Wilson's disease E83.0

Hereditary metabolic disease with disturbance of coeruloplasmin synthesis and copper accumulation in the tissue. In Wilson's disease the liver can produce apo-coeruloplasmin, but copper is not incorporated into the protein. Instead, Cu is deposited primarily in the hepatocytes and secondarily in other tissues (e.g. in the skin). Before the age of 5 years, no clinical symptoms are usually detected.

Worldwide, 10-30 million patients are affected. Prevalence (Germany): 1/30,000 inhabitants. Heterozygotes are affected with a frequency of about 1: 80-100. It occurs in some ethnic groups (e.g. Sardinia: prevalence: 1/10-20.000 inhabitants), especially in the case of an increased proportion of consanguineous marriages.

Autosomal recessive mutations of the copper transport adenosine triphosphatase (ATPase) gene (ATP7B gene; gene locus: 13q14.3-q21.1) with consecutive disruption of the ATP7B protein which plays a key role in maintaining copper homeostasis in the cell. Copper transport from the cytosol to the excretory compartment of the cell is also disturbed. Thus, copper cannot be incorporated into apocoeruloplasmin and excreted with the bile.

Cu accumulation: Cu accumulates diffusely in the cytosol of hepatocytes. Cu content of the liver is increased. Aminotransferases mostly normal. Patients are clinically asymptomatic.

Cu redistribution: When a critical threshold of copper distribution in the cytosol is reached, redistribution to the lysosomes occurs. During this process Cu is also released into the plasma. This redistribution occurs slowly and clinically inapparent in most patients. In a few patients the redistribution occurs rapidly with the release of high copper amounts into the plasma. Development of chronic active hepatitis, which can lead to liver cirrhosis and liver failure.

Cutaneous manifestations:

• In rare cases picture of acanthosis nigricans. Frequently spotty brown-black to blue-black diffuse hyperpigmentation on exposed skin areas, pruritus, blue lunulae, jaundice.

Extracutaneous manifestations:

• Hepatic manifestations (100%). Spectrum ranges from asymptomatic increase of transaminases to fatty liver, fulminant hepatitis and liver cirrhosis.
• Neurological-psychiatric manifestations: behavioural disorders, cognitive weakness, apathy, psychoses, Parkinson-like symptoms.
• Eye symptoms: Highly characteristic: Kayser-Fleischer-Ring; furthermore: sunflower cataract.
• Haematological symptoms: Coombs negative haemolytic anaemia. Bleeding and thrombosis tendency, leukopenia, thrombopenia.
• Other: degenerative joint diseases, gynecomastia, pubertas praecox, renal dysfunction, cardiomyopathy

Total copper in serum > 70ug/dl

Free copper in serum: >10ug/dl

Copper in urine: >100ug/dl

Coeruloplasmin in the sodium: <20mg/dl

Often pathological liver values.

• Detection of a Kayser-Fleischer ring in the slit lamp examination
• Significantly reduced coeruloplasmin serum level (< 15 mg/dl)
• Excessively elevated copper excretion in 24-hour urine > 250 µg/dl (in case of slightly to moderately elevated copper excretion in urine (100-250 µg/d), a repeat measurement is recommended after a strictly low-copper diet for 3-4 days).
• Excessively elevated liver copper content (250 µg/g dry weight)

Notice! By taking contraceptives or other liver enzyme inducers, a normal coeruloplasmin level can be simulated!

Low copper diet (pay attention to water pipes containing copper - drinking water analysis)

Chelation therapy:

• Trentine (triethylene-tetramine-dihydrochloride = Syprine®). Agent of choice. Good tolerability.
• D- Penicillamine (e.g. Metalcaptase) 1. to 2. week 150 mg/day, increase to 600 mg/day within one week (max. 1.2 g/day), maintenance dose 300-600 mg/day after copper levels in urine have decreased. In patients with neurological manifestations, initially higher dose of 1800-2400 mg/day over the first two years (copper return across the blood-brain barrier is significantly slower than from other organs), with neurological manifestations, dose reduction to 300-600 mg/day. Therapy control: 24-hour excretion in urine. Kayser-Fleischer-Ring only disappears in 80% of patients and therefore cannot serve as a therapy control. In case of terminal liver cirrhosis: liver transplantation.

Once a patient has been decoppered, he can either be further treated with a low dose of D-penicillamine (900-1200 mg/day) or trientine (1200-1500 mg/day) or be transferred to zinc therapy with zinc acetate 2-3 times/day 37.5-50 mg p.o. or 5-7.5 mg/kg bw/day.

Remember! Check drinking water for copper content!

1. El-Youssef M (2003) Wilson disease. Mayo Clin Proc 78: 1126-1136
2. Gitlin JD (2003) Wilson disease. Gastroenterology 125: 1868-1877
3. Maier KP (2002) Rare, but important chronic liver diseases. Switzerland Rundsch Med Prax 91: 2077-2085
4. Smolarek C et al (1999) Therapy of Wilson disease. Z Gastroenterol 37: 293-300
5. of Frerich's FT (1861) Clinic of Liver Diseases. Second improved edition, F. Vieweg and Son, Brunswick, Volume 2, pp. 62-64
6. by Strümpell A (1898) About Westphal's pseudosclerosis and about diffuse brain sclerosis, especially in children German Z Neurology (Berlin) 12: 115-149
7. Westphal KFO (1883) On a disease of the central nervous system similar to cerebrospinal gray degeneration without anatomical findings, together with some remarks on paradoxical contraction. Arch Psychiatrist Nervous Disease (Berlin) 14: 87-134
8. Wilson SAK (1912) Progressive lenticular degeneration. A familial nervous disease associated with cirrhosis of the liver. Brain (Oxford) 34: 295-507