In a patient with new‑onset psychiatric symptoms, subtle movement signs (tremor, dystonia, dysarthria), unexplained elevation of liver enzymes, or a family history of early‑onset liver disease, how should I screen for Wilson disease and what is the recommended initial treatment?

Wilson Disease Screening and Management in Psychiatric Presentations

When to Screen for Wilson Disease

Any patient aged 3–55 years presenting with new psychiatric symptoms—especially when accompanied by subtle movement abnormalities (tremor, dystonia, dysarthria, drooling), unexplained liver enzyme elevations, or family history of early liver disease—must be screened for Wilson disease. 1, 2

High-Risk Psychiatric Presentations Requiring Screening

• Personality changes including irritability, impulsiveness, labile mood, or inappropriate sexual behavior, particularly in children and adolescents 1, 2
• Declining school or work performance that may be initially dismissed as behavioral problems of puberty 1, 2
• Depression with suicidal ideation or attempts 1, 3
• Psychotic features resembling paranoia, schizophrenia, or delusional disorder 1, 4
• Behavioral deterioration with anxiety or neuroses 1, 2, 3

Critical Red Flags That Mandate Immediate Evaluation

• Psychiatric symptoms plus any movement disorder (tremor, dystonia, coordination problems, deteriorating handwriting/micrographia) 1, 2, 5
• Psychiatric symptoms plus elevated aminotransferases or other liver abnormalities 6, 2
• "Treatment-resistant" psychiatric illness, particularly when standard therapies fail 2, 4
• Dysarthria and drooling appearing as early neurologic signs alongside behavioral changes 1, 7

Common pitfall: Approximately one-third of Wilson disease patients initially present with psychiatric abnormalities alone, and diagnostic delays of up to 12 years have been documented when the disease is misdiagnosed as primary psychiatric illness. 1, 4

Diagnostic Algorithm

Step 1: Initial Screening Tests

Order these tests simultaneously in any suspected case:

1. Serum ceruloplasmin 6, 2

   • Values <20 mg/dL (200 mg/L) support the diagnosis 6, 8
   • Critical caveat: 15–36% of children and up to 50% of hepatic Wilson disease patients have normal or low-normal ceruloplasmin 6
   • Ceruloplasmin can be falsely elevated by inflammation, pregnancy, or estrogen supplementation 6
   • A normal ceruloplasmin does NOT exclude Wilson disease 6

2. Slit-lamp examination for Kayser-Fleischer rings by an experienced ophthalmologist 6, 2

   • Present in ~95% of neuropsychiatric cases but only 50–62% of primarily hepatic presentations 2
   • Usually absent in children with liver-predominant disease 2
   • Direct visual inspection without magnification misses the majority of cases 2

3. Liver function panel (AST, ALT, bilirubin, INR, albumin) 6, 2

   • Aminotransferases may be only mildly elevated despite advanced disease 6

Step 2: Confirmatory Testing When Initial Screening Is Abnormal or Suspicion Remains High

1. 24-hour urinary copper excretion (use copper-free containers) 6, 2

   • Values >100 μg/24 hours (>1.6 μmol/24 hours) indicate Wilson disease 1, 6
   • Measure total creatinine to confirm complete collection 6

2. Calculate non-ceruloplasmin-bound (free) copper 6

   • Formula: Free copper (μg/dL) = Total serum copper (μg/dL) – (3 × ceruloplasmin in mg/dL) 6
   • Values >25 μg/dL strongly suggest Wilson disease 6

3. ATP7B genetic testing 6, 2

   • Identification of two pathogenic mutations confirms the diagnosis 6
   • Particularly useful when biochemical results are equivocal 6

4. Hepatic copper concentration (if liver biopsy performed) 1, 8

   • Values >250 μg/g dry weight (>4 μmol/g) provide the best biochemical evidence 1, 8

Step 3: Assess Extent of Organ Involvement

• Comprehensive neurologic examination documenting tremor, dystonia, dysarthria, drooling, coordination deficits, and handwriting changes 6, 2
• Brain MRI when neurologic manifestations are present 6
• Psychiatric assessment for depression, anxiety, personality changes, behavioral deterioration, or psychosis 6, 2
• Screening for extrahepatic involvement: renal function, bone density, cardiac evaluation 6

Initial Treatment

Initiate copper chelation therapy immediately upon diagnosis to prevent irreversible organ damage. 6

First-Line Chelation Therapy: D-Penicillamine

Starting regimen: 6, 8

• Begin with 250 mg/day orally 6
• Gradually increase to 0.75–1.5 g/day in divided doses 6
• Must be taken on an empty stomach: at least 1 hour before or 2 hours after meals 6, 8
• Supplement with pyridoxine 25 mg/day 8

Alternative chelator: Trientine (if penicillamine is not tolerated) 6

Dietary Copper Restriction

• Limit daily copper intake to 1–2 mg 8
• Exclude: chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, copper-enriched cereals 8
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper 8

Critical Treatment Warnings

Neurological symptoms may paradoxically worsen during the first 1–3 months of penicillamine therapy. 6, 8

• Do not discontinue treatment despite initial worsening 8
• Temporary interruption increases risk of sensitivity reactions upon resumption 8
• If symptoms continue worsening after 1 month, consider short courses of 2,3-dimercaprol (BAL) while continuing penicillamine 8

Monitoring During Treatment

Every 6–12 months: 6

• Free serum copper (target <10 μg/dL) 6
• 24-hour urinary copper (target 3–8 μmol/24 hours on treatment; initial week should show >2 mg) 6
• Liver function tests 6
• Neurological examination 6
• Serial slit-lamp examinations (Kayser-Fleischer rings gradually fade over years with effective therapy) 6

Warning sign of non-compliance: Reappearance or worsening of Kayser-Fleischer rings during therapy strongly indicates medication non-adherence. 6

Prognosis and Psychiatric Outcomes

• Noticeable improvement typically requires 1–3 months of chelation therapy 8
• Behavioral and cognitive symptoms often reverse over 1–2 years of treatment 3
• Personality changes (irritability, incongruous behavior) and cognitive impairment show the most significant improvement 7
• Depression, psychosis, and other psychiatric symptoms may improve but response is variable 3, 9, 10
• Untreated Wilson disease is universally fatal 1
• With treatment, life is prolonged and symptoms prevented indefinitely in asymptomatic patients 8

Interdisciplinary collaboration between psychiatry, neurology, and hepatology is crucial for optimal outcomes. 4