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Wilson's disease: from the liver to the brain

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VOL: 97, ISSUE: 30, PAGE NO: 38

RACHEL TAYLOR, MSc, RGN, RSCN, is research nurse, paediatric liver transplantation at King's College Hospital, London

ANIL DHAWAN, MD, FRCPCH, is consultant paediatric hepatologist at King's College Hospital, London

RACHEL TAYLOR, MSc, RGN, RSCN, is research nurse, paediatric liver transplantation at King's College Hospital, London

Wilson's disease (WD) is a rare but potentially treatable condition with an estimated incidence of one in 30,000 (Schilsky, 1996). It usually presents in childhood, but about 30% of patients are adults when they are diagnosed. The symptoms are diverse, which means that nurses in all specialties could find themselves caring for a patient with the condition.

In 1912, Kinnear Wilson first described the progressive degeneration of lenticular nuclei with associated liver cirrhosis when he was reviewing a series of autopsies. He stated that the disease was 'familial, invariably fatal [and caused by] a toxin generated in connection [with] the hepatic cirrhosis that is always found after death' (Wilson, 1912). Thirty-six years later Cummings (1948) identified that toxin as copper.

The chemical dimercaprol, a chelating agent that removes heavy metals from the body which is also known as British anti-lewisite or BAL, was used as a treatment. But it had to be administered by injection and had severe side-effects, such as nephrotoxicity.

Eight years later Walshe (1956) developed penicillamine, another copper-removing agent, as the standard treatment for patients with WD. Although the familial nature of WD had been noted by Wilson (1912), it was only in 1985 that the defect was ascribed to chromosome 13, and the candidate gene (ATP7B) was cloned in 1993 (Scheinberg and Sternlieb, 1996; Tanner, 1999).

Normal copper metabolism

Normal copper intake in the western diet is about 2-5mg a day. Copper binds to a protein, metallothionein, in the enterocyte and is absorbed mainly in the duodenum. The copper molecules bind with amino acids, polypeptides and albumin and are transported to the liver.

Copper in the liver cells aid various enzyme processes and excess copper is excreted from the liver in bile. The role of copper in the body is shown in Box 1. About 50% of metabolisable copper is stored in the muscles and bone, 15% in the liver and the remainder in the brain, heart and kidneys (Sokol and Narkewicz, 2001).

The liver is central to copper homeostasis. The hepatocytes sense the copper status in the blood and regulate its excretion. This is mainly through biliary excretion or by binding the copper to caeruloplasmin, although eight other carriers have been identified.

Caeruloplasmin is a glycoprotein synthesised by the hepatocytes independent of the amount of copper. Copper binds to caeruloplasmin, which enables renal excretion. Excretion through the biliary system depends on glutathione and the ATP7B protein. Bound copper in the bile cannot be reabsorbed in the intestine, ensuring faecal excretion (Loudianos and Gitlin, 2000).

Pathophysiology

The exact pathogenesis of copper accumulation in WD is unknown but the main hypotheses (Sokol and Narkewicz, 2001) are:

- Diminished synthesis of caeruloplasmin by the liver. As a singular cause, this does not explain the accumulation of copper because 5-25% of patients with WD have normal caeruloplasmin, while patients with acaeruloplasminaemia, a congenital deficiency, have no excess copper;

- A block in transfer at the site of the hepatocyte uptake to the lyosomes. This might involve a deficiency or abnormality in a copper-binding protein or enzyme required for intracellular transport of the metal;

- Reduced biliary excretion as a result of mutations in ATP7B, the gene defect believed to be associated with WD.

Presentation

While hepatic and neurological symptoms are the most common presentations of WD, many other features have been described. One study of 400 adults with WD revealed that 20% presented with hepatic symptoms; 20% with hepatic and neurological symptoms; 50% with neurological and psychiatric symptoms; and 10% had other presenting features (Dening and Berrios, 1989).

WD is rarely seen before the age of six as the infant liver can bind copper 30-50 times the normal concentration. For this reason hepatic dysfunction, which can range from a mild elevation in liver enzymes to complications such as cirrhosis or acute liver failure, is the most common clinical presentation in childhood.

Neurological symptoms, such as speech problems and movement disorders, occur from adolescence until the fifth or sixth decade and are the initial symptoms in 60% of those presenting in the third or fourth decade (Oder et al, 1993).

Renal dysfunction may occur because copper can be deposited in the tubules, but it is rarely a presenting feature. Bone demineralisation is common because of renal tubular phosphate leak.

The increased amount of copper released into the circulation peroxidises red cell membrane lipids, which results in haemolytic anaemia. It is advisable, therefore, that all patients with Coombs-negative haemolytic anaemia are checked for WD as it may be the sole presentation.

Early in the last century two German ophthalmologists, Bernhard Kayser and Bruno Fleischer, described a pigmented corneal ring, the Kayser-Fleischer or KF ring, caused by an accumulation of copper (Finelli, 1995). This is one of the diagnostic features. It has no long-term detrimental effects and disappears after treatment. Copper can also collect in the lens, causing cataracts called 'sunflower cataracts'.

Endocrine abnormalities, such as amenorrhoea and delayed puberty, may be present. Excess copper can also cause collagen damage, which may result in arthritis. See Box 2 for the features of WD.

Diagnosis

Diagnosis of WD depends on the presence of two out of seven features (Box 3). The wide variety of presentations means that diagnosis is difficult, which is complicated by the fact that none of the features are diagnostic in isolation. Steindl et al (1997) formulated an algorithm for the diagnosis of WD in older patients with predominantly neurological symptoms.

A newer test added to the investigation protocol of WD is the penicillamine challenge. A 24-hour urine collection is made in an acid-wash bottle to prevent contamination. A second collection is made after 500mg of penicillamine is given at the onset and at 12 hours. Diagnosis is confirmed with a post-penicillamine urinary copper excretion ≥25μmol over a period of 24 hours (Da Costa et al, 1992).

Limitations of diagnostic features

- KF rings: These rings are usually absent in children aged under 10 and are generally difficult to see in patients who have green/brown eyes. KF rings can be also present in patients with prolonged cholestasis (Tanner, 1999);

- Low caeruloplasmin: other causes of low caeruloplasmin are protein-losing enteropathy, nephrotic syndrome, kwashiorkor, Menkes' syndrome and normal neonates. Caeruloplasmin is an acute-phase reactant so levels may be elevated because of other inflammatory causes (Scheinberg and Sternlieb, 1996);

- Elevated liver copper: increased liver copper is found in acute cholestasis, idiopathic childhood cirrhosis, Alagille syndrome and sclerosing cholangitis (Sokol and Narkewicz, 2001);

- Elevated 24-hour urine copper excretion: can also be seen in severe autoimmune hepatitis, sclerosing cholangitis, chronic active hepatitis and in patients with nephrotic syndrome (Sokol and Narkewicz, 2001).

Treatment

Treatment centres on the removal of excessive copper from the body using various agents known as chelators to bind the toxins so that they can be excreted from the body, usually in the urine. Early chelation therapy prevents the complications of WD, but in those presenting with fulminant liver failure transplantation may be the only effective treatment. Patients on chelation therapy are advised to avoid excessive intake of copper-rich foods, such as chocolate, nuts and shellfish.

Penicillamine

The mainstay of treatment is penicillamine. Initially thought to remove copper from the circulation, it has now been suggested that it detoxifies copper by converting it into a non-toxic form. Penicillamine is gradually introduced to avoid side-effects, such as gastrointestinal problems, rash and fever. Neurological symptoms may get worse when treatment is introduced.

Other side-effects associated with penicillamine are bone-marrow depression, lupus and proteinuria. Penicillamine can also cause zinc deficiency and pyridoxine deficiency, so supplements may need to be given.

Trientine

When side-effects occur with penicillamine, trientine can be used. Trientine has a similar mode of action to penicillamine and fewer side-effects, but its efficacy over penicillamine is unproven.

Zinc

Zinc sulphate and recently zinc acetate have been suggested for chelation therapy because they can induce the production of metallothionein in the enterocyte and liver. This binds copper, reducing absorption in the intestine and detoxifying copper in the liver. The use of zinc as the only treatment is still unproven and is not recommended for the initial management of hepatic presentation of WD.

If zinc is given with penicillamine, they should never be administered at the same time because zinc is chemically similar to copper and is therefore chelated in the same way (Sokol and Narkewicz, 2001; Scheinberg and Sternlieb, 1996).

Chelation therapy is for life. Cessation of treatment can lead to fulminant liver failure and death unless the patient has a liver transplant.

Liver transplantation is the treatment of choice for those presenting with fulminant liver failure, although it has also been used where chelation treatment fails. Survival of transplant is reported to be between 69-88% (Robles et al, 1999; Bellary et al, 1995; Rela et al, 1993).

Asymptomatic siblings

WD is a genetic disorder, so when a patient is diagnosed with it the rest of the family needs to be screened as there is a one in four chance of siblings being affected. Screening involves clinical examination, blood tests for liver function, serum caeruloplasmin and 24-hour urine for copper estimation. A liver biopsy is performed if any of these tests are positive in the sibling. Quantitative copper estimation is also performed and a value >250μg/g dry weight is suggestive of WD.

Young parents should also be screened. To remain asymptomatic, chelation therapy is needed for life (Walshe, 1988).

Conclusion

Patients with WD may present in any field at any age, usually with an unusual variety of symptoms. These can delay diagnosis, with dire consequences. Early treatment is essential to recovery so the nurse can play a vital role in diagnosis. Another essential role for the nurse is supporting patients and their families to promote treatment compliance and ensure a long and disease-free life.

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