Wilson's disease

Wilson's disease is present at birth, but signs and symptoms don't appear until copper builds up in the brain, liver, or other organs. The signs and symptoms depend on the parts of the body affected by the disease. These include:

Liver Symptoms

In Wilson's disease, the majority of patients present with hepatic symptoms at diagnosis, and almost all have signs of liver damage over the course of the disease. In some cases, people develop these symptoms when they have acute liver failure. These symptoms may include:

• Nausea and vomiting
• Poor appetite
• Darkened color of urine
• Yellowish tint to the whites of the eyes and skin, called jaundice
• Pain in the upper part of the abdomen

In some individuals, symptoms of the disease develop in cases of chronic liver disease and complications from cirrhosis. The clinical features of cirrhosis include spider naevi, splenomegaly, portal hypertension, and ascites. It is recommended that all young patients with unexplained chronic liver disease, with or without cirrhosis, should be screened for Wilson’s disease if the following symptoms are present:

• Swelling of the lower legs, ankles, or feet, called edema
• Itchy skin
• Jaundice
• Feeling tired

Neurological and Neuropsychiatric Symptoms

Neurological and neuropsychiatric signs are present in 40–50% of patients with Wilson’s disease. Some signs may appear before the characteristic neurological features, including changes in behavior, deterioration of school work, or an inability to carry out activities requiring good hand-eye coordination. Common neurological symptoms may include:

• Tremors (unintentional and uncontrollable rhythmic movement of one part or one limb of the body)
• Lack of motor coordination
• Drooling of saliva
• Slurred or slow speech
• Dystonia (involuntary muscle contractions causing repetitive or twisting movements)
• Headaches
• Insomnia
• Seizures

Mood disturbances, along with behavioral changes, may include:

• Depression
• Anxiety
• Hallucinations and delusions
• Suicidal tendencies
• Psychosis (a severe mental disorder in which thought and emotions are impaired and contact is lost with external reality)

Eye Symptoms

The main ophthalmic findings of Wilson’s disease include:

• K-F (Kayser-Fleischer rings) - usually greenish, gold, or brownish rings around the edge of the corneas
• Sunflower cataracts - brilliantly multicolored and visible only by slit-lamp examination

Other less common symptoms include:

• Night blindness
• Exotropic strabismus - a form of eye misalignment in which one or both eyes turn outward
• Optic neuritis - characterized by inflammation of the optic nerve, which carries visual information from the eye to the brain, usually causing temporary vision loss
• Optic disc pallor - an abnormal pale yellow coloration of the optic disc

Other Changes

Pathological changes in bone have been recorded to account for osteomalacia, osteoporosis, spontaneous fractures, adult rickets, and osteoarthritis.

Copper accumulation in heart tissues can cause cardiomyopathy and arrhythmias.

Other rare manifestations include hypoparathyroidism, infertility, repeated miscarriages, and kidney abnormalities.

Wilson's disease is caused by changes (mutations) in the ATP7B gene. This gene encodes a protein that plays an important role in the transport of copper from the liver to the rest of the body. Mutations in the ATP7B gene prevent this protein from functioning properly, leading to an accumulation of copper in the body.

The ATP7B mutations that cause Wilson's disease are inherited, meaning they are passed from parent to child. These mutations are autosomal recessive, which means a person must inherit two ATP7B genes with mutations—one from each parent—to develop Wilson's disease. Individuals who possess one ATP7B gene without a mutation and one ATP7B gene with a mutation do not have Wilson's disease; however, they are carriers of the disease.

The risk of Wilson’s disease is genetic; it is inherited, and the risk increases if your parents or siblings have the condition. A genetic test can be performed if a child shows symptoms of Wilson’s and has one or both parents who have the disease.

There is no one test for the diagnosis of Wilson’s disease. The diagnostic challenge is that the symptoms are often nonspecific and the disease affects many different organ systems, resulting in confusion with other disorders. Many symptoms may evolve over time rather than appear all at once. In a few cases, the diagnosis is easy to establish in individuals with neurological symptoms, K-F rings, and a low ceruloplasmin concentration. Doctors diagnose Wilson's disease based on medical and family history, a physical exam, an eye exam, and tests.

Medical History

A doctor will inquire about the family and personal medical history of Wilson's disease and other conditions that could be causing the symptoms.

Physical Exam

During a physical exam, the doctor will look for physical signs related to Wilson’s disease.

Eye Examination

Using a microscope with a high-intensity light source (slit lamp), an ophthalmologist checks the eye for Kayser-Fleischer rings, which are caused by excess copper in the eyes. Wilson's disease is also associated with a sunflower cataract, which can be seen during an eye exam.

Blood Tests

The doctor may order one or more blood tests, including tests that check amounts of:

• Liver Biochemistry: People with Wilson's disease may have abnormal alanine transaminase (ALT) and aspartate transaminase (AST) levels.
• Ceruloplasmin: This protein is the major carrier of copper in blood circulation, carrying six copper atoms per molecule. A ceruloplasmin concentration of less than 0.2 g/L (normal laboratory range 0.2 to 0.5 g/L) is considered consistent with Wilson’s disease. Infants should not be tested until after age 1 year due to low ceruloplasmin levels in the first few months of life. Children under 6 years with normal test results should be retested 5 to 10 years later.
• Copper Levels: The normal copper content of the liver is less than 55 μg/g. A hepatic copper content of 250 μg/g dry weight or more is considered the hallmark of Wilson’s disease and is the method of choice for confirming the diagnosis. Hepatic copper concentration should be obtained in cases where the diagnosis is not straightforward and in younger patients.

Urinary Excretion of Copper

A 24-hour urinary copper excretion is increased in Wilson’s disease, reflecting the amount of serum-free copper in circulation. In symptomatic individuals, a urinary copper excretion in a 24-hour period of greater than 1.6 μmol (greater than 100 μg/24 h) is considered diagnostic. The reference limits for normal 24-hour excretion of copper vary between laboratories, with many considering 40 μg per 24 h (0.6 μmol/24 h) as the upper limit of normal.

Liver Biopsy

Liver biopsy is an important tool for evaluating patients with hepatic disease if the results of blood and urine tests do not confirm or rule out a diagnosis of Wilson's disease. During a liver biopsy, the doctor evaluates small pieces of tissue from the liver. A pathologist examines the tissue under a microscope to look for features of specific liver diseases, such as Wilson's disease, and checks for liver damage and cirrhosis.

Genetic Testing

All first-degree relatives of a patient with newly diagnosed Wilson’s disease must be screened for the disease. Molecular genetic analysis can be useful for families where both mutations have been identified in the index patient, enabling molecular analysis for the same mutation in family members.

Imaging Tests

Neurologic evaluation and radiologic imaging of the brain should be considered prior to treatment in all patients with neurologic Wilson’s disease and should be part of the evaluation of any patient presenting with neurological symptoms:

• Magnetic Resonance Imaging (MRI): MRI is a non-invasive imaging technology that produces three-dimensional detailed anatomical images. MRI of the brain appears to be more sensitive than CT (Computed Tomography) scanning in detecting early lesions of Wilson's disease.
• Computed Tomography (CT): A CT scan of the head is an imaging scan that uses X-rays to develop a 3D image of the skull, brain, and other related areas of the head.

Wilson’s disease is a genetic disorder. People with a family history of Wilson’s disease should always seek genetic counseling as part of pregnancy planning.

Genetic counseling provides a means to:

• Estimate personal genetic risk information
• Translate genetic risk into practical information for families
• Understand information about genetic disorders
• Explain patterns of inheritance

This process enables individuals and families to gain better insight into their future.

Successful treatment of Wilson’s disease depends upon timing more than medication. Treatment often occurs in stages and should last a lifetime. If a person stops taking the required medications, copper can build back up again. Compliance is a challenge for patients because they find it difficult to adhere to life-long treatment when they feel healthy. The various treatment modalities are discussed in detail:

Chelating Therapy

The first treatment is to remove excess copper from the body through chelation. Penicillamine and trientine are chelating agents used to treat Wilson's disease. These medications work by binding excess copper in body tissues and carrying it to the kidneys, where it is ultimately removed via urine.

• Penicillamine: Penicillamine is the most commonly used chelating medication. While taking this medication, it is advisable to have regular monitoring of full blood count and urinary protein due to possible adverse effects. Early side effects in the first 1–3 weeks may include sensitivity reactions such as fever, rash, swelling of lymph nodes, thrombocytopenia, and increased levels of protein in urine. These side effects can be severe, requiring discontinuation in many patients.
• Trientine Hydrochloride: Trientine is regarded as an accepted alternative to penicillamine for the initial treatment of Wilson’s disease. It has fewer side effects, and although they are similar to those of penicillamine, the frequency is much lower.

To Maintain Normal Levels of Copper After Removal

The second stage involves maintaining normal levels of copper after removal. The doctor may prescribe zinc or ammonium tetrathiomolybdate to prevent the intestines from absorbing copper.

• Ammonium Tetrathiomolybdate: This medication forms a complex with copper and protein. When taken with meals, it forms complexes with copper in the food, which are then secreted into the intestine, thus preventing absorption.
• Zinc Acetate: Zinc was first used in the 1960s to treat Wilson’s disease. Its mode of action involves inhibiting copper absorption in the intestine. Zinc monotherapy appears to be effective and safe in neurologic Wilson’s disease and may serve as first-line therapy in this setting.

Note: Penicillamine or trientine must not be taken at the same time as zinc because either drug can bind with zinc, forming a compound with no therapeutic effect.

Long-Term Maintenance Therapy

After symptoms improve and copper levels normalize, doctors typically focus on long-term maintenance therapy. This includes continuing zinc or chelating therapy and regularly monitoring copper levels. Patients should also avoid foods high in copper, such as dried fruits, mushrooms, nuts, chocolate, shellfish, and multivitamins.

Other Therapeutic Agents

Toxic concentrations of copper in the liver produce oxidant damage to mitochondria with lipid peroxidation, which can be reduced experimentally by vitamin E administration. Vitamin E concentrations may be low in patients with Wilson’s disease.

Liver Transplantation

Liver transplantation may be lifesaving for patients with severe Wilson’s disease or severe hepatic insufficiency unresponsive to drugs. Liver transplantation is a curative therapy, with neurologic and psychiatric conditions stabilizing or improving, and Kayser-Fleischer rings disappearing over time.

Home Remedies

• Milk Thistle: A natural remedy that may help reduce the risk of liver failure in individuals with Wilson’s disease. This potent antioxidant has been shown to regenerate injured liver cells and slow the progression of cirrhosis in those with inflammatory liver conditions. It may also improve liver function and survival rates in patients with cirrhosis.
• Turmeric: Contains curcumin, a compound with strong antioxidant properties, and acts as a copper chelating agent.
• Vitamin E: May serve as an adjunctive treatment for Wilson’s disease. Oxidative stress plays a critical role in this condition, and vitamin E may help mitigate its effects.
• Zinc Supplements: Zinc salts can inhibit the absorption of copper in the digestive tract, thus helping to reduce copper accumulation in the body.
• Follow a Low Copper Diet: An essential aspect of managing Wilson’s disease. Avoid high-copper foods such as mushrooms, chocolate, nuts, dried fruits (prunes, dates, raisins), soy products, shellfish, and organ meats.
• Ayurvedic Regimen: Ayurveda classifies Wilson’s disease as a liver condition dominated by pitta. Treatment focuses on regulating pitta, expelling toxins (ama), enhancing digestive fire (Agni), and detoxifying and protecting the liver.
• Medicines that Expel Copper: This is the first line of treatment for Wilson’s disease, aimed at controlling the amount of copper that accumulates in the body. These medications facilitate the release of copper from organs into the bloodstream.

Cirrhosis of the liver

Cirrhosis of the liver is one of the potential complications that may develop from Wilson's disease. As the patient's body attempts to clear the buildup of excess copper from the liver, scar tissue is formed, compromising normal liver function. During the early stages of cirrhosis, patients may be asymptomatic, with symptoms appearing only in the most advanced stages. In the later stages, the symptoms of cirrhosis include:

• Jaundice
• Itchy skin
• Fatigue
• Swelling in the legs
• Loss of appetite

For patients with Wilson's disease, liver abnormalities can begin as early as six years of age.

Kidney stones

Patients with Wilson's disease have an increased risk of developing kidney stones, which are formed from tiny deposits of salts and minerals that are normally filtered by the kidneys. Due to their increased risk for kidney stones, it is recommended that patients with Wilson's disease have an annual x-ray to check for any stones. If small stones are found, these can often be passed with the help of pain relievers, alpha-blockers, and plenty of fluids. Larger stones may require other surgical interventions.

Hemolysis

Hemolysis is characterized by the abnormal destruction of red blood cells and is a potential complication for patients with Wilson's disease. This condition causes patients to feel fatigued, and they may also have an increased heart rate and an enlarged spleen or liver. Patients may feel weak and could become dizzy or confused.

Neurological issues

Patients with Wilson's disease may experience a variety of neurological issues. These may include:

• Lack of coordination
• Gait abnormalities
• Tremors
• Slurred speech

Some individuals might experience involuntary muscle movements or twitching, and speech difficulties have been observed. For some patients, neurological issues could be accompanied by psychological changes such as:

• Depression
• Irritability
• Mood swings
• Changes in personality

Bipolar disorder and episodes of psychosis may develop.

All Wilson's disease patients need to take some type of medication therapy to remove excess dietary copper every day, for life. In some cases, Wilson’s disease patients may benefit from additional forms of therapy to help control emotional or physical symptoms or regain lost movement or speech. These other forms of therapy may include:

1. Physical Therapy

Physical therapy restores function for individuals who have neuromuscular or skeletal problems like arthritis, osteoporosis, joint and muscle pain, and coordination issues. The physical therapy will include:

• Exercise programs to increase muscle function, coordination, balance, and endurance
• Training in mobility, gait stability, posture, and positioning

2. Occupational Therapy

Occupational therapy assists individuals with adapting to their social and physical environment. Therapists help improve function through:

• Activities that help maintain memory, orientation, and cognitive integration
• Adaptive techniques or equipment to overcome physical disabilities
• Education and training in areas such as dressing, bathing, eating, and grooming

3. Psychiatric Care

People with Wilson’s disease may experience a range of psychological disorders over their lifetimes. Depression is the most common and may occur at a rate more than double that of the general population. The feelings that the person may experience include:

• Persistent sad, anxious, or empty mood
• Feelings of guilt, worthlessness, or helplessness
• Thoughts of death or suicide, or suicide attempts
• Difficulty sleeping, early morning awakening, or oversleeping
• Difficulty concentrating, remembering, or making decisions

If any of these are suspected, get in touch with your personal physician or mental health professional for an evaluation.

Self-care
Self-care is an integral part of daily life. It means taking responsibility for your health and well-being, with support from those involved in your care. Self-care involves activities to stay fit, maintain good mental and physical health, and effectively manage other minor ailments.

Low copper diet
Foods with a high concentration of copper should generally be avoided, especially in the first year of treatment when excess copper is being cleared from the body. These foods include:
- Liver
- Cashews
- Black-eyed peas
- Vegetable juice
- Shellfish
- Mushrooms
- Chocolate
- Cocoa

Regular follow-ups with doctors
Poor long-term adherence to drug therapy for Wilson’s disease is common. However, continual, lifelong treatment of Wilson’s disease is essential, regardless of whether symptoms are present. Regular follow-up care with an expert in liver disease is highly recommended.