Wilson's Disease–Treatments and Disease Management

Both chelating agents and zinc therapy are treament options for Wilson’s Disease that can halt disease progression, manage disease, and treat existing symptoms. However, patients must undergo these treatments for their entire lifetime, or as long as their body continues to respond to them, because they are not curative. Wilson’s Disease patients are also encouraged to decrease their dietary copper intake.(Cleveland Clinic, Wilson’s Disease) There are currently no long term, curative treatments for Wilson’s Disease, but liver transplant can provide a short term cure. (Gupta 2014).

Chelating Agents:

Chelating agents are molecules that bind to copper and facilitate its excretion through urine. Penicillamine was the first chelation treatment developed for Wilson’s Disease in 1956 by Walshe. (Walshe 1956) Penicillamine was developed to replace 2,3-dimercaptopropanol (B.A.L.) therapy, the only previously known treatment for Wilson’s Disease that was developed in 1951 by J.N. Cummings but that solicited a toxic reaction in many patients. (Cummings 1951) (Walshe 1956) Unlike BAL, Penicillamine could be given orally and on a regular basis and had minimal side effects. Penicillamine possesses a –SH group which allows it to chelate copper and can be seen in the structure shown in Figure 1. Penicillamine promotes the excretion of copper by binding it and then because the molecule is so water soluble in the reduced form, it is easily excreted in urine. Penicillamine was the most popular therapy for Wilson’s disease for several decades. (Rosencrantz and Schilsky 2011). However, in recent years increased side effects and patient toxicity have made it less popular than zinc therapy.

The structure of Penicillamine is shown above. The -SH group allows the molecule to act as a chelating agent and the reduced form of the molecule is water soluble, making it an effective and safe therapy as it is easily excreted in urine. (Image from Sigma Aldrich)
Figure 1: The structure of Penicillamine is shown above. The -SH group allows the molecule to act as a chelating agent. The reduced form of the molecule is water soluble, making it an effective and safe therapy as it is easily excreted in urine. (Image from Sigma Aldrich)

Zinc Therapy:

Zinc therapy is an oral therapy typically given in the form of zinc sulfate or zinc acetate. It’s a lifelong therapy, and it is recommended that the therapy be monitored with blood and urine tests at least twice a year. (Dziezyc et. al. 2014) Zinc therapy blocks the uptake of dietary copper from the intestinal tract by inducing a negative copper balance.(Brewer 2001) It also prevents the re-uptake of copper from bodily secretions in the gastrointestinal track such as saliva and gastric juices.(Brewer 2001) 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)

Zinc therapy has lower toxicity than typical chelating agents like Penicillamine and is therefore a very popular treatment. The main risks with zinc therapy are stomach upset and developing a copper defficiency.(Brewer 2001) When patients are treated appropriately, they should have free copper levels in their blood of 25 ug/dl as opposed to overtreatment where patients have less than 5 ug/dl in their serum.(Dziezyc et. al. 2014) Patients should also be excreting no more than 75ug/dl of copper in their urine every 24 hours—any more than that could lead to coppr defficiency.(Dziezyc et. al. 2014) Copper defficiency is dangerous because copper is required for so many of the body’s enzymes such as cytochrome C oxidase, copper zinc dismutase, and dopamine β-hydroxylase.

Decrease Dietary Copper Intake:

Humans get copper from their diet. It is not synthesized de novo in the body. Because Wilson’s Disease results in the accumulation of copper in vital organs and increased amounts of free copper in the serum, the easiest thing patients can do to help manage their Wilson’s Disease is decrease their dietary copper intake. The less copper the patient consumes, the less of it there is to cause problems. (Cleveland Clinic, Wilson’s Disease)

Wilson’s Disease patients avoid copper rich foods such as shellfish, liver, and initially even mushroom, nuts and chocolate. Sometimes during maintenance therapy once their disease is under better control, patients can reintroduce small amounts of mushrooms, nuts, and chocolate back into their diet. (Cleveland Clinic, Wilson’s Disease)

Liver Transplant:

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) Liver transplant works because it replaces the patient’s diseased liver with a new, healthy liver. (Rosencrantz and Schilsky 2011) Therefore, the genetic mutation that caused the patient’s ATP7B protein to become dysfunctional is no longer an issue in the new liver. With functional ATP7B proteins in their hepatocytes the patient is able to manage the copper in their body effectively. The basics of how a liver transplant works can be seen below in Figure 2. However, there is debate about when Wilson’s Disease has advanced enough to require a transplant.

Liver transplants also come with a new list of side effects and risks such as immunosuppression and potential rejection of the organ and many patients wait an extended period of time on transplant lists. Additionally, a liver transplant is only a temporary cure. Eventually the transplant liver may lose its function, and because the patient still has the Wilson’s Disease mutation in their body, another transplant will be required.

This figure shows the basics of a liver transplant. The Patient's diseased liver is removed
Figure 2: This figure shows the basics of a liver transplant. A portion of the donor’s liver is removed. The patient’s diseased liver is then removed and replaced with the donor liver. The donated liver must be reconnected properly in the patient for it to function. A liver transplant is the closest thing to a cure currently available for WIlson’s Disease, but it is only a short term cure. (Image from WebMD).

Other Pages on Wilson’s Disease:

Wilson’s Disease–Title Page

Wilson’s Disease–History and Metabolic Context

Wilson’s Disease–Molecular Basis of the Disease State

Wilson’s Disease–Conclusions and Proposals for Future Work

5 Replies to “Wilson's Disease–Treatments and Disease Management”

  1. If I am not mistaken, liver transplant is curative in Wilson’s disease because the pathogenesis is that the ATP7B gene mutation prevents expression of the copper transporting ATPase in the hepatocyte preventing copper excretion into the bile. This is why the copper levels increase in the body. By transplanting a liver you are providing the patient with a liver that has a functioning Cu-transporting ATPase and will therefore never have any issues with Cu accumulation. The problems seen in other parts of the body are simply due to Cu accumulation and associated oxidative stress as was said in the first section on WD. Therefore, no Cu accumulation in the liver means no Cu accumulation elsewhere in the body and thus no more WD. This is not to say that a transplanted liver may not fail for other reasons, but that WD will not recur in a transplanted liver. That being said, I also think that the amount of patients with WD that receive a liver transplant is very small due to few patients progressing to cirrhosis these days (not 100% sure on that though).

    1. I like your your discussion of transplant as a therapeutic. Wilson’s disease Patients with liver transplant can still present elevated serum copper, liver enzymes and persistent neurological symptoms/renal symptoms even with a new liver. So it’s not a total “cure” per-se, but certainly better off than the patient was initially (as the new liver can take on most of the copper metabolic burden that the old one could not). Like what Jason said, liver transplant (along with any graft) carries the risk of rejection and a whole other set of issues.

    2. Hi Jason and Dana! Thank you for taking the time to read and comment. Transplanting the liver does offer immense benefit and the closest thing we currently have available to a cure. Unfortunately, it is not a perfect cure. There are ATP7B proteins in the brain and kidneys that are still mutated and thus cause copper accumulation in those organs. Additionally, if the WD patient still has low ceruloplasmin, a liver transplant will not address that. Additionally, there are many risks associated with organ transplant and potential for rejection, It is also possible that the transplanted liver will eventually need to be replaced, too, especially if the initial transplant was done on the patient at a young age. You are correct that very few Wilson’s Disease patients currently receive transplants because we are detecting the disease earlier and we have more treatment management options now. Thanks!

  2. Hi Kelly,

    Thank you for the very clear disease management page- the succinctness really drives home the key points for both progression of the disease and treatment options. I was curious as to alternatives to chelating agents for the excretion of copper, and the capacity to modify the agents themselves so as to limit their toxic effects. Given the propensity of the -SH groups to bind copper, and the apparent long-term damage that can be done by exhaustive zinc therapy, do you believe there stands any reason to attempt a modified zinc cluster, with a thiol or other polar group, so as to reduce the amount of free floating zinc left behind after treatment? Are there other metal agents which you might view as being particularly useful for this task?

    1. Hi Anthony! Thank you for reading and commenting. The alternatives currently available to the chelating agents are zinc therapies, Zinc therapy is actually very well tolerated with only 10% of people experiencing gastric upset and the fact that it has an overall low toxicity. The only big risk is copper deficiency but monitoring treatments with blood and urine test twice a year tends to keep that in check. I am not familiar with an issue involving free floating zinc in the body. There have been a variety of chelating agents over the years with slightly modified structures, the first being B.A.L. Penicillamine was developed from these other chelating agents to address the issues that you point out, However, at this point it seems zinc therapy is overall a less toxic option that achieves the same result. Perhaps future research will address other possible chelators, but the research push in treatment right now seems to be hepatocyte transplantation and gene therapy. Thanks!

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