Normal Copper Metabolism
Copper is an essential metal as the cofactor in vital enzymes such as cytochrome oxidase, lysyl oxidase, superoxide dismutase and dopamine beta-hydroxylase. In excess however copper forms harmful free oxygen radicals that cause damage to cellular DNA and proteins and may cause damage by being wrongly incorporated into proteins in the place of other metals.
The normal diet contains 2-5mg of copper a day though only around 0.75mg is actually needed. In healthy individuals the excess is excreted via the bile.
The human copper excretory pathway involves the transmembrane, hepatic enzyme ATP7B, a copper-transporting P-type ATPase, present on the golgi network of liver cells. This enzyme loads copper onto other proteins for export in the bile or onto the protein caeroloplamin for transport in the plasma.
A defect in the ATP7A gene, which imports copper in the intestine causes Menke's disease.
Wilson’s disease is an autosomal recessive disorder resulting from absence or reduced ATP7B function. It occurs with a frequency of about 1 in 30,000 individuals. The ATP7B gene itself is roughly 80kb long with 21 different exons. Over 60 separate mutations have been identified in Wilson’s disease patients, the most common being H1069Q and G1267R point mutations, although other point mutations, deletions, frame shift and splice site mutations have been found.(1) The variety of mutations makes it difficult to genetically screen for the disease, and small patient numbers mean this would be unlikely to be financially viable. A doctor who spoke to us at the WD conference described the difficulty in mass screening for the disease because often previously unknown minor variants were identified and treated even though they were unlikely to be clinically relevant.
Wilson’s disease results in copper accumulating in the liver causing liver disease. Eventually this kills the hepatocytes (liver cells) and the copper leaks into the blood stream and is deposited in tissues such as the brain and the cornea. Deposition in the cornea causes Kayser–Fleischer rings (see below), which occurs in about two thirds of cases. These rings do not usually cause vision loss; however, they can be used to identify Wilson's disease.
Wilson’s disease is typically diagnosed between the ages of 5 and 35, although some patients are diagnosed much later. Children and younger adults tend to present with predominantly the liver symptoms, whilst patients with predominantly neurological symptoms tend to present later. Asymptomatic patients may also be diagnosed when siblings presenting with Wilson's disease are diagnosed, as a sibling of a Wilson's disease patient has a one in four chance of having the disease also.
|Hepatic Symptoms||Neurological symptoms|
|Increased bleeding||Slurred speech|
|Jaundice||Anxiety or depression|
|Abdominal swelling||Memory loss|
|Acute hepatitis||Migraines and insomnia|
There are drugs available to treat Wilson's disease. In addition, a low copper diet (avoidance of chocolate, mushrooms, nuts, died fruit, beans and lentils, wheat, soya and shellfish) and the avoidance of alcohol are recommended.
The first treatment prescribed after diagnosis is usually D-penicillamine, a penicillin derivative. This drug is taken orally up to four times a day and can chelate dietary copper as well as enter the blood stream and chelate body copper leading to its excretion in the urine. After copper toxicity has been reduced (typically two-six months) a lower dose can be used for maintenance treatment. Common side effects of penicillamine are diarrhoea, loss of appetite and nausea. However, in up to 30% of patients it can induce severe side effects such as bone marrow suppression, vomiting, joint pain, fever, bleeding and skin rash.(2)
Patients may be moved to Trientine, another copper chelating drug, if they are intolerant to D-penicillamine. Though having fewer side effects, the price of Trientine has increased dramatically (over 800%) despite the cost of production being relatively cheap. This is making it difficult for many patients to obtain their medication.(3)(4) Patients we talked to said that they were under pressure from their NHS Foundation Trusts to switch from Trientine back to Penicillamine, which they had bad experiences with previously. Doctors we talked to said that procedures were taking place to pay for these drugs out of a central government funding rather than devolved trusts, but this would only move the cost elsewhere not reduce it.
Children identified early (usually via familial screening) can normally be treated sufficiently with high dose zinc metal which induces intestinal metallothioneins that reduce copper absorption. Whilst this treatment is generally less intolerable for patients than other drugs, it can only really be used as a maintenance drug for a select group of patients diagnosed before they are symptomatic.
- (1) Terada K., Schilsky M., Miura N. et al. (1998) “ATP7B (WND) protein” International Journal of Biochemistry and Cell Biology, 1998 30(10) pp. 1063-1067
- (2) https://www.britishlivertrust.org.uk/liver-information/liver-conditions/wilsons-disease
- (3) Chandok N., Roberts E. (2014) “The trientine crisis in Canada: A call to advocacy” Can J Gastroenterol Hepatol 2014 Apr, 28(4): 184
- (4) http://www.wilsonsdisease.org.uk/documents/Trientine-A-Personal-Account.pdf