Wilson Disease - Symptoms, Diagnosis And Treatment

Last Updated on May 25, 2020

Wilson disease is a rare inherited disorder in which excessive amounts of copper accumulate in the body, particularly in the liver, brain, and eyes.

It is also called hepatolenticular degeneration syndrome or copper storage disease.

Most people present with symptoms between 5 to 35 years of age, but it can affect younger and older people, as well.

It is a rare disease that affects approximately 1 in 30,000 individuals.

The clinical features include a combination of liver disease, neurological and neuropsychiatric problems. In the absence of treatment, Wilson disease can cause liver failure, severe brain damage, and even death.

When diagnosed early, before serious organ damage occurs, Wilson’s disease is treatable, and many people lead normal lives.

Cause and Pathophysiology

Copper is a trace mineral that is required by the body for the development of nerves, bones, collagen, and melanin (the skin pigment). It is required by the body in small amounts and is obtained from the food we eat. The excess copper is excreted through the liver into the bile.

In people with Wilson’s disease, there is a genetic defect caused by mutations in the ATP7B gene. This gene provides instructions for the formation of copper transporting protein. Due to the deficiency of this protein, the liver does not release copper into bile. This leads to the accumulation of copper in the body.

Copper begins to build up in the liver immediately after birth and ultimately damages the liver. Once the liver is unable to hold the excess copper, it is released into the bloodstream. It then travels and gets deposited in other organs ultimately causing their damage.

This condition is inherited in an autosomal recessive pattern which means that a person must have inherited two separate genes, one from their mother and one from their father to have the condition. If a person only inherits one defective gene they are said to be a carrier, and do not have the condition itself, but possess the ability to pass it onto their offspring.

Signs and Symptoms

Wilson’s disease is present at birth. However, signs and symptoms of the disease start to appear only when copper starts accumulating in the liver, brain, or other organs.

Patients who present earlier show mainly symptoms related to the liver, while those presenting later are more likely to present with neurological symptoms.

Wilson Disease — Image Credit: ghr.nlm.nih.gov

Signs and symptoms vary depending on the parts of the body affected by the disease.

Liver disease

It is the presenting feature in more than half of the patients.

Common symptoms of liver disease include fatigue, weakness, loss of appetite, muscle cramps, nausea, vomiting, abdominal pain, weight loss, jaundice, easy bruising, hepatomegaly, splenomegaly, etc.

Liver disease can present as

chronic liver disease
acute hepatitis
fulminant hepatic failure
cirrhosis

Neurological disease

Common symptoms include stiff and weak muscles, slow or repeated movements, involuntary movements, tremors, slurring of speech, difficulty in swallowing, drooling, decreased fine motor abilities, poor coordination, etc.
Neuropsychiatric symptoms include changes in behavior, depression, stress, anxiety, suicidal tendencies, and psychosis ( losing touch with reality)

Eye symptoms

Almost all individuals ( > 97%) of Wilson’s disease have golden greenish-brown discoloration of the eye (Kayser-Fleischer rings ) due to copper being deposited in the cornea of the eye.

Sunflower cataracts that have a multicolored center with spokes that radiate outward are present in about 20% of patients.

There may be abnormalities in eye movements, such as a limited ability to gaze upwards.

The-Kayser-Fleischer-ring in Wilson Disease — Kayser Fleischer ring in Wilson Disease
Image Credit: researchgate.net

Other symptoms

The buildup of copper in other organs can cause:

Destruction of red blood cells leading to hemolytic anemia.
Skin pigmentation and a bluish discoloration at the base of the fingernails
Low blood pressure
Cardiomyopathy, heart failure, arrhythmias
Renal tubular dysfunction, kidney stones
Premature osteoporosis, spontaneous fracture
Arthritis and reduced joint spaces
Hypothyroidism
Menstrual irregularities, loss of menstruation (amenorrhea), miscarriages and infertility

Diagnosis

Early diagnosis is important for stopping the progression of Wilson’s disease. Because it is a relatively rare disease, signs and symptoms of liver disease or neuropsychiatric symptoms may initially be attributed to other causes.

Physical examination

General examination
Look for hepatomegaly or splenomegaly
Checking eyes under a bright light (slit-lamp examination) by an ophthalmologist for Kayser-Fleischer rings or sunflower cataracts
Testing motor and memory skills

Liver Function Tests

It is done to assess inflammation and damage in the liver.

Ceruloplasmin level

It is the protein that carries copper through the blood.

In Wilson’s disease, lower levels of ceruloplasmin are found (< 20 mg/dl)

The normal range for ceruloplasmin in the blood is between 20 to 50 mg/dl.

24-hour urinary excretion of copper

Total urine produced in 24 hours is collected in a bottle free of copper and then the level of copper in this urine is estimated. Levels > 100 μg/24 hours confirm the diagnosis of Wilson disease while levels > 40 μg/24 hours are strongly indicative of the disease.

Copper level

Raised serum free copper level (non–ceruloplasmin-bound) >25 μg/dL

The total serum copper is made up of ceruloplasmin-bound copper and free copper. The ceruloplasmin and the ceruloplasmin-bound copper levels are typically low in Wilson Disease. This explains the overall reduction in total serum copper concentration. However, the free (i.e., non–ceruloplasmin-bound) copper is usually found to be elevated.

Liver biopsy

A tiny piece of the liver is taken after passing a fine hollow needle through the skin into the liver. This small liver sample is then studied under a microscope. It is done for the following purposes

To assess the severity of liver damage or cirrhosis
For chemical analysis of the copper concentration in the tissue sample. This is a standard test for the diagnosis of Wilson disease. Copper levels > 250 μg /g of dry weight are diagnostic of Wilson disease even in asymptomatic patients.

Genetic testing

It is done to detect the gene mutation. Genetic testing is also recommended for all first-degree relatives of a person diagnosed with Wilson disease to see if they are a carrier or could have the disease. It can help parents determine the potential risk of passing this disease to their offspring.

Magnetic resonance imaging (MRI) and computerized tomography (CT) scans

These may help show any brain abnormalities or liver damage. These investigations can’t diagnose the disease, but they can help determine the extent or severity of the disease.

A practical approach to diagnosis

The presence of Kayser-Fleischer rings, low ceruloplasmin levels (< 20 mg/dL) and the presence of neurological symptoms are suggestive of the diagnosis of Wilson disease.
If a patient shows only liver disease, the presence of a liver copper concentration of more than 250 μg/g of dry weight and a low serum ceruloplasmin level (< 20 mg/dL) are used to confirm the diagnosis.
Thus, in the absence of Kayser-Fleischer rings or neurologic symptoms, a liver biopsy for the quantitative determination of copper is necessary to establish the diagnosis of Wilson disease.

Treatment

Treatment involves 3 stages and should continue throughout life. If treatment is delayed or stopped, copper can again build-up in the organs.

First stage

The first part of the treatment involves removing excess copper from the body. This is done through chelating agents that remove the extra copper from the organs and release it into the bloodstream. The kidneys then filter this copper into the urine.

Commonly used chelating agents include drugs like d-penicillamine (Cuprimine, Depen) and trientine (Syprine).

D-penicillamine can cause serious side effects, including skin rashes, kidney problems, bone marrow suppression, and worsening of neurological symptoms. It also increases the urinary excretion of vitamin B-6 (pyridoxine), so vitamin B-6 supplements should be taken along with this treatment.

Trientine produces lesser side effects than penicillamine. Still, it can cause worsening of neurological symptoms

Second stage or Maintenance therapy

Once the excess copper is removed from the body, the next step is to maintain the normal level of copper. The commonly used drug is zinc acetate (Galzin).

This drug prevents the body from absorbing copper from the foods eaten.

Zinc may be used as first stage treatment if a person can’t take chelating agents. Zinc can cause stomach upset.

Third stage

Once the copper levels return to normal and the symptoms improve, the next part of treatment involves long-term maintenance therapy.

This includes

Continuing chelating therapy or zinc.
Regularly monitoring the copper levels in the body.

Lifestyle and home remedies

Dietary changes: Foods containing a high level of copper should be avoided. These include:

dried fruit
nuts
mushrooms
liver
shellfish
chocolate
multivitamins containing copper Liver

The copper content of the water at home should be checked. If the home has copper pipes, there may be excess copper present in the water.

Liver transplant

The diseased liver is removed and replaced with a healthy liver from a donor. It is done in the following cases:

Non-responsive to treatment
In case of severe liver damage

If successful, a liver transplant results in curing Wilson disease. The success rate for liver transplants is 85 percent after one year.

Long-term Outlook

The sooner the diagnosis of Wilson disease is made, the better is the long term outlook or prognosis. If left untreated, Wilson disease can result in liver failure and brain damage.

Early treatment can prevent neurological and liver damage and can even reverse the damage. If treated in later stages, the progression of the disease can be stopped but the damage which has already occurred can’t be reversed.

Since Wilson disease is an inherited condition, nothing can be done to prevent it. One can, however, prevent or delay the onset of symptoms and the complications.

Future Options

In the future, treatments like hepatocyte transplantation and gene therapy may revolutionize the treatment of Wilson disease. Although both these treatments have shown promising results in animals, definite human studies are needed to establish their long-term usefulness and ability to replace medical treatment and liver transplantation.

References

Kieffer DA, Medici V. Wilson disease: at the crossroads between genetics and epigenetics-A review of the evidence. Liver Res. 2017 Sep. 1(2):121-30.
Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: A review of what we have learned. World J Hepatol. 2015 Dec 18. 7(29):2859-70.
Dusek P, Roos PM, Litwin T, Schneider SA, Flaten TP, Aaseth J. The neurotoxicity of iron, copper and manganese in Parkinson’s and Wilson’s diseases. J Trace Elem Med Biol. 2015 Jul. 31:193-203.
Schilsky ML. Wilson disease: current status and the future. Biochimie. 2009 Oct. 91(10):1278-81.
Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut. 2007 Jan. 56(1):115-20.