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)
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
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)
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.
Other Pages on Wilson’s Disease: