What are the symptoms and treatment options for Wilson disease?

Symptoms and Treatment Options for Wilson Disease

Wilson disease presents with a wide spectrum of hepatic, neurologic, and psychiatric symptoms, and treatment requires lifelong copper chelation therapy with D-penicillamine, trientine, or zinc salts to prevent progressive organ damage and death.

Clinical Manifestations

Hepatic Symptoms

• Asymptomatic hepatomegaly
• Isolated splenomegaly
• Persistently elevated liver enzymes (AST, ALT)
• Fatty liver
• Acute hepatitis (may mimic viral or autoimmune hepatitis)
• Cirrhosis (compensated or decompensated)
• Fulminant hepatic failure with characteristic features 1:
  • Coombs-negative hemolytic anemia
  • Coagulopathy unresponsive to vitamin K
  • Rapid progression to renal failure
  • Relatively modest rises in aminotransferases (typically <2000 IU/L)
  • Low serum alkaline phosphatase (typically around 40 IU/L)
  • Female:male ratio of 2:1

Neurological Symptoms

• Movement disorders (tremor, involuntary movements) 1
• Facial grimacing, open jaw, running saliva, and lip retraction 1
• Speech changes and drooling (often early neurologic symptoms) 1
• Dysarthria and dysphonia
• Rigid dystonia
• Pseudobulbar palsy
• Tremor-rigidity syndrome ("juvenile Parkinsonism") 1
• Seizures
• Migraine headaches
• Insomnia

Psychiatric Symptoms

• Behavioral changes (often misdiagnosed as puberty-related in children) 1
• Declining school performance
• Personality changes
• Impulsiveness and labile mood
• Depression
• Anxiety
• Neuroses
• Psychosis resembling paranoia or schizophrenia 1

Other Manifestations

• Kayser-Fleischer rings (corneal copper deposits) - pathognomonic finding
• Renal abnormalities: aminoaciduria and nephrolithiasis
• Skeletal abnormalities: premature osteoporosis and arthritis
• Cardiomyopathy
• Pancreatitis
• Hypoparathyroidism
• Menstrual irregularities, infertility, repeated miscarriages

Diagnostic Approach

1. Clinical suspicion based on:

   • Age (typically 5-35 years, though can present earlier or later)
   • Family history
   • Presence of Kayser-Fleischer rings (present in ~78% of patients overall, almost always present in those with neuropsychiatric symptoms) 2

2. Laboratory tests:

   • Low serum ceruloplasmin (<200 mg/L) - present in 98% of cases 2
   • Elevated 24-hour urinary copper excretion (>40 μg/day)
   • Increased urinary copper after D-penicillamine challenge

3. Imaging:

   • Brain MRI showing abnormalities in basal ganglia in 77.7% of patients 2
   • Liver imaging may show cirrhosis or steatosis

4. Confirmatory tests:

   • Liver biopsy with hepatic copper quantification (>250 μg/g dry weight)
   • Genetic testing for ATP7B mutations

Treatment Options

Copper Chelation Therapy

1. D-penicillamine (first-line therapy) 3, 2:

   • Mechanism: Promotes urinary copper excretion
   • Dosage: Typically 750-2000 mg/day in divided doses
   • Monitoring: 24-hour urinary copper (target: 200-500 μg/day)
   • Side effects: Hypersensitivity reactions, bone marrow suppression, autoimmune disorders, nephrotoxicity
   • Approximately 21% of patients require switching due to adverse effects 2

2. Trientine (second-line therapy) 4:

   • Used for patients intolerant to D-penicillamine
   • Dosage: 1000-2000 mg/day in divided doses
   • Fewer side effects than D-penicillamine
   • Monitoring: 24-hour urinary copper (target: 200-500 μg/day)

Zinc Therapy

• Mechanism: Blocks intestinal absorption of copper
• Dosage: Elemental zinc 150 mg/day in divided doses
• Monitoring: 24-hour urinary copper (target: <75 μg/day)
• May be used as maintenance therapy after initial chelation or in asymptomatic patients

Liver Transplantation

• Indicated for:
  • Acute liver failure due to Wilson disease (prognostic index >11 is fatal without transplantation) 1
  • Decompensated cirrhosis unresponsive to medical therapy
• One-year survival ranges from 79-87% 1
• Not recommended as primary treatment for neurologic Wilson disease 1

Dietary Modifications

• Low copper diet (<1-2 mg copper daily)
• Avoid high-copper foods: chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals 3
• Use distilled or demineralized water if drinking water contains >0.1 mg copper/L 3

Symptomatic Treatment for Neuropsychiatric Symptoms

• Careful use of psychiatric medications due to potential hepatic side effects
• Treatment should be guided by specialists familiar with Wilson disease

Monitoring Treatment

• Physical examination for liver disease and neurological symptoms (minimum twice yearly) 1
• Laboratory tests:
  • Liver function tests
  • Serum copper and ceruloplasmin
  • 24-hour urinary copper excretion
  • Complete blood count for patients on chelators
  • Urinalysis

Prognosis

• Untreated Wilson disease is universally fatal 1
• With proper treatment, prolonged survival is expected
• Hepatic symptoms typically improve within 1-2 years of treatment
• Neurological symptoms may only partially improve and can sometimes worsen initially with treatment
• Lifelong treatment is required to prevent disease progression

Common Pitfalls

1. Delayed diagnosis due to psychiatric presentation (can be delayed up to 12 years) 1
2. Misdiagnosis as autoimmune hepatitis, especially in younger patients 1
3. Neurological worsening after initiating treatment (should not lead to permanent discontinuation) 3
4. Inadequate monitoring of treatment compliance
5. Failure to screen family members of affected individuals

Remember that early diagnosis and treatment are critical for preventing irreversible organ damage and improving long-term outcomes in Wilson disease.