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 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.
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)
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.
Other Pages on Wilson’s Disease: