Wilson’s disease: a complex picture
Wilson’s disease is a rare inherited metabolic disorder that causes thebody to retain copper. Here is described a case of Wilson’s diseasethat proved particularly challenging from a therapeutic viewpoint
Wilson’s disease is a rare inherited metabolic disorder that causes the body to retain copper.
Here is described a case of Wilson’s disease that proved particularly challenging from a therapeutic viewpoint
Wilson’s disease is a rare hereditary disorder of copper metabolism, with an estimated prevalence of 1 in 30,000.1
It is caused by a defect in an enzyme that enables ingested copper to be excreted from the body by the liver. As a result, the liver fails to release copper into bile, leading to its accumulation in liver cells.
When these become saturated, copper moves into the blood and is deposited in other tissues, particularly the brain and eyes (see Box 1). Copper is toxic to bodily tissues and, left untreated, Wilson’s disease can cause severe brain damage, liver failure and death.
This case report describes a complex case of Wilson’s disease treated at Southampton General Hospital.
Box 1: Characteristics of Wilson’s disease1,2
Symptoms usually appear between the ages of six and 20 years but can begin as late as age 50. The clinical features of Wilson’s disease are a direct result of copper deposition in various tissues.
Copper deposition in the eyes leads to the appearance of Kayser-Fleischer rings (copper-coloured rings surrounding the iris). They are usually only seen on slit-lamp examination, but if dense can be detected with the naked eye.
Deposition of copper in the brain causes neurological symptoms including tremor and other abnormal movements, ataxia, seizures, dementia, psychiatric problems and speech and swallowing difficulties. Other manifestations of copper toxicity include heart failure, infertility and joint pain.
Diagnosis of Wilson’s disease is based on clinical suspicion together with the finding of Kayser-Fleischer rings on slit-lamp examination, and characteristic abnormalities of laboratory results. Blood tests reveal low levels of caeruloplasmin, the protein that binds copper to remove it from the body.
A suppressed level of caeruloplasmin is present in over 80% of patients with the disease and plasma caeruloplasmin levels are typically less than 30% of normal.
Also, patients usually have high levels of urinary copper. Serum copper is not an indicator for Wilson’s disease as it is affected by the levels of caeruloplasmin and can actually be low when caeruloplasmin levels are low or elevated as a consequence of release of free copper from a damaged liver.
Untreated, Wilson’s disease is fatal. Treatment is aimed at removing excess accumulated copper and preventing its reaccumulation. Treatment options include the chelating agents D-penicillamine and trientine, and zinc. Therapy must be lifelong and initiated as soon as the diagnosis is suspected, since treatment delays can cause irreversible organ damage.
Wilson’s disease is a rarebut serious condition that can cause significant morbidity andmortality. There are effective treatment options available that canhalt disease progression, but evidence is lacking as to the mosteffective of these and the optimum treatment regimen for this condition.
This case highlights the importance of considering alternativetreatment options (which might be less well known or less favoured)when first-line therapy is ineffective.
Our patient responded poorly to D-penicillamine alone but did well on dimercaprol and penicillamine combined.
A 22-year-old, left-handed psychology graduate presented to the neurology department in July 2007. She complained of clumsiness of her hands and had begun dropping things.
She had also developed a tremor of her right hand and was having increasing difficulty writing. She noticed that at times her right hand would adopt unusual postures.
She also complained of gait disturbance and had begun to trip and fall. Her speech had become slurred but there were no sensory symptoms or headaches.
On examination, there was a fine resting tremor of the right hand. There was loss of manual dexterity and a paucity of fine finger movements. In the lower limbs there was mild heel-shin unco-ordination, particularly on the right side.
Examination of the eyes revealed bilateral copper-coloured rings around the iris, suggesting the possibility of Wilson’s disease. The patient was referred for slit-lamp examination, which confirmed the presence of Kayser-Fleischer rings.
Blood tests revealed low levels of caeruloplasmin (139mg/L; reference 210–620mg/L). Serum copper was slightly low at 9.2µmol/L (normal range 12–20µmol/L). Urinary copper was high at 15.8µmol/24h (normal <0.9µmol/24hr).
There was evidence of compensated chronic liver disease, with normal liver function tests, but a diffusely abnormal liver with probable cirrhosis on liver ultrasound scan. Taken together, and in the clinical context, these results were believed to be diagnostic of Wilson’s disease.
The patient was started on D-penicillamine, at a dose of 125mg twice a day, increasing by 125mg/week to 500mg mane and 375mg nocte.
Blood count and renal function were monitored (see Box 2) and remained normal throughout treatment. The patient was also started on pyridoxine, as penicillamine causes a reduction in vitamin B6 levels.
Ferrous sulphate was given for iron deficiency anaemia. Vitamin E was also prescribed as an antioxidant to replace the antioxidant properties of caeruloplasmin. Clonazepam was started for symptomatic control of her tremor and dyskinesias.1,5–7
Box 2: Penicillamine monitoring3,4
For patients with Wilson’s disease, full blood count and urine dipstick should be carried out before starting penicillamine treatment, then every one or two weeks for the first two months, and monthly thereafter, to detect blood disorders and proteinuria. Tests should also be carried out one week after any dose increase.
A reduction in platelet count requires treatment discontinuation with subsequent reintroduction at a lower dose and then, if possible, gradual dose increases.
Treatment can be continued provided that renal function tests remain normal, oedema is absent, and the 24-hour urinary excretion of protein does not exceed 2g.
Initially the patient showed a good response to treatment, with symptomatic improvement and a fall in urinary copper measurements.
However, following three months of treatment she returned with increasing tremor, worsening gait disturbance and frequent falls. She had developed dysphagia and marked dysarthria. She did not feel that the penicillamine was working and so requested an alternative medicine.
Penicillamine was stopped and trientine initiated. Trientine is usually reserved for patients who are intolerant of penicillamine, but in view of the patient’s marked neurological deterioration, it was deemed clinically appropriate.
Trientine was started at an initial dose of 300mg twice daily, to be increased by 100mg weekly to a target dose of 900mg twice a day.
Two months later the patient was admitted to hospital with further neurological deterioration, despite having reached a trientine dose of 900mg mane and 600mg nocte. Her mobility had deteriorated significantly and she was unable to walk unaided.
As a result of severe dysphagia and anorexia, she had lost over 6kg in weight. A nasogastric (NG) tube was inserted for enteral feeding and intravenous fluids were initiated to correct dehydration.
The patient was started on standard NG feeds (Nutrison Standard) to improve her nutrition. However, it transpired that the formula contained high levels of copper, and the feeds were therefore stopped due to fears they might exacerbate the underlying condition.
She was seen by a dietitian, who advised the need for a copper intake of less than 1.5mg per day. It was difficult to meet the patient’s energy requirements while restricting copper, so the dietitians suggested using paediatric feeds which contained the least amount of copper while adding additional calories to meet nutritional requirements.
The patient was also having problems swallowing her medicines. The trientine capsules could be cut open and added to water to allow ease of administration.
However, the trientine still needed to be given during a break in NG feeding. Because of continued difficulty with NG feeding, a percutaneous gastrostomy tube was inserted.
Aseptic services prepared a copper-free enteral feed using copper-free trace vitamins for use while the patient was in hospital (to allow us to reduce her copper levels and improve her condition). This had a limited expiry of four hours so the dietitian designed a feeding regimen around this.
On discharge the patient was started on Maxijul, a high carbohydrate food supplement with minimal copper, to help maintain her weight.
Another treatment option
In view of her ongoing deterioration, alternative therapeutic options were sought. A Wilson’s disease specialist in Sheffield, who had been involved in the patient’s care from the beginning, suggested the use of dimercaprol.8
On specialist advice, the trientine was stopped and penicillamine was restarted at a dose of 500mg mane and 250mg nocte, because there was little evidence or experience to support the use of dimercaprol with trientine.
The penicillamine tablets were crushed and given via the gastrostomy tube. The recommended dimercaprol dose was 300mg/day for five days of the week. The total dose was divided into three 100mg injections (2ml) given every eight hours because of the medicine’s short half-life.
In total the patient received a two-month course of dimercaprol. Her symptoms vastly improved and her urinary copper measurements fell significantly. She remained on clonazepam as symptomatic treatment of her tremor and dyskinesias, and procyclidine was added to combat the problems of tolerance with long-term use of clonazepam.
Her penicillamine was also continued, and she was monitored as an outpatient with the required blood tests, as well as urinary copper measurements to determine treatment efficacy.
Wilson’s disease is a severe condition that can cause significant morbidity and mortality. However, early recognition and treatment can prevent accumulation of copper in tissues and therefore prevent the occurrence of complications.
Treatment options include the chelating agents D-penicillamine and trientine, and zinc.
Penicillamine has been used traditionally as an immunosuppressant in rheumatoid arthritis. In Wilson’s disease it acts as a chelator, binding to free copper ions, thus preventing their deposition in tissues, and leading to increased urinary copper excretion. Treatment with penicillamine results in symptomatic improvement for most patients.2
Side effects of penicillamine include potentially life-threatening blood disorders, and blood monitoring is therefore essential (see Box 2 and Box 3). If thrombocytopaenia occurs penicillamine must be discontinued, but it can be reintroduced at a lower dose once the platelet count normalises.
Immune complex nephritis occurs in up to 30% of patients; patients therefore should be monitored for proteinuria (Box 2).
Nausea can occur but is not usually a problem provided that penicillamine is taken before food or at bedtime and that low initial doses are used and increased gradually.1,3,4
Box 3: Side effects of Wilson’s disease treatments3
|Penicillamine||Nausea, anorexia, fever, skin reactions, delayed rashes (considerwithdrawing treatment), taste loss (mineral supplements not recommended)|
Blood disorders: thrombocytopaenia, leucopaenia, agranulocytosis, aplastic anaemia
Renal effects: proteinuria, rarely haematuria (withdraw immediately), haemolytic anaemia, nephrotic syndrome
|Trientine||Nausea, rash, rarely anaemia|
|Dimercaprol||Hypertension, tachycardia, malaise, nausea, vomiting, salivation,lacrimation, sweating, burning sensation (mouth, throat, eyes), feelingof constriction of throat and chest, headache, muscle spasm, abdominalpain, tingling of extremities, pyrexia (in children), local pain andabscess at injection site, haemolysis (in patients withglucose-6-phosphate deficiency)|
Trientine is used as second-line therapy for the treatment of Wilson’s disease. It works in the same way as penicillamine — as a copper chelator.
Unlike penicillamine, it has to be taken on an empty stomach (at least one hour before meals or two hours after) because food significantly reduces its absorption (from 20–30% to 2%). It has few side effects.9
Trientine is usually used in combination with zinc, which helps prevent gastrointestinal absorption of copper. There have been anecdotal reports that zinc itself can lead to neurodegeneration.8
It was decided not to use zinc at any stage of the patient’s treatment because of her already considerable neurological symptoms.
Dimercaprol is usually used as a chelator to treat heavy metal poisoning.3
It is electrically uncharged and is probably able to cross vascular and cellular membranes more readily than penicillamine, which has charged carboxyl and amino groups.
Dimercaprol may therefore accelerate the removal of copper from brain tissue and may be used together with penicillamine for patients who remain symptomatic or show deterioration with penicillamine alone.
Dimercaprol is given as an intramuscular injection, which is particularly useful for patients with significant dysphagia who cannot readily take oral medicines, such as our patient.9,10
Because dimercaprol is suspended in peanut oil, patients need to be checked for peanut allergy before starting therapy. The half-life of the drug is short, with complete excretion within four hours.
Dimercaprol chelates copper, but if the dimercaprol-copper complex is oxidised, the copper is released and can exert its toxic effect again.
The dose of dimercaprol must be high enough to ensure there is an excess of free dimercaprol in body fluids until the copper is excreted. Hence, it must be administered three times a day.
Concurrent administration of medicinal iron with dimercaprol results in the formation of a toxic complex that can cause nephrotoxicity. If iron deficiency is present its treatment should be postponed until therapy with dimercaprol has been discontinued for at least 24 hours.9,10
For this reason the ferrous sulphate treatment for our patient was discontinued.
Dimercaprol is not a practical lifelong treatment for Wilson’s disease due to the pain involved with the injections and the risk of bleeding or abscesses. In addition, a dose of 300mg would require three 2ml injections per day, which creates difficulties in injection-site rotation.11
Accordingly, dimercaprol is best used in courses of several weeks, with periods of interruption, to bring severely ill patients back to a state of good health.
The management of Wilson’s disease relies largely on tradition, with limited evidence to support treatment decisions.
There are randomised controlled trials currently being undertaken in the US to compare the efficacy of zinc, trientine and tetrathiomolybdate (another chelator, currently unavailable in the UK) in Wilson’s disease patients with liver or neurological involvement.2
There is also EuroWilson — a European project that is collecting data on newly diagnosed patients with Wilson’s disease — although it is focused mainly on paediatric patients.7
These studies will hopefully provide us with evidence-based guidance on the management of this rare but treatable condition. Currently drug choice and treatment decisions are made on a case-by-case basis using expert knowledge and case study guidance. In our patient, dimercaprol was used instead of zinc based on a single case report.8
This case highlights the importance of considering alternative treatment options when first-line treatment is ineffective and emphasises that failure of first-line agents to arrest progression of symptoms does not necessarily mean that lesser known and less favoured agents will also fail. Our patient responded poorly to penicillamine alone but did extremely well on dimercaprol and penicillamine combined.
Victoria Lee is specialist pharmacist for diabetes and Emyr Morgan is neurosciences care group lead pharmacist, both at Southampton General Hospital.
Joanna Kitley is specialist registrar in neurology, Wessex Neurological Centre, Southampton General Hospital.
1 Wilson’s Disease Association. www.wilsonsdisease.org (accessed 8 April 2009).
2 Green C, Maher J. Caeruloplasmin: the Copper Chameleon (accessed 15 April).
3 Joint Formulary Committee. British National Formulary. 57th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.
4 Alliance Pharmaceuticals Ltd. Distamine. Summary of product characteristics. January 2009 (accessed 8 April 2009).
5 National Institute of Neurological Disorders and Stroke. Wilson’s disease information page (accessed 8 April 2009).
6 Worldwide Education and Awareness for Movement Disorders (accessed 8 April 2009).
7 EuroWilson (accessed 8 April 2009).
8 Walshe JM, Munro NA. Zinc-induced deterioration in Wilson’s disease aborted by treatment with penicillamine, dimercaprol, and a novel zero copper diet. Archives of Neurology 1995;52:10–1.
9 Sweetman SC (ed). Martindale: The Complete Drug Reference. 35th ed. London: Pharmaceutical Press; 2007.
10 Sovereign Medical. Dimercaprol Injection BP. Summary of product characteristics. June 2003 (accessed 15 April 2009).
11 Scheinberg IH, Sternlieb I. Wilson’s disease. In: Smith LH Jr (ed). Major Problems in Internal Medicine. Philadelphia: WB Saunders Company; 1984. Vol 23, pp145–8.
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