What is Wilson's disease?

Wilson Disease: Definition and Overview

Wilson disease is an inherited autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13, resulting in defective biliary excretion of copper and its toxic accumulation primarily in the liver and brain. 1, 2

Genetic Basis and Epidemiology

• The ATP7B gene encodes a copper-transporting P-type ATPase responsible for copper excretion into bile and incorporation into ceruloplasmin 1, 2
• More than 500 distinct mutations have been described, with approximately 380 confirmed to cause disease 1, 2
• Gene frequency is 1 in 90-150, with disease incidence as high as 1 in 30,000 1, 2
• When both parents are carriers, there is a 25% chance that a sibling will be homozygous and develop the disease, 50% chance of being a carrier, and 25% chance of inheriting two normal alleles 2

Pathophysiology

• The defective ATP7B protein leads to impaired biliary excretion of copper, causing accumulation first in hepatocytes 3
• When hepatic storage capacity is exceeded, copper is released into circulation and deposits in extrahepatic sites including brain, kidneys, eyes, heart, muscles, and bones 4, 3
• Copper accumulation generates reactive oxygen species (ROS) through Haber-Weiss and Fenton reactions, leading to copper-dependent cell death (cuproptosis) 3
• Iron deposits may also accumulate in the liver, potentially causing iron-related ferroptosis and phospholipid peroxidation 3

Clinical Presentations

Hepatic Manifestations (40% of initial presentations)

• Jaundice, anorexia, and vomiting occur in 14-44% of patients presenting with liver disease 5
• Ascites/edema in 14-50%, variceal hemorrhage in 3-10%, and hepatomegaly/splenomegaly in 15-49% 5
• Acute liver failure occurs in approximately 17% of hepatic presentations 5
• Hemolysis (Coombs-negative hemolytic anemia) occurs in 5-20% of cases, often associated with severe liver disease 5, 3
• Some patients remain asymptomatic with only elevated transaminases or incidental findings 5

Neurological Manifestations (35% of initial presentations)

Neurological symptoms typically present in the third decade of life and can be classified into four main syndromes: 5

1. Akinetic-rigid syndrome (resembling Parkinson's disease or "juvenile Parkinsonism") 5
2. Pseudosclerosis dominated by tremor, particularly the characteristic "wing-beating" coarse, irregular proximal tremor 5
3. Ataxia 5
4. Dystonic syndrome ranging from focal to severe generalized dystonia with contractures 5

• Speech changes (dysarthria) and drooling are often early neurologic symptoms 5
• Facial grimacing, open jaw, running saliva, and lip retraction are characteristic manifestations 5
• Progressive disability can lead to patients becoming bedridden, severely disabled but alert, and unable to talk 5

Psychiatric Manifestations (10-33% of initial presentations)

• About one-third of patients initially present with psychiatric abnormalities 5
• In children: declining school performance, personality changes, impulsiveness, labile mood, sexual exhibitionism, and inappropriate behavior 5, 6
• In older persons: psychotic features resembling paranoia, schizophrenia, or depression 5, 6
• Diagnostic delays of up to 12 years can occur when neuropsychiatric symptoms are misdiagnosed as primary psychiatric disorders 5, 7
• Severe cognitive deterioration occurs in advanced neurological disease, though cognitive function is generally not markedly impaired 5

Other Clinical Manifestations

Less common presentations include: 5

• Renal abnormalities (aminoaciduria, nephrolithiasis, hypercalciuria, nephrocalcinosis)
• Cardiomyopathy and cardiac arrhythmias 3
• Musculoskeletal issues (myopathy, rhabdomyolysis, chondrocalcinosis, osteoarthritis, osteoporosis, osteomalacia) 5, 3
• Endocrine disorders (hypoparathyroidism) 5
• Pancreatitis 5
• Infertility or repeated miscarriages 5

Age of Presentation

• Wilson disease should be considered in any individual between ages 3 and 55 years presenting with unexplained liver abnormalities, neurological symptoms, or psychiatric disorders 7
• The majority of patients present between ages 5 and 35 years 1, 7
• Approximately 3% of patients present beyond the fourth decade 7
• Age alone should never be the basis for eliminating a diagnosis of Wilson disease (AASLD Class I, Level B recommendation) 7

Diagnostic Features

Kayser-Fleischer Rings

• Golden-brownish pigment deposits in Descemet's membrane at the corneal limbus 1, 8
• Present in 90% of patients with neurological manifestations but only 50-62% with primarily hepatic disease 1, 7
• Visible only with slit-lamp examination in most cases 5
• Disappear on average within 3-5 years following copper chelating therapy 6

Laboratory Findings

• Serum ceruloplasmin <20 mg/dL (though 18% of non-fulminant patients may have normal levels) 1, 8
• 24-hour urinary copper excretion: normal <40-50 μg/24h; in Wilson disease typically >100 μg/24h (in fulminant failure: 844-9375 μg/24h) 1
• Hepatic copper concentration >250 μg/g dry weight provides critical diagnostic information 1, 8
• Undetectable serum haptoglobin due to Coombs-negative hemolytic anemia 3

Diagnostic Scoring System

The Leipzig Scoring System (modified at the 8th International Meeting on Wilson's disease, 2001) provides diagnostic accuracy: 5

• Score ≥4: Diagnosis established
• Score 3: Diagnosis possible, more tests needed
• Score ≤2: Diagnosis very unlikely

Scoring parameters include: 5

• Kayser-Fleischer rings (present = 2 points)
• Neurologic symptoms (severe = 2, mild = 1, absent = 0)
• Serum ceruloplasmin (<0.1 g/L = 2 points, 0.1-0.2 g/L = 1 point, >0.2 g/L = 0)
• Coombs-negative hemolytic anemia (present = 1 point)
• Hepatic copper, urinary copper, and genetic testing results

Prognosis

• Untreated Wilson disease is universally fatal, with most patients dying from liver disease 5, 1, 8
• With appropriate treatment, life is prolonged and clinical improvement occurs in most patients 1, 8
• In acute liver failure, a prognostic score >11 (modified King's College criteria) is associated with high probability of death without liver transplantation 5
• Liver function normalizes over 1-2 years in most patients with no or compensated cirrhosis at presentation 5
• Neurologic symptoms are only partly reversible with treatment and may even worsen initially following treatment initiation 5, 8

Treatment Principles

Dietary Management

• Daily diet should contain no more than 1-2 mg of copper 1, 8
• Exclude chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals 8
• Use distilled or demineralized water if drinking water contains >0.1 mg/L of copper 8

Pharmacological Treatment

First-line treatment for symptomatic patients is copper chelation: 1, 8

• D-penicillamine: Traditional first-line chelator, though up to 30% experience adverse events leading to discontinuation 9, 10
• Trientine (trientine hydrochloride): Alternative chelator with fewer side effects, particularly less neurological deterioration compared to D-penicillamine 4, 9, 11
• Zinc acetate: Blocks intestinal absorption of dietary copper and reabsorption of endogenously secreted copper by inducing metallothionein production in enterocytes 12, 10
  • Dosing: 50 mg three times daily for adults (25 mg three times daily alternative regimen) 12
  • Must be separated from food and beverages (except water) by at least one hour 12
  • Approved by FDA for maintenance therapy 10

Liver Transplantation

• Indicated in fulminant hepatic failure, progressive hepatic insufficiency despite therapy, and cirrhosis with complications of portal hypertension 10
• Medical therapy is rarely effective in acute liver failure due to time required to remove toxic copper 5
• Liver transplantation is curative by replacing the hepatic gene mutation 3
• May improve neurological symptoms even in patients with severe neurological disability 11

Critical Clinical Pitfalls

• Neurological symptoms in advanced liver disease may be mistaken for hepatic encephalopathy 5
• Initial psychiatric symptoms are frequently misdiagnosed as behavioral problems associated with puberty 5
• Ceruloplasmin may be falsely normal due to inflammation (acute phase reactant) or estrogen treatment 5
• Noticeable improvement may not occur for 1-3 months after treatment initiation 8
• Neurological symptoms may worsen during initiation of chelation therapy, but treatment should not be withdrawn 8, 9
• Family screening is essential due to 25% risk of siblings being affected 2