What is Wilson’s Disease?
Wilson’s Disease, also known as hepatolenticular degeneration, is a rare, genetic disorder that results in the accumulation of copper in several vital organs such as the liver, eyes, and brain as well as increased levels of copper in the blood stream. (Wilson 1912) (Bearn 1953) Over time this accumulation of copper can cause neurological damage and, if left untreated, death. (Wilson 1912) However, if properly diagnosed and treated, the disease progression can be stopped and existing symptoms may even improve. One in every 30,000 people will develop Wilson’s Disease in their lifetime and likely begin to display symptoms between the ages of 5 and 35 (Rosencrantz and Schilsky 2011).
Causes:
Many biological processes in humans require copper which is obtained from diet. (Turnlund 1998) However, excess copper accumulation in the body is poisonous. In healthy individuals the transmembrane protein ATP7B works in the liver where it pairs copper with another protein called ceruloplasmin that can carry the copper through the blood stream to other tissues where it can be used for other metabolic processes. When there is excess copper in the liver, ATP7B can repackage it and send it to the bile. (Turnlund 1998) Then, the bile is secreted into the digestive tract and the copper is excreted from the body in feces. (Turnlund 1998) However, individuals with Wilson’s Disease have inherited a mutation in the gene that codes for the transmembrane protein ATP7B which is responsible for transporting copper out of liver cells (Gourdon et al. 2012). This mutation is inherited in an autosomal recessive pattern and impairs ATP7B such that it is unable to excrete copper from the liver cells, thus causing toxic copper accumulation (Gourdon et al. 2012). Some ATP7B proteins can also be found in the brain and kidneys.
Symptoms:
Wilson’s Disease presents with a wide range of symptoms caused by toxic accumulation of copper in the body. These symptoms can present in the liver, brain, central nervous system, kidney, and eyes. There are also some psychiatric symptoms associated with Wilson’s Disease. Perhaps the most characteristic symptom of Wilson’s Disease are the Kayser-Fleisher Rings: brown colored rings around the irises of the eyes resulting from excess copper accumulation in the eyes. Accumulation of copper in the liver causes a variety of liver symptoms including cirrhosis, acute hepatitis, nonalcoholic fatty liver, hepatomegaly, and acute liver failure. Neurological symptoms include migraines, insomnia, seizures, drooling, and movement disorders such as muscle tremors. Psychiatric symptoms include personality changes, psychosis, neurotic behaviors, and depression (WDA 2009).
Treatment:
There are several treatment options for Wilson’s Disease that can halt disease progression and treat existing symptoms. Chelating agents, molecules that bind to copper and facilitate its excretion through urine, are one of the most popular therapies (Rosencrantz and Schilsky 2011). Treatment with zinc is also effective and has gained popularity over the years. Zinc therapy is focused at maintaining a normal level of copper in the blood stream to prevent copper poisoning. (Hoogenraad 2006). Chelating agents and zinc therapy are lifelong treatments that manage Wilson’s Disease very well and offer patients the opportunity to live a fairly symptom free life. However, there is currently a debate in the scientific community and among patients as to which treatment–chelating agents or Zinc therapy–provides the best results with the fewest side affects. There is also new research into cell therapy that would replace diseased liver cells with healthy ones may provide a cure in the future. As of now, the only short term cure for Wilson’s Disease is a liver transplant which is only an option for patients with advanced liver damage (Rosencrantz and Schilsky 2011). There are currently no widely available therapies to provide a lifelong cure for Wilson’s Disease (Gupta 2014).
Other Resources on Wilson’s Disease:
The Wilson’s Disease Association
National Institute of Diabetes and Digestive and Kidney Disorders
References:
Bearn AG. (1953) Genetic and biochemical aspects of Wilson’s disease. Am J Med.15, 442–449. DOI:10.1016/0002-9343(53)90134-X
Gourdon, P., Sitsel, O., Karlsen, J. L., Møller, L. B., and Nissen, P. (2012) Structural models of the human copper P-type ATPases ATP7A and ATP7B. Biological Chemistry. 393, 205–216. DOI: 10.1515/hsz-2011-0249
Gupta, S. (2014) Cell therapy to remove excess copper in Wilson’s disease. Ann. N.Y. Acad. Sci. 1315, 70–80. DOI: 10.1111/nyas.12450
Hoogenraad, T. U. (2006) Paradigm shift in treatment of Wilson’s disease: zinc therapy now treatment of choice. Brain Dev. 28, 141–146. DOI: 10.1016/j.braindev.2005.08.008
Rosencrantz, R., and Schilsky, M. (2011) Wilson Disease: Pathogenesis and Clinical Considerations in Diagnosis and Treatment. Seminars in Liver Disease. 31, 245–259. DOI: 10.1055/s-0031-1286056
Turnlund, J. (1998) Human Whole-Body Copper Metabolism. J. Clin. Nutr. 67, 960S-964S. PMID: 9587136
Wilson, S. a. K. (1912) Progressive Lenticular Degeneration: A Familial Nervous Disease Associated with Cirrhosis of the Liver. Brain. 34, 295–507. DOI:http://dx.doi.org/10.1093/brain/34.4.295
Wilson (Wilson’s) Disease Symptoms [online] http://www.wilsonsdisease.org/wilson-disease/wilsondisease-symptoms.php (Accessed April 1, 2015).
Other Pages on Wilson’s Disease:
Wilson’s Disease–History and Metabolic Context
Wilson’s Disease–Molecular Basis of the Disease State
I really liked this article because I think it did a good job of outlining the disease and giving examples of symptoms and treatment. I was better able to understand the disease on a non-clinical level.
Hi Juliana! Thank you for reading the page! I’m glad it was informative!
Hi Kelly,
First of all, I think this article is really well-done. I like the links to references throughout, and I also think the pictures you picked were excellent. Very informative! I just have a few suggestions:
1) In the beginning, you link to the term “degeneration,” but it sounds like the term “hepatolenticular degeneration” is actually the whole term here. If “hepatolenticular degeneration” is just another term for Wilson’s syndrome, I don’t think “degeneration” needs to be linked to. I would just leave the term as is (or, if you prefer to link it, I would link the entire phrase, “hepatolenticular degeneration” rather than just “degeneration”).
2) I was initially confused by what ATP7B was. I would suggest introducing what ATP7B is at the first mention of it rather than later on (as it is currently).
3) I would provide a links for the following terms: “transmembrane” and “hepatic.”
Other than that, it looks great!
Hi Chelsea! Thank you so much for taking the time to read my page and leave a constructive comment! I took your suggestions into account and made some modifications that I hope will be more helpful! I removed the confusing “degeneration” link, swapped out the word “hepatic” for “liver”, added linked definitions for “transmembrane” and “ATP7B”, and tried to put more of an explanation for ATP7B towards the beginning of the “Causes” paragraph. I hope that these changes have made the page more accessible for everyone!
Very nicely done! I appreciate the topic headings and found most of the information easy to comprehend. The section under “causes” was the most challenging. An explanation of ATP7B: what it is and what “coding for a transmembrane” means would help me to understand this better.
I enjoyed the eye picture!
Hi Dr.C’s Mom! Thank you so much for taking the time to read my page and leave a constructive comment! I tried to rework the wording of the “Causes” section to make it a little clearer for everyone. I tried to put more of the explanation of ATP7B at the start of the paragraph and I also linked it to a definition in the biochemistry primer for added information. I also added links to the biochemistry primer for “codes” and “transmembrane protein” to try to provide some more information. I hope that these adjustments make the content more understandable for everyone!
Good article, i understood wilson’s disease after reading the article. i checked my iris next time i was near a mirror. 🙂
Hi Chris! I’m so glad that you enjoyed the article and found it helpful! I hope you didn’t see any Kayser-Fleisher rings!
I found this article very straightforward, if not a little sterile and textbook-sounding. I now understand what Wilson’s disease is (and I’m pretty sure it was mentioned on House, MD). At one point, in the treatment section, the use of the word “curative” seemed a little out of place as it’s not a word used in conversation or outside of the sciences. There might be simpler ways to say that. Overall, looks good!
Hi Becca! Thank you so much for taking the time to read my page and provide feedback! I revised the page to use the word “cure” rather than “curative”. I hope that makes the page more straightforward and easier to understand!
Thank you for teaching us about Wilson’s disease! The material was presented in a very coherent and cogent manner. Some questions I was left with as a reader:
1) What are some of the chemical chelators used? I would love to see a chemical structure.
2) Is the mechanism known for how Zinc treatment normalizes blood copper levels?
3) Is the genetic basis a loss-of-function or hypomorphic mutation?
4) Why is excess copper toxic?
Great work!
Hi John! Thank you for taking the time to read and comment on my page!
1. One example of a chemical chelator is penicillamine.An image of it’s structure and more information about how it works can be found on the Wilson’s Disease–Treatments and Disease Management page (there is a link at the bottom of this page above the comments). There is also information on that page about the molecular basis of how zinc therapy works!
2. In a nutshell, Zinc therapy focuses on the reduction of free copper and preventionof copper uptake, rather than decoppering of vital organs like Penicillamine. (Hoogenraad 2006) On a biochemical level, zinc therapy works by increasing the concentration of zinc in the intestine which induces intestinal cell metallothionien (Mt), thus increasing the concentration of Mt in the enterocytes.(Brewer 2001) The zinc binds the Mt, but because copper has a higher afinity for Mt than zinc does, the copper dispalces the zinc and binds the Mt.(Brewer 2001) The Mt with the copper bound to it is then sloughed off into the intestinal tract and excreted in feces, rather than in the urine like Penicillamine.(Brewer 2001)
3. The mutations for Wilson’s Disease are varied and it seems that the mutations all impact ATP7B differently. It seems that both hypomorphic and loss of function mutations are known. In 2014 a study by Braiterman et. al. even discovered a mutation that impacts a ATP7B from leaving the golgi which shifted the paradigm for how we previously understand Wilson’s Disease mutations as disrupting the stablity or activity of ATP7B.
4. Excess copper is toxic in the body because it generates reactive oxygen species like superoxide and hydrogen peroxide which are damagins to DNA, protein, and lipids. Therefore copper poisnonig puts many of the body’s pathways at risk.
I hope this is helpful in answering your questions. Feel free to check out the other pages on Wilson’s Disease for more info!