Wilson Disease: An Analysis of Newer Treatment Methods
Instructor:
Student:Shahnoza Kamalova
Abstract
Wilson disease is a disease in which copper is not properly metabolized in the body. The excessive amount of copper that builds up in the body will sometimes manifest itself through other disorders such as depression and bipolar disorder, particularly when it develops in children and teenagers. The disease can be treated and cured if it is properly diagnosed. There are a variety of treatments available for Wilson disease including various types of medications that individuals with the disease can take in order to help their bodies get rid of the excess copper in their systems. This brief paper will examine the different types of newer treatments that are available for Wilson disease in order to ascertain which treatments are the best. The paper will also examine the treatments that are available which help to treat concurrent diseases such as depression and bipolar disorder. It is hypothesized that there will be a few different new treatments which are effective in treating the disease, and that the treatments that are the most effective in treating Wilson disease will also treat any concurrent issues that present themselves in the individuals who are afflicted with the disorder.
Wilson disease is an interesting one because the side effects of the disease can appear as mental disorders such as bipolar disorder and depression. The disease itself is “a genetic disease that prevents the body from removing extra copper. Normally, the liver filters extra copper and releases it into bile. In Wilson disease, the liver does not filter copper correctly and copper builds up in the liver, brain, eyes, and other organs” (2016, 533). The disease has a variety of treatments available, but it is unclear what the best treatment for the disease is and whether or not the newer treatments are more effective in treating the disease. Further, it is unclear as to what treatments are best for the disease when considering the potential side effects of the disease.
Wilson disease prevents the liver from filtering extra copper from the body, so rather than being removed from the body, the extra copper builds up in the eyes, brain, liver, and other organs (Baglikar, 2016, 533). It was discovered by Samuel Alexander Kinnier Wilson in 1912 when the British neurologist described the condition for the first time. Wilson disease is very rare, and is the only case in which dietary copper can be toxic to human beings (Baglikar, 2016, 533). Copper is essential for human beings to survive because it is a necessary part of cuproproteins. It is absorbed in the intestinal tract and then taken to the liver and to the bone marrow (Baglikar, 2016, 533). Baglikar states, “In the liver it is incorporated into a copper-protein complex called ceruloplasmin which then circulates in the blood stream. Cuproprotein enzymes are needed for the proper utilization of iron and for the manufacture of hemoglobin and red blood cells in the bone marrow” (2016, 533). When Wilson disease is present, copper builds up in the liver and other organs, causing liver damage. The disease is sometimes slow and progressive and sometimes very severe. Wilson disease will also cause damage to the brain and nervous system, which manifests itself in a variety of potential mental disorders (Baglikar, 2016, 533). People usually get more copper from the food that they eat than they require, but are able to filter it out through the liver (Baglikar, 2016, 533). People with Wilson disease are unable to filter out the excess copper, which is why it will build up in the system.
People who have Wilson disease are lacking a protein which allows for the body to transport copper. A person with Wilson disease will not be able to release the excess copper in their bodies into the bile as a normal person would be able to. The copper builds up in the liver first, and then when the liver has been sufficiently damaged and cannot contain any more copper, it ends up releasing the copper into the bloodstream where it will begin to build up in the other organs of the body. The disease is fatal unless it can be detected and treated before the person begins to experience copper poisoning. One in 30,000 people throughout the world have Wilson disease (Baglikar, 2016, 533). This means that these individuals need to be treated for their Wilson disease as well as any neurological symptoms that they are displaying in order to fully address the problems that are associated with the disease.
Wilson disease is a disease that is most commonly found in southern Italian people, Sicilians, and eastern Europeans. Usually people are under 40 years old when they begin displaying symptoms of the disease, and children who display the disease are under 4 years old. The signs and symptoms of Wilson disease typically include hepatic dysfunction, cirrhosis, chronic active hepatitis, and fulminant hepatic failure (Baglikar, 2016, 534). Those who display fulminant hepatic failure will have signs such as spider nevi, digital clubbing, ascites and prominent abdominal veins, jaundice, hematemesis, and neuropsychiatric features. The patients with neuropsychiatric features are the ones whose Wilson disease has progressed to the point where they have developed cirrhosis of the liver (Baglikar, 2016, 534). The symptoms of Wilson disease can include changes in personality, clumsiness with one’s hands, masklike facies, excessive salivation, difficulty speaking, and ataxia. Due to improvements that have been made to diagnosis and treatment procedures, the late stage symptoms which follow rarely occur: spasticity, rigidity, flexion contractures, grand mal seizures, and dystonia (Baglikar, 2016, 535). The psychiatric issues associated with Wilson disease occur within 10-20% of the patients, and include disinhibition, impulsiveness, self-injurious behavior, an emotional lability. The behaviors can be categorized as cognitive, affective, behavioral, or schizophrenic-like (Baglikar, 2016, 535). Wilson disease is a rare disease with the psychiatric manifestations being a rare outcome of the disease.
Wilson disease can be diagnosed in a variety of ways, but patients tend to display the following during tests. In approximately 90% of Wilson disease patients, serum ceruloplasmin levels are lower than 20mg/dL. Average people will excrete 40mcg/day of copper, but people with Wilson disease tend to excrete 100mcg/day or more. Patients who have Kayser-Fleischer rings will have serum ceruloplasmin levels of lower than 0 mg/dL and a 24 hour urine copper excretion of greater than 40 mcg/day (Baglikar, 2016, 535). Baglikar claims, “Hepatic copper concentration (criterion standard) on a liver biopsy specimen is >250mcg/g of dry weight even in asymptomatic patients; a normal result (15-55mcg/g) effectively excludes the diagnosis of untreated Wilson disease” (2016, 535). A hepatic copper metabolism can be directly assayed by radiolabeled copper. Genetic testing can determine if an individual has Wilson disease as well. Brain imaging with early lesions can be detected through a CT scan, which is indicative of Wilson disease (Baglikar, 2016, 535). Once an individual has been diagnosed for Wilson disease, they must be treated for both the disease and the psychiatric manifestations associated with the disease if psychiatric manifestations have occurred in the patient.
In order to understand the treatments of Wilson disease and which ones work best for treating the disease, it will be necessary to analyze the effectiveness of the various types of treatments as well as how well the treatments interact with specific concurrent diseases. For example, experiments have been done to test the effectiveness on treating Wilson disease and bipolar disorder using olanzapine and lithium (Kar et al., 2015). There are other medical therapies that will be analyzed in order to see what treatments are most effective for Wilson disease. This brief paper will contribute to literature about the effectiveness of the different treatments of Wilson disease. The specific question that this paper will be examining is, “What is the best method of treatment for Wilson disease?” A follow up question is, “Does the effectiveness of certain treatments vary depending upon the concurrent disease that is accompanying the Wilson disease in the patient?”
Research Details
Wilson Disease Defined
Wilson disease is a disorder related to the metabolism of copper in the body, following an autosomal recessive pattern (Kar et al., 2015, 110). Specifically, Kar et al. claim that Wilson disease is a disorder in which there is tissue damage in the neurons due to, “the accumulation of copper gives rise to diverse neurobehavioral symptoms. The basal ganglia, especially the caudate nucleus and putamen, are usually involved in Wilson disease, and in later stages there may be cavitation in the putamen as well as frontal lobes” (2015, 110). There are different psychiatric problems which can develop in people who have Wilson disease, but depression is the most common psychiatric development. At some point while affected by Wilson disease, patients will display behavioral problems. Bipolar affective disorder is also a common manifestation of psychiatric issues associated with Wilson disease (Kar et al., 2015, 110). Many people who have Wilson disease require treatments for the symptomatic psychiatric disorders that they develop alongside the disease itself.
Treatment for Wilson Disease
Treatment for Wilson disease can sometimes involve chelation treatment or liver transplantation depending upon how severe the Wilson disease is in the patient (Weiss & Stremmel, 2014, 81). According to Weiss and Stremmel, “Current guidelines demand lifelong medical treatment, as the copper uptake cannot be controlled by a low-copper diet” (2014, 81). People who quit treatment for Wilson disease typically will run the risk of developing neurological deterioration or intractable hepatic deterioration. Sequential treatments will differentiate between initial de-coppering therapy and maintenance therapy. After initial aggressive treatment to address the high amounts of copper in the body, reductions to the dosage of the chelating drug or treatment approaches using zinc can be less toxic for the patient during treatment (Weiss & Stremmel, 2014, 81). Clearly, medical professionals are seeking a treatment for Wilson disease that is effective and continues to treat the disease after the initial issues have been addressed, but is not as toxic to the patient as the initial treatment needs to be in order to get the body to dump the excessive amounts of copper that are trapped in the body safely out of the system.
Treatment for Concurrent Diseases
Literature suggests that, for example, the bipolar disorder alongside Wilson disease should be treated using mood stabilizers. The treatment is suggested based on the logic that disturbances in how the brain networks develop will cause the emotional behavior of a person to be modified. This leads to “abnormal connections between ventral and prefrontal networks and limbic brain regions, especially the amygdala” (Kar et al., 2015, 110). This means that the use of medication is recommended for people who have bipolar disorder alongside Wilson disease because there are issues with the connections in the brain that prevent people from having appropriate emotional responses. Mood stabilizers for bipolar disorder can treat the emotional symptoms that are caused by Wilson disease.
D-Penacillamine
In a study of Iranian children suffering from Wilson disease, 62 patients were admitted to the children’s medical center in Tehran, Iran between 2003 and 2012. The average diagnosis age for the children was 9 years old, but the patients were between 5 and 17 years old. Approximately 56% of the patients were male (Najafi et al., 2014, 25). According to Najafi et al., “64.5% of the patients had the hepatic symptoms at the time of diagnosis and he most common type of hepatic involvement was cirrhosis (39.3%) and hepatitis (17.5%) respectively. 17.7% of the patients also had early neurological symptoms” (2014, 25). In this study, the patients were on the high side of the percentage in which neurological symptoms will develop in people who are afflicted with Wilson disease.
Evaluation measures were found to be important in the Iranian study, as 27.4% of the patients were discovered to have had Wilson disease. Approximately 83.9% of the patients in the study were successfully treated using D-penicillamine, but there were also adverse drug reactions to the medication in 30% of the patients (Najafi et al., 2014, 25). Regarding this study, it can be concluded that the treatment using D-penicillamine is an effective form of treatment for Wilson disease, but it is also toxic for the patients. This agrees with previous information which was mentioned about beginning treatment for Wilson disease with an aggressive treatment method, and following it up with something less aggressive during the maintenance stages of the disease so that the medication is not poisoning the individual and causing them more damage than help with the treatment of their disease.
Although D-penicillamine is an aggressive medication for Wilson disease, it is a treatment that is typically heavily relied upon because it is a reliable treatment method that helps patients to get positive results from their treatment. For example, in a study of Wilson disease with patients who were experiencing manic symptoms, when the patients stopped taking D-penicillamine as part of their treatment manic episodes occurred while patients who added D-penicillamine to their treatment experienced symptom improvement with their disease (Kenar & Menteseoglu, 2014, 381). This particular study acknowledged that the psychiatric symptoms associated with Wilson disease will tend to develop in 50% of the patients before they are diagnosed with Wilson disease (Kenar & Menteseoglu, 2014, 381). The study completed by Kenar and Mentesoglu asses the case of a 22 year old female patient who was diagnosed with Wilson disease when she was 5 years old.
In this case study, the female presented with her first depressive attack accompanied by psychotic symptoms when she was 15 years old. When the patient turned 18, she received a diagnosis of bipolar affective disorder because she had had a manic episode as a result of discontinuing her treatment with d-penicillamine (Kenar & Menteseoglu, 2014, 382). Kenar and Meneseoglu assert, “A year later, she was hospitalized with a second manic episode as a result of irregular treatment. She was prescribed 1000mg/day valproic acid, 400mg/day quetiapine, 1mg/day risperidone, 300mg/day d-penicillamine and 1 capsule/day zinc sulphate for maintenance therapy” (2014, 382). The patient’s d-penicillamine treatment was slowly increased to 600mg/day, and showed remission of her manic symptoms after two weeks of being on this treatment. The patient’s manic symptoms remained in remission for two years after beginning a regular regimen of medications which included d-penicillamine in the treatment (Kenar & Meneseoglu, 2014, 382). The authors found that the d-penicillamine used to treat the patient was able to address the copper that was freely flowing in the patient’s system and affecting her neurons (Kenar & Meneseoglu, 2014, 382). In other words, the patient’s mania was being triggered by the copper that was flowing in her system because she did not have a medication that was dumping the copper from her body included in her treatment. Therefore, the d-penicillamine, although a rather toxic medication, was required for the maintenance of homeostasis in this patient because her mania was triggered by the excessive amount of copper in her body. She was a case which could not simply use maintenance drugs to prevent her system from receiving the effects of copper poisoning because the copper was so severe that she needed to continue the d-penicillamine treatment in order to make sure that her neurons were not being affected by her disease.
Alternatives to D-Penacillamine
Patients who have mild hepatic symptoms should not take d-penicillamine if they can avoid doing so, and should take trientine and zinc salts before starting a d-penicillamine treatment to see if the milder treatment is effective on the patient. The d-penicillamine treatment, although effective, can be toxic itself and should be used as a last resort for people who have hepatic symptoms that are moderate to severe (Weiss & Stremmel, 2014, 82). Weiss and Stremmel assert, “In patients with hepatic disease with or without the presence of acute hemolytic anemia, the degree of the hepatic disease determines the further treatment” (2014, 82). Weiss and Stremmel place a lot of importance on the level of hepatic symptoms involved in the treatment process because of the importance to the level of medication that is going to be used while the patient is being treated.
Lithium and Olanzapine
Some patients with bipolar affective disorder can be treated using a mood stabilizer on their symptoms. In a study completed by Kar et al. (2015), the patient in the study had moderate depressive episodes of mania within the 5 year period prior to treatment, and lithium was used to treat the episodes because the patient had had a good response to lithium in the past. However, the patient had poor response to lithium alone in the past, so olanzapine was added to the treatment, which is an antipsychotic medication (Kar et al., 111). By adding the antipsychotic medication, the patient was able to have a positive response to the lithium treatment. According to Kar et al., “Evidences suggest lithium’s interference in the intracellular signaling pathway by inhibiting the glycogen synthase kinase-3beta, which is a pro-apoptotic enzyme. Lithium’s neuroprotective role is mediated by its anti-apoptotic activity” (2015, 111). Lithium is able to stabilize the mood of patients who experience bipolar affective disorder in addition to Wilson disease, but it is important that patients be evaluated on a case by case basis so that they are receiving the proper treatment for their Wilson disease and psychiatric disorder. Patients all react differently to certain medications and dosages, and therefore it is important for doctors to experiment with different medications in order to provide their patients with the proper treatment for their disorder.
Implications
Research has indicated that there is no optimal medication regimen for Wilson disease, and that it is more likely that an optimal dosage will be created before an optimal regimen is created because of the varied effects that medical treatment can have on different people and on different levels of the disease. For future study, researchers propose a registry for the various medication combinations so that physicians can take a statistical approach to finding the best medication regimen for those affected by Wilson disease in the future (Weiss & Stremmel, 2014, 84). Weiss and Stremmel assert, “A prospective registry-based approach would be tremendously helpful and necessary for analysis of the various drugs and dosages. Of course, future studies should determine hard clinical endpoints like survival or discontinuation of therapy due to adverse events” (2014, 84). A detailed assessment of how copper is presenting in the patient based on their treatment, as well as an analysis of the symptoms that they are displaying, would also be beneficial in the statistical analysis (Weiss & Stremmel, 2014, 84). Although there is no optimal treatment for Wilson disease due to the different ways that the disease can present itself in a patient and the individual body chemistry that each patient will have, a registry is an excellent solution for finding an appropriate treatment for people with Wilson disease. If this registry includes information about the symptoms that the patients were presenting, physicians will be able to compare the symptoms that their patients are currently experiencing in order to match the patient with a treatment which is the most likely to work for them from the beginning of their treatment. The physician can then make adjustments to the treatment based on the patient’s individual reactions, which can also be added to the database.
Discussion and Summary
Wilson disease occurs as a hereditary disease in which people are unable to properly metabolize copper in their body. One of the manifestations of Wilson disease are psychiatric disorders which occur concurrently with the disease due to the copper build up that takes place in the organs, and neurons of the brain. People with Wilson disease may require treatment for mental health issues in addition to the disease itself.
There is no specific treatment that works best for Wilson disease because the optimal treatment is dependent upon how the disease manifests in the individual, as well as how severe the disease is for the patient. The following conclusions can be drawn about treatment for Wilson disease:
• Patients with mild hepatic symptoms should not take d-penicillamine before attempting to use trientine and zinc salts as their treatment.
• Severe cases of Wilson disease should use d-penicillamine consistently in their treatment and make sure not to stop their treatment regimen.
• Patients with concurrent psychiatric disorders can benefit from taking mood stabilizing drugs such as lithium and antipsychotics such as olanzapine in order to obtain relief from their psychiatric symptoms that occur with the disease.
There is no treatment that is necessarily best for everyone, and therefore it is recommended that a registry of treatments is developed so that physicians can make decisions about treating their patients with Wilson disease based on the concurrent diseases that are presenting in the patients, as well as the severity of the disease. Medicating for Wilson disease is not an exact science, but it can become more precise and helpful to patients over time.
References
Bagilkar, V. V. (2016). Wilson disease. Asian Journal of Nursing Education and Research, 6(4), 533. doi:10.5958/2349-2996.2016.00099.9
Kar, S., Pundhir, A., Tripathi, P., Goyal, P., & Singh, A. (2015). Can the combination of lithium and olanzapine be an effective treatment strategy in the management of bipolar disorder with Wilson′s disease? International Journal of Nutrition, Pharmacology, Neurological Diseases, 5(3), 110. doi:10.4103/2231-0738.158376
Kenar, A., & Menteseoglu, H. (2014). Manic episode induced by discontinuance of D-penicillamine treatment in Wilson’s disease. Klinik Psikofarmakoloji Bulteni, 24(4), 381. doi:10.5455/bcp.20131021025658
Najafi, M., Alimadadi, H., Arastoo, L., Motamed, F., Khodadad, A., Fallahi, G., … Doroudian, R. (2014). The clinical manifestations, treatment efficacy and adverse drug reactions in 62 Iranian children with Wilson disease. International Journal of Pediatrics, 2(3), 25-29.
Weiss, K. H., & Stremmel, W. (2014). Clinical considerations for an effective medical therapy in Wilson’s disease. Annals of the New York Academy of Sciences, 1315(1), 81-85. doi:10.1111/nyas.12437