Transplant livers in wilson's disease for hepatic, not neurologic, indications

We are very concerned by the report entitled, “Liver Transplantation for Wilson’s Disease: A Single-Center Experience” which appeared in your journal (vol 5, pp 467-474, November 1999).1 Throughout the article, the authors infer, and in some places outright claim, that orthoptic liver transplantation (OLT) is an effective, and perhaps advantageous, way to treat the neurological symptoms of Wilson’s disease. For example, the last sentence of the abstract: “Earlier transplantation in patients with an unsatisfactory response to medical treatment may prevent irreversible neurological deterioration and less satisfactory improvement after OLT.” This statement leads to a risk that OLT will be used to manage neurological symptoms; in our opinion, this would be a serious mistake. The authors are apparently unaware that OLT is simply another anticopper therapy as far as neurological symptoms, other than hepatic encephalopathy, are concerned. The risks of morbidity and mortality from needless transplantation resulting from such assertions are of concern. The neurological symptoms of Wilson’s disease are caused by copper toxicity in specific areas of the brain, areas that coordinate movement.2,3 Any approach to reducing copper levels below toxic levels will stop further copper damage at that point, but symptoms arising from that damage will not begin improving until 5 to 6 months later, and will continue to improve for another 18 months (24 months from initiation of anticopper therapy).2,4,5 In other words, anticopper drugs and OLT have no direct effect on the neurological symptoms, they only control copper. The brain has to repair itself, and will, slowly, to the extent that damage isn’t irreversible. The authors speak of “an unsatisfactory response to medical treatment” and suggest that “earlier transplantation” “may prevent irreversible neurological deterioration.” If “an unsatisfactory response to medical treatment” means the failure to respond in the first 6 months, this is simply the natural history of the repair of the injury. None of the brain damage from copper toxicity will have repaired itself enough to allow symptomatic improvement during the first 5 to 6 months of anticopper therapy.5-7 It is not valid to claim an unsatisfactory response to medical therapy during this period. Yet, if they are transplanted during this period, they will likely then improve (being in the 6to 18month window when neurological improvement occurs), appearing to justify the authors’ concept that OLT has done something beyond what anticopper drugs are able to do. If “an unsatisfactory response to medical treatment” means the persistence of symptoms, sometimes quite disabling, after 2 years of therapy, these symptoms are permanent and will not be helped by any anticopper therapy, including OLT.2,4-7 The authors seemed to have bumped into this phenomenon in some of their patients, but attribute the problem to patients not receiving transplants early enough, rather than to some patients simply having relatively severe and permanent damage. There is one caveat to this discussion, and that is, we are not talking about using penicillamine for initial treatment of neurologically presenting Wilson’s disease patients. Penicillamine should never be used in this setting because it causes 50% of patients to get worse neurologically, and 25% never recover.8 The great risk from the authors’ report is that some physicians, following their advice, are going to have patients undergo transplants for the wrong indications and, therefore, needlessly. For the last 20 years, one of us (G.J.B.) has struggled to improve the therapy of Wilson’s disease and has seen and treated 250 patients, 100 of whom were referred for initial neurological treatment. Based on that experience, we offer the following guidelines: