Wilson disease

Definition

Wilson disease (hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of copper (Cu) metabolism in which excessive amounts of Cu accumulate in tissues. Excess Cu leads to damage in the liver, brain, and eyes. Although Cu accumulation begins at birth, symptoms of the disorder only appear later in life (DHHS n.d.).

Etiology

Wilson disease (WD) is caused by mutations in the ATP7B gene that produces a defective ATP7B Cu transport protein.  

Normally:

1. Cu enters the body from dietary sources
2. Enterocytes in the small bowel absorb Cu
3. Enterocytes secrete Cu into the blood
4. Blood carries Cu to the liver where ATP7B catalyzes Cu binding to the plasma protein ceruloplasmin.
5. Normally hepatocytes use ceruloplasmin to secrete Cu into the blood and bile.
6. Cu bound to ceruloplasmin in the bloodstream is available for use by nerves, bones, collagen and the skin pigment melanin. 
7. Excess Cu bound to ceruloplasmin in the bile is excreted in the stool (Chaudhry 2021).

In WD, the faulty ATP7B protein can not bind Cu to ceruloplasmin.  When Cu fails to bind to ceruloplasmin, unbound (free) Cu damages hepatocytes and spills into the blood. Excess free Cu in the blood causes Cu to increase to toxic levels in the brain, corneas, kidneys, liver, bones. Free Cu lead to oxidative stress in these tissues by producing free oxygen radicals. In the liver the free oxygen radicals produced chronic active hepatitis, fibrosis, and cirrhosis (Chaudhry 2021).

Signs and symptoms

The most characteristic sign of WD is the Kayser-Fleisher ring – a rusty brown ring around the cornea of the eye that can best be viewed using an ophthalmologist’s slit lamp. The primary consequence for most individuals with WD is liver disease, appearing in late childhood or early adolescence as acute hepatitis, liver failure, or progressive chronic liver disease in the form of chronic active hepatitis or cirrhosis of the liver.

In some patients, the first symptoms are neurological, occur later in adulthood, and commonly include slurred speech (dysarthria), difficulty swallowing (dysphagia), and drooling. Other symptoms may include tremor of the head, arms, or legs; impaired muscle tone, and sustained muscle contractions that produce abnormal postures, twisting, and repetitive movements (dystonia); and slowness of movements (bradykinesia). Individuals may also experience clumsiness (ataxia) and loss of fine motor skills.

One-third of individuals with WD will also experience psychiatric symptoms such as an abrupt personality change, bizarre and inappropriate behavior, depression accompanied by suicidal thoughts, neurosis, or psychosis. WD is diagnosed with tests that measure the amount of Cu in the blood, urine, and liver (US DHHS n.d.).

Diagnosis - based on medical and family history, physical exam, eye exam and lab tests (NIDDK 2018).

• Medical/family history of WD or other conditions consistent with symptoms
• Eye Examination for Kayser-Fleischer rings - Slit-lamp
• Physical exam for signs of liver damage
  • skin changes
  • enlargement of liver or spleen
  • tenderness or swelling in the abdomen
  • dependent edema
  • jaundice
• Blood tests
  • Ceruloplasmin; may be low, but not always. A low level with Kaiser-Fleischer ring is diagnostic.
  • Serum Cu levels could be lower than normal, but acute liver failure due to WD may cause high blood Cu levels.
  • liver enzymes; alanine transaminase (ALT) and aspartate transaminase (AST) may be abnormal
  • CBC to look for signs of anemia
  • DNA test to confirm WD diagnosis or genetic couseling for carriers, as needed
• 24-hour urine collection to evaluate Cu excretion
• Liver biopsy for inflammation, cirrhosis and Cu levels
• Imaging - MRI of the brain (basal ganglia) for neurological symptoms
• ECG - for ventricular hypertrophy, arrhythmias and non-specific changes in T waves and ST segments.

Medical management of WD is focused on removing excess Cu and prevention of Cu reaccumulation. Removing excess Cu is accomplished through chelation. Chelation drugs approved for WD are D-penicillamine (Cuprimine® and Depen®) and trientine dihydrochloride (Syprine®). Chelating agents bind with certain toxic metals ions creating an inactive soluable complex that can be excreted.

• D-penicillamine oral - chelation therapy can have serious side effects. Up to 10% of patients experience autoimmune phenomena such as pemphigus, DPA-induced lupus erythematosus, polymyositis/dermatomyositis, membranous glomerulopathy and hypersensitivity pneumonitis and myasthenia.
• Zinc salts inhibit enterocyte absorption of Cu. 3-7% of patients have adverse events.  Slow urinary excretion
• Trientine oral - chelation with less adverse events than D-penicillamine

Trientine dihydrochloride is often the drug of choice for WD chelation due to its safety profile. No hypersensitivity reactions have been reported when Trientine dihydrochloride used in the normal dosage range. 

Trientine chelates heavy metals including copper, iron, and zinc and forms stable complexes that can be excreted by the kidneys. Urinary copper, iron, and zinc concentrations all increased in parallel with trientine excretion. Both trientine and a metabolite acetyltrien chelate copper, although the chelating ability of acetyltrien is lower. In addition to increased urinary copper excretion, trientine decreases intestinal copper absorption.

Prevention of re-accumulation is accomplished through lifelong dietary restriction and zinc therapy.

• Chocolate, shellfish, nuts, mushrooms and organ meat are known to be sources of Cu.
• Well water and water piped through Cu should be evaluated for Cu content.
• Copper cookware and food storage containers should be avoided.

Reference

Chaudhry HS, Anilkumar AC. Wilson Disease. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 . Available from: https://www.ncbi.nlm.nih.gov/books/NBK441990/

U.S. Department of Health and Human Services (DHHS n.d.). Wilson Disease Information Page. National Institute of Neurological Disorders and Stroke. Retrieved November 5, 2021, from https://www.ninds.nih.gov/Disorders/All-Disorders/Wilson-Disease-Information-Page.

U.S. Department of Health and Human Services. (n.d.). Diagnosis. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK 10/18). Retrieved November 7, 2021, from https://www.niddk.nih.gov/health-information/liver-disease/wilson-disease/diagnosis.

U.S. Department of Health and Human Services. (n.d.). Office of dietary supplements - copper. NIH Office of Dietary Supplements. (Updated 3/21). Retrieved November 7, 2021, from https://ods.od.nih.gov/factsheets/Copper-HealthProfessional/. U.S. National Library of Medicine (NLM) (2020,). Wilson disease: Medlineplus Genetics. MedlinePlus. Retrieved November 6, 2021, from https://medlineplus.gov/genetics/condition/wilson-disease/#causes.

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