patient’s ceruloplasmin levels which are often low in Wilson’s Disease patients. (labtestsonline.org) Blood testing can also be used to monitor liver enzyme function to help determine if accumulated copper in the liver is causing disregulation.

Urine Testing: Urine testing can be used to determine the amount of copper excreted in the urine over a 24 hour period. (labtestsonline.org) High levels of copper excretion are indicative of Wilson’s Disease. (labtestsonline.org) Additionally, urine testing can offer insight into the functioning of the kidneys  and whether they are being potentially impacted by copper accumulation or inflammation.

Eye Exam: An eye exam is used to look for the presence of a Kayser-Fleischer ring caused by deposition of copper in the eye. It can also be used to look for any yellowing in the whites of the eyes that may be evidence of jaundice caused by liver dysfunction. (Wilson 1912) Today, ophthalmologists and optometrists use a slit lamp to examine and detect Kayser-Fleischer rings in the eyes.

Liver Biopsy: Liver Biopsy is used to examine a piece of liver tissue to check for copper deposition in the liver. (labtestsonline.org)  While this is typically positive in Wilson’s Disease patients, copper deposition in the liver is sporadic. (labtestsonline.org) Therefore, it is possible to take a sample that happens to have no copper deposits, even if other parts of the liver contain copper deposits. (labtestsonline.org) The biopsy also allows pathologists to check for hepatitis, cirrhosis, and nonalcoholic fatty liver disease. Most Wilson’s Disease patients have some form of liver disease, although it may not be that advanced at the time of diagnosis. (labtestsonline.org)

Genetic Testing: Genetic testing can be done with a simple blood test. It is used to check for a mutation in the Wilson’s Disease gene. There are a variety of types of mutations in the Wilson’s Disease gene that can cause Wilson’s Disease and many of them can be screened for with genetic testing. Once one member of the family has been diagnosed with Wilson’s Disease, the rest of the family typically undergoes a genetic screen to see if anyone has the same Wilson’s Disease mutation. (WDA) Genetic testing is the most conclusive way to diagnose a patient with Wilson’s Disease.

MRI: MRI is used to image the brain of Wilson’s Disease patients to look for copper deposition. (Singh et. al. 2011) This also allows physicians to correlate location and extent of copper deposition in the brain with clinical presentation of neurological symptoms as research continues on Wilson’s Disease. (Singh et. al. 2011) Wilson’s Disease patients often have a characteristic ‘face of the giant panda’ shaped copper deposition in the brain, which is pictured in Figure 3 below. (Singh et. al. 2011)

Above is an MRI image of a patient with Wilson's Disease. The 'face of the giant panda' shaped copper deposition can be seen in the midbrain. (Singh et. al. 2011)
Figure 3: Above is an MRI image of a patient with Wilson’s Disease. The ‘face of the giant panda’ shaped copper deposition can be seen in the midbrain. (Singh et. al. 2011)

There is still research going on in the field of Wilson’s Disease diagnosis. For example, a new research paper suggested the implementation of biochemical stages to characterize hepatic copper toxicosis in combination with Wilson’s Disease phenotyping (hepatic, acute, and neurologic) to better understand the biochemical features of Wilson’s Disease hepatic legions. (Katano et. al. 2014) A clearer understanding of these legions paves the way for developing more specific diagnostic testing for Wilson’s Disease in order to move towards earlier diagnosis.  (Katano et. al. 2014)

Disease Free Metabolic State:

Copper serves a necessary role in the human body and participates in several metabolic pathways. It is required for several important enzymes such as cytochrome C oxidase, copper zinc dismutase, and dopamine β-hydroxylase. We consume copper as part of our diet and in a healthy individual that copper is absorbed by the intestinal mucosa and transported via the portal blood to the liver. (Turnlund 1998) ATP7B is a copper-transporting ATPase (a protein family that uses ATP to transport metals in and out of cells)  is found in the Golgi, of the liver cells.(NIH Genetics Home Reference ATP7B 2015) When copper arrives at the liver, ATP7B transports the copper to the ceruloplamsin protein which then carries copper via the blood stream to other bodily tissues requiring copper for their enzymes. (NIH Genetics Home Reference ATP7B 2015) When there is excess copper in the liver, ATP7B leaves the Golgi and instead works to package copper into vesicles to remove the excess copper before it damages the liver. (NIH Genetics Home Reference ATP7B 2015)Those vesicles are then sent out of the liver via bile. (Turnlund 1998) The bile containing the copper is secreted into the gastrointestinal tract and eventually the copper is excreted as part of feces. (Turnlund 1998) The basic flow of this process is shown below in Figure 4.

These processes are important because accumulating excess copper in vital organs or too much free copper in serum is toxic to the human body. Too much free copper in the blood stream allows for the generation of reactive oxygen species such as superoxide and hydrogen peroxide which can damage DNA, proteins, and lipids.

ATP7B is also found in smaller quantities in the brain and in the kidneys.

The above figure explains the path for the absorption, use and excretion of heavy minerals from the human body. In the case of copper, we consume copper in our diet and it is
Figure 4: The above figure illustrates the path of  heavy minerals through the human body. In the case of copper, we consume copper in our diet and it is absorbed via our intestinal mucosa. It is then sent to the liver via the portal blood. In the liver, ATP7B packages modifies ceruloplasmin (the copper carrying protein) by binding copper to it. The ceruloplasmin bound copper then travels through the blood stream to the rest of the body. When there is excess copper, ATP7B packages the copper into vesices which are sent to the bile. The bile is secreted into the gastrointestinal tract and the copper is eventually excreted in feces. (Turnlund 1998)  (NIH Genetics Home Reference ATP7B 2015) 

Other Pages on Wilson’s Disease:

Wilson’s Disease–Title Page

Wilson’s Disease–Molecular Basis of the Disease State

Wilson’s Disease–Treatments and Disease Management

Wilson’s Disease–Conclusions and Proposals for Future Work

8 Replies to “Wilson's Disease–History and Metabolic Context”

  1. Excellent summary of history and clinical presentation. To increase specificity about the Kayser-Fleischer rings, you usually need a slit lamp exam to see them, especially early on when most patients are diagnosed these days.

    1. Hi Mazen! Thank you for taking the time to read and comment! Yes, I did see in my research that Wilson’s Disease patients are referred for eye exams and that a slit lamp is indeed used to detect Kayser-Fleischer rings! I will go back and include that in my page for clarity. Thank you for drawing this to my attention!

  2. Hi Kelly,

    Great work! I was reading through your summary, and I noticed that one of the tools use to diagnose Wilson’s is blood testing, which would show increased levels of copper. I find this a little bit confusing because I thought that normally ATP7B transfers free copper in the liver to ceruloplasmin, and then the copper-ceruloplasmin complex moves into the blood and into cells throughout the body. But if ATP7B is mutated, as in Wilson’s disease, then wouldn’t the copper be trapped in the liver, since it can’t be excreted via bile or attached to ceruloplasmin? I would think, then, that the copper levels would be very high in the liver, but low in the blood because all of the copper is stuck in the liver. In addition, the copper from the diet should be sent directly to the liver via the hepatic portal veins, which don’t connect directly to systemic circulation, and would not enter the blood either; thus, systemic blood copper levels should remain low. Am I misunderstanding something, or, if I am not, what do you think might account for the incongruously high levels of copper in the blood tests?

    Also you mention that decreasing the amount of copper in the diet would be a really useful treatment method. While this certainly makes sense that a low-copper diet would result in less copper accumulation, is this a practical option? What kinds of food contain copper, and would it be possible to remove all of them from the diet? Is there any level of copper that would be safe to eat, or would this have to be a no-copper diet?

    Finally, I like your idea of using a new imaging technique to diagnose Wilson’s disease, especially because finding the sign of the “giant panda” may be difficult, especially for a doctor that has little experience treating patients with WD. How sensitive, though, is this tool? If it relies on the actual accumulation of copper in the brain, would this imaging technique actually be able to detect early stages of Wilson’s disease? Or would it only detect later stages where there is significant accumulation of copper?

    1. Hi Mike! Thanks for reading and commenting!
      In regards to your fist set of questions, it is true that a lot of the copper does get trapped in the liver. However much of it is still released as free copper in the bloodstream. Even healthy individuals have some free copper in the blood stream (it is bound to albumin or other small molecules, just not ceruloplasmin). So, when ceruloplasmin is not present, there is more copper in the liver that isn’t getting transported out with ceruloplamin so more of it starts getting sent out of the liver as free copper. The problem is that ceruloplasmin is really the protein that carries the copper to other tissues in the body that need the copper for enzymes. Free copper is not capable of being transported into the tissues the same way, so it begins to accumulate in the bloodstream. When that happens it generates reactive oxygen species which cause copper toxicity symptoms. It is also true that the copper is traveling form the digestive track through the hepatic portal veins to the liver. The liver is then exporting the copper into systemic circulation. ATP7B mutation does not impact the way that the liver was originally releasing free copper or copper bound to albumin, so those pathways are still occurring, except now there is also increased free copper because of the lack of ceruloplasmin. Therefore, the systemic copper levels will be increased. I hope this helps to clarify any confusion!
      In regards to the dietary copper restriction, I enhanced my page to include more specific information about that which I hope will be helpful to you. Dietary changes are really the most practical, most cost effective, and least invasive treatment option we currently have available to us. Please note though that dietary copper restriction is not a cure or even a stand alone treatment. It is really an addition to a patient’s existing therapy regimen. I have listed some foods above that are high in copper that WD patients avoid such as shellfish and liver. Once patient’s WD is better managed then they are able to add in copper containing foods like chocolate that they would have been restricted from upon initial diagnosis.
      Because SWI is a new tool that is not yet being used in the mainstream, we are not exactly sure yet how much copper would need to accumulate to e detected by SWI. It is certainly more sensitive than existing MRI techniques and offers greater contrast, but how sensitive it really is for Wilson’s Disease we are not yet sure. Additionally, by the time copper is accumulating in the brain Wilson’s Disease is progressing steadily. In an ideal world we would have diagnostic techniques that detect Wilson’s Disease before copper is accumulating significantly in the brain. But, for now SWI is definitely a step in the right direction.
      Thanks!

  3. Kelly – Very nicely done! I have a few questions from multiple pages; I am commenting here because my first question is for this page.

    1. I appreciate the strong historical narrative that you paint in this page – research well done 🙂 That being said, I am a little confused as to the role of copper in a healthy body. You repeat yourself throughout the website in writing that we get copper from the diet. But can you tell me more? Specifically, what is copper doing for us? If, for example, you mentioned iron, my mind would jump to Iron-IV-oxo and the +4 oxidation state and the associated reactions we learned in class. Can you make similar connections for copper? What else does it do, and does that role provide some context as to this disease’s pathophysiology or harmfulness?

    2. You mentioned on the mechanism page that ATP7B is liver-specific and that ATP7A is in the rest of the body. You also note that ATOX1 chaperones copper to both 7B and 7A. So why is a 7A defect so harmful if it’s the minority of ATP7_ proteins in the body? I suppose this is about metabolic context because it raises the question Why is dietary copper shunted to the liver in such a way that Wilson’s is fatal?

    3. On the treatment page – I don’t understand what you mean by “Zinc therapy manages copper levels by inducing metallothionien”. What does induce mean, and why does Zinc do it? Why not just inject metallothionien (or ceruloplasmin) into the patients? I clicked the link for Hoogenraad paper but I only had access to the abstract (alas!), so I’m wondering about the mechanism of the treatment.

    1. Hi Zach!Thanks for taking the time to read and comment! I have added information to several of my pages to address your questions and clarify things. I will give a brief recap here, too.
      1. Copper is required for many of the body’s vital enzymes such as cytochrome C oxidase, copper zinc dismutase, and dopamine β-hydroxylase. We can certainly imagine that loss of copper and therefore loss of function of these critical enzymes would reek havoc on several metabolic processes and systems–so we really do need copper! However, the issue with Wilson’s Disease really comes from accumulation of copper in places where it doesn’t belong (AKA the liver, brain, and blood stream), and therefore isn’t really directly linked the copper’s canonical role in enzymes. Part of what makes the disease so harmful is that increased free copper levels in the blood stream cause copper toxicity. The high serum levels of free copper actually generate reactive oxygen species, which we know cause a whole slew of issues.
      2. So, to clarify ATP7B is found in it’s highest concentration in the liver, but is also present in the brain and kidney’s (just in smaller concentrations). ATP7A is found in several other tissues. However, a mutation in ATP7A causes an equally large issue–Menkes Diseases (another copper storage disorder). Much of what we know about ATP7B and Wilson’s Disease was built off of the characterization of ATP7A and Menkes Disease (and much of the literature cited in my pages points to that in case you are still interested in the connections between Menkes and Wilson’s or ATP7 A and B). What really kills people in Wilson’s Disease is accumulation of copper in the brain and liver that causes inflammation in those tissues. The inflammation is what causes many of the symptoms. When the patient eventually dies, it is often from liver failure or Cirrhosis due to inflammation–mutations in ATP7B themselves are not inherently fatal. The good news is that with increases in treatment options, Wilson’s Disease does not typically progress to the fatal stage it did in patients diagnosed in 1912.
      3. I had to inter-library loan that paper–sorry Zach! I have gotten several questions on zinc therapy and reworked that entire section of the page to try to make it clearer, so it might be worth another read! Treatment with injected ceruloplasmin would not necessarily be effective. Although many WD patients do have decreased levels of ceruloplasmin, not all of them do. The real issue is that because ATP7B is mutated, it is unable to modify the ceruloplasmin with the copper. So, simply increasing ceruloplasmin would not facilitate it’s modification by copper. Perhaps injecting copper modified ceruloplasmin could transport copper via ceruloplasmin to other tissues, but this would just be increasing the amount of copper in the systems of patients who are already accumulating copper. Therefore, this may not be the best strategy we have. In terms of injection with Mt, that may not be the best idea in light of Dzeiyzc et. al.’s 2014 study that highlighted the risks of copper deficiency after zinc therapy. It seems that injection with Mt would run an increasingly high risk of over-treating the excess copper and result in patients with copper deficiency—thus exchanging one issue for another.

  4. I really liked your breakdown of the diagnostic modalities; splitting up the info into sections was really helpful! It is always helpful when there are so many different tests to list which is the “gold standard”, i.e. the test that is the most accurate and to which other tests are compared. This may not be the test used most often, however. In this case, if the patient doesn’t have KF rings or the classic combo of the neuro symptoms you listed plus liver damage, a liver biopsy is necessary to establish the diagnosis. As you note in the section on biopsy, most patients have at least some liver damage on presentation. In fact, one of the most, if not most common, way for patients to present is with acute liver damage in a young patient, with or without other major risk factors for liver disease (alcohol and Hepatitis C being big ones). This would lead to some tests to rule out those things, and usually to a liver biopsy which would confirm the diagnosis due to the excess copper deposition. Great job!

    1. Hi Mazen! Thank you for pointing this out! I went back up and added that the genetic testing is the only way to conclusively tell that an individual has a mutation in ATP7B and thus has Wilson’s Disease. While a liver biopsy is very helpful, not all patients have liver damage in the early stages of the disease. Additionally, liver damage could be indicative of several different diseases or issues, not just Wilson’s Disease. Therefore, liver biopsy alone cannot be used to definitively diagnose Wilson’s Disease. It seems that Wilson’s Disease is really diagnosed through a combination of tests, rather than by one featured test. This is also likely because some of the previously characteristic symptoms such as the Kayser-Fleischer rings are less common now that Wilson’s Disease is detected earlier before copper deposition has become so extensive. Thanks!

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