Treatment of Wilson’s disease: our patients deserve better

This editorial represents my opinion on the best management of treatment for Wilson’s disease (WD) following 40 years of experience. Unlike many rare inherited diseases, there are multiple effective drugs available for the treatment of WD. However, there are various presentations and stages of WD that have different optimal therapies in my opinion, thus leading to a certain amount of complexity in treating the disease. This complexity is not understood by many physicians treating WD patients. It is my view that currently some patients are being inappropriately treated, leading to unnecessary patient damage and even death. I have spent the last 40 years of my career developing new treatments, and evaluating old treatments, for WD, and claim considerable expertise in this area. I believe there are two situations where treatment is mismanaged. It is my intention in this editorial to point out what I consider to be the two treatment errors harmful to patients, and to discuss misunderstood aspects of the various drugs. First, I shall give a quick primer on WD for those not familiar with the disease [1]. It is inherited as an autosomal recessive, and is rare, occurring in about 1 in 40,000 births in most populations, with probably around 10,000 patients in the U.S. It is therefore, an orphan disease. The gene that produces ATP7B is mutated in this disease. ATP7B is an ATPase enzyme that is a critical part of the path that causes excretion of copper from the liver into the bile for loss in the stool, thereby keeping copper excretion in balance with copper absorption. With their copper excretory path crippled, WD patients accumulate a little copper every day of their lives. The extra copper is stored in the liver for a time, but eventually the liver storage capacity is exceeded. The liver becomes damaged, and about half the patients present with liver disease, such as hepatitis and/or cirrhosis, and occasionally, acute liver failure. The liver damage may be subclinical, and copper accumulates in other organs, with certain areas of the brain being most sensitive. These are areas of the brain that coordinate movement, and about half the patients (the half that doesn’t present with liver disease) present with a movement disorder, with tremor, dystonia and coordination problems, becoming progressively severe if not treated. As the disease progresses these patients have increasing difficulty with speech, sometimes swallowing, eventually develop abnormal body positions, and have difficulty in walking. Both the liver presentation and the neurologic presentation tend to occur in the second and third decades of life, although the age of presentation can be quite broad for occasional patients. Walshe introduced the first orally effective anticopper drug, penicillamine, for the treatment of WD in 1956 [2]. This drug revolutionized the treatment of WD and a generation of WD patients owed their survival to this drug. Penicillamine acts by chelating and mobilizing copper and causing its excretion in the urine. Because some patients couldn’t take penicillamine due to severe side effects, later Walshe [3] introduced trientine as another chelator, which like penicillamine, bound copper and caused its excretion in the urine. It too has some serious side effects, but at a lower frequency than penicillamine.