Wilson disease - Nelson
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"Wilson disease" children diagnosis treatment
Here is the complete Wilson disease chapter from Nelson Textbook of Pediatrics 2024 (Chapter 405.2, pp. 2457-2459), authored by Julie Bonn and William F. Balistreri:
Wilson Disease (Hepatolenticular Degeneration)
Nelson Textbook of Pediatrics, 2024 - Chapter 405.2
Definition & Epidemiology
Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder associated with:
- Liver disease
- Degenerative changes in the brain
- Psychiatric symptoms
- Kayser-Fleischer (K-F) rings in the cornea
Incidence: ~1/30,000 births worldwide. Specific treatment is available, but the disease is progressive and potentially fatal if untreated. Prompt diagnostic evaluation in all patients over age 5 presenting with any form of liver disease is recommended.
Pathogenesis
- The variant gene is on chromosome 13 (13q14.3), encoding ATP7B, a copper-transporting P-type ATPase expressed mainly in hepatocytes.
- ATP7B is critical for biliary copper excretion and copper incorporation into ceruloplasmin.
- Absence/malfunction of ATP7B → decreased biliary copper excretion → copper accumulates in hepatocyte cytosol → overloads and redistributes to brain, kidneys → toxicity (primarily by inhibiting enzymatic processes).
- Ionic copper inhibits pyruvate oxidase in the brain and ATPase in membranes, leading to decreased ATP-phosphocreatine and potassium content of tissue.
- >500 pathogenic variants identified; >380 confirmed pathogenic. Most patients are compound heterozygotes.
- Severe variants: disease onset as early as 3 years of age.
- Milder variants: neurologic or liver disease as late as 80 years of age.
- The most common variants produce a protein that binds copper but cannot traffic to the apical surface to export it.
Clinical Manifestations
Table 405.3 - Most Common Presentations:
| Presentation (Frequency) | Symptoms |
|---|---|
| Hepatic (40-60%) | Asymptomatic aminotransferase elevation; acute hepatitis (jaundice, abdominal pain); acute liver failure (coagulopathy, jaundice, encephalopathy); compensated/decompensated cirrhosis (fatigue, spider naevi, portal HTN, splenomegaly, bleeding) |
| Neurologic (40-50%) | Involuntary movements (tremor, dystonia, ataxia, ballism, chorea, parkinsonism); speech disturbances (dysarthria); dysphagia; autonomic dysfunction; gait/balance disturbances |
| Psychiatric (10-25%) | Personality disorders (antisocial behavior, irritability, disinhibition); mood disorders (bipolar, depression, suicidal); psychosis; cognitive impairment |
| Ophthalmologic | K-F rings (90-100% in neurologic patients; 40-50% in hepatic patients; 20-30% in presymptomatic); sunflower cataract (1.2-25%) |
| Other | Renal (tubular dysfunction, nephrolithiasis); bone (osteoporosis, chondrocalcinosis); cardiac (arrhythmia, cardiomyopathy); skin (hyperpigmentation, azure lunulae of nails); hematopoietic (thrombocytopenia, hemolytic anemia); gynecologic (menstrual irregularity, delayed puberty); endocrinologic (glucose intolerance, parathyroid insufficiency) |
Key clinical pearls:
- Liver disease is the most common manifestation in children and can precede neurologic symptoms by up to 10 years.
- Females are 3x more likely than males to present with acute hepatic failure.
- When Wilson disease presents after age 20, neurologic symptoms dominate.
- K-F rings are absent up to 50% of the time in young patients with hepatic Wilson disease, but present in 95% of patients with neurologic symptoms.
- Coombs-negative hemolytic anemia may be an initial manifestation (related to release of copper from damaged hepatocytes); usually fatal without liver transplantation.
- Renal Fanconi syndrome (altered tubular transport of amino acids, glucose, uric acid) may be present.
Pathology
All grades of hepatic injury occur:
- Most common: steatosis, hepatocellular ballooning/degeneration, glycogen granules, minimal inflammation, enlarged Kupffer cells.
- Earliest feature: mild steatosis (may mimic NAFLD/NASH or autoimmune hepatitis).
- Progressive parenchymal damage → fibrosis and cirrhosis.
- Ultrastructural changes: primarily mitochondrial - increased matrix density, lipid and granular inclusions, increased intracristal space with dilation of cristae tips.
Diagnosis
Suspect Wilson disease in children/teenagers with:
- Unexplained acute or chronic liver disease
- Neurologic symptoms of unknown cause
- Acute hemolysis
- Psychiatric illness or behavioral changes
- Fanconi syndrome
- Unexplained bone disease (osteoporosis, fractures) or myopathy/arthralgia
Diagnostic workup:
| Test | Finding in Wilson Disease |
|---|---|
| Serum ceruloplasmin | <20 mg/dL (decreased in most patients) - interpret with caution: falsely elevated in acute inflammation, pregnancy, estrogen use; falsely low in autoimmune hepatitis, celiac disease, carriers |
| Serum free copper | Elevated in early disease (>1.6 μmol/L) |
| 24-hr urinary copper | >100 μg/day (often up to 1,000+ μg/day); normal <40 μg/day; typical untreated: >1.6 μmol/24hr (adults), >0.64 μmol/24hr (children) |
| Penicillamine challenge | Give 2 × 500 mg oral d-penicillamine 12 hr apart; affected patients excrete >1,600 μg/24hr |
| K-F rings | Requires slit-lamp examination by ophthalmologist; may be absent in younger children |
| Liver biopsy (hepatic copper) | >250 μg/g dry weight (>4 μmol/g dry weight) is best biochemical evidence; lowering threshold to 1.2 μmol/g improves sensitivity; only required if noninvasive tests are inconclusive |
- Liver biopsy: used to determine extent/severity of liver disease and measure hepatic copper content (normally <10 μg/g dry weight).
- In later-stage cirrhosis, hepatic copper content can be unreliable due to variable distribution and sampling error.
Screening first-degree relatives: serum ceruloplasmin + 24-hr urinary copper; if abnormal/equivocal → liver biopsy. Genetic screening (linkage analysis or direct DNA) is possible - especially useful if the proband mutation is known. The H1069Q variant is present in 50-80% of patients in Central and Eastern Europe.
Treatment
Lifelong treatment aimed at limiting copper uptake and promoting copper excretion.
Dietary restriction:
- Restrict dietary copper to <1 mg/day (normal diet contains 2-5 mg/day).
- Avoid: liver, shellfish, nuts, chocolate.
- If drinking water copper >0.1 mg/L, demineralize the water.
Pharmacologic therapy:
| Drug | Dose | Notes |
|---|---|---|
| Trientine (triethylene tetramine dihydrochloride; TETA) - first-line preferred | Adults: 750-1500 mg/day in 2-3 divided doses; Children: 20 mg/kg/day (rounded to nearest 250 mg) in 2-3 divided doses; Maintenance: 750-1000 mg/day | Few known side effects. Preferred over penicillamine. |
| d-Penicillamine (β,β-dimethylcysteine) - alternative | Adults: max 1000-1500 mg/day in 2-4 divided doses before meals; Children: 20 mg/kg/day (rounded to nearest 250 mg) in 2-3 divided doses | 10-50% neurologic worsening initially; toxic effects in 10-20% (Goodpasture syndrome, SLE, polymyositis, aplastic anemia, nephrosis, zinc deficiency). Requires supplemental vitamin B6 (antimetabolite of pyridoxine). |
| Ammonium tetrathiomolybdate - investigational | 120 mg/day (20 mg between meals × 3 + 20 mg with meals × 3) | Fewer neurologic deteriorations than penicillamine; side effects include anemia, leukopenia, thrombocytopenia, elevated ALT/AST; also has antiangiogenic effects |
| Zinc acetate - adjuvant/maintenance/presymptomatic | Adults: 50 mg elemental zinc × 3/day; Children >5 yr: 25 mg × 3/day | Impairs GI absorption of copper; side effects: gastric irritation, reduced leukocyte chemotaxis, elevated lipase/amylase |
Key treatment principles:
- Chelating agents (trientine or penicillamine) recommended for all symptomatic patients.
- Patients must not suddenly stop therapy - abrupt discontinuation can precipitate fulminant Wilson disease.
- Zinc: may have a role as first-line in neurologic disease, but monotherapy with zinc in symptomatic liver disease is controversial and not recommended.
- Antioxidants (vitamin E, curcumin) and pharmacologic chaperones (4-phenylbutyrate, curcumin) may have adjunctive roles - more research needed.
Liver transplantation:
- Indicated for acute liver failure or decompensated cirrhosis caused by Wilson disease.
- 5-year survival: 85-90%. Curative.
- For progressive neurologic disease - remains controversial.
- Medical therapy is rarely effective in those presenting with acute liver failure.
Prognosis
- Untreated: can die of hepatic, neurologic, renal, or hematologic complications.
- Prompt continuous chelation therapy: variable prognosis depending on time of initiation and individual response.
- Asymptomatic siblings of affected patients: early chelation or zinc therapy can prevent disease manifestations.
- K-F rings resolve after adequate treatment.
Source: Nelson Textbook of Pediatrics, 2024 Edition, Chapter 405.2 - Wilson Disease (pp. 2457-2459). Authors: Julie Bonn & William F. Balistreri.
Recent evidence note: A 2025 meta-analysis (PMID 39468897) examined deep brain stimulation for severe dystonia in Wilson disease, suggesting a role for DBS in refractory neurologic cases not covered in the Nelson chapter.
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