Wilson’s Disease¶

Chapter 427 | Part 12: Endocrinology and Metabolism

KEY CLINICAL POINTS¶

Wilson’s disease is an autosomal recessive disorder caused by ATP7B mutations, leading to copper accumulation in liver and brain.
Clinical features include hepatic (jaundice, cirrhosis), neurological (dystonia, tremor), psychiatric (mood disorders), and ocular (Kayser-Fleischer ring) manifestations.
Diagnosis relies on low serum copper/ceruloplasmin, elevated urinary copper (>100 µ g/24h), Kayser-Fleischer rings, liver biopsy (hepatic copper >200 µ g/g), and ATP7B genetic testing.
Treatment includes zinc (first-line), copper chelators (penicillamine, trientine, tetrathiomolybdate), and liver transplantation for end-stage disease.
Early diagnosis and lifelong management are critical to prevent mortality and neurological decline.

1. DEFINITION & OVERVIEW¶

Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by mutations in the ATP7B gene, which encodes a copper-transporting P-type ATPase. This defect impairs copper excretion via bile, leading to systemic copper accumulation, particularly in the liver and brain. The condition is one of the best-characterized inborn errors of metabolism, with early diagnosis and treatment preventing severe morbidity and mortality.

Table 427-1 Main Diagnostic Features of Wilson’s Disease¶

CLINICAL SIGNS AND SYMPTOMS	BIOCHEMICAL FINDINGS	MOLECULAR FINDINGS
Hepatic: Jaundice, Anorexia, Vomiting, Ascites/Splenomegaly	Low serum copper, Low serum ceruloplasmin, Increased urinary copper (>100 mg/24h), Elevated liver enzymes	Variants in ATP7B on both chromosomes
Neurologic: Dysarthria, Dystonia, Tremor (wing-beating), Ataxia	Hypoalbuminemia, Fatty liver, Cirrhotic liver, Hemolytic anemia, Renal Fanconi syndrome	Variants or polymorphisms in other genes (e.g., CAT, SOD2, MTHFR) may influence clinical expression
Ocular: Kayser-Fleischer ring, Sunflower cataract (rare)
Psychiatric: Decline in school performance, Personality change, Mood disorder, Schizophrenia

1.1 Genetic Basis¶

Wilson’s disease is caused by biallelic pathogenic variants in ATP7B, a gene encoding a copper-transporting ATPase primarily expressed in the liver and kidney. Mutations disrupt copper homeostasis, leading to hepatic and neurological toxicity.

1.2 Pathophysiology¶

Impaired ATP7B function prevents copper excretion via bile, causing hepatic copper accumulation. Excess copper is deposited in the brain (especially basal ganglia), leading to neurodegeneration. Copper also accumulates in the cornea (Kayser-Fleischer rings) and kidneys, causing Fanconi syndrome.

2. EPIDEMIOLOGY¶

Wilson’s disease has an estimated prevalence of 1 in 7,000 to 1 in 30,000, with higher rates in populations with specific ATP7B variants. It typically presents in individuals <30 years old for hepatic symptoms, while neurologic or psychiatric manifestations may occur in the first to fifth decade. Risk factors include family history, and the condition is more common in northern European populations (Celtic/Nordic descent).

2.1 Demographics¶

Most cases present in individuals <30 years old (hepatic), with neurologic or psychiatric symptoms occurring in the first to fifth decade. Males and females are equally affected.

2.2 Geographic Distribution¶

Prevalence is higher in northern Europe (Celtic/Nordic descent) and lower in non-European populations. Non-HFE-related genetic traits may contribute to iron overload in sub-Saharan Africa and African Americans.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

Wilson’s disease is caused by loss-of-function mutations in ATP7B, a P-type ATPase critical for copper transport. Defective ATP7B impairs copper excretion via bile, leading to systemic copper accumulation. Copper toxicity damages hepatocytes, neurons, and renal tubules, causing liver failure, neurodegeneration, and Fanconi syndrome.

3.1 Molecular Mechanisms¶

ATP7B mutations disrupt copper transport from the liver to bile, leading to hepatic copper accumulation. Copper is deposited in the brain (basal ganglia), cornea (Kayser-Fleischer rings), and kidneys, causing progressive organ dysfunction.

3.2 Copper Toxicity¶

Excess copper induces oxidative stress, mitochondrial dysfunction, and cell death in target organs. Copper chelation therapy and zinc supplementation reduce systemic copper absorption and prevent progression.

4. CLINICAL FEATURES¶

Wilson’s disease presents with diverse clinical manifestations, including hepatic, neurological, psychiatric, ocular, and renal abnormalities. Age influences symptom presentation, with liver disease typically occurring in younger patients and neurologic symptoms in older individuals.

4.1 Hepatic Presentation¶

Jaundice, hepatomegaly, ascites, and cirrhosis are common. Hemolytic anemia and hypoalbuminemia may occur due to renal tubular dysfunction and hepatic copper release.

4.2 Neurological Presentation¶

Movement disorders (dystonia, chorea, tremor), dysarthria, and gait abnormalities are hallmark features. Neurologic signs reflect basal ganglia involvement. Psychiatric symptoms include mood disorders, personality changes, and schizophrenia. Ocular findings include Kayser-Fleischer rings (pathognomonic) and sunflower cataracts.

4.4 Renal Involvement¶

Renal Fanconi syndrome causes aminoaciduria, electrolyte loss, and Fanconi syndrome, contributing to osteoporosis and rickets.

5. DIFFERENTIAL DIAGNOSIS¶

Wilson’s disease must be differentiated from viral hepatitis, other copper-related disorders, Parkinson’s disease, and psychiatric conditions. Key distinguishing features include Kayser-Fleischer rings, low ceruloplasmin, and elevated urinary copper.

5.1 Liver Diseases¶

Differentiate from viral hepatitis, hemochromatosis, and metabolic liver disease using clinical features, imaging, and biochemical tests.

5.2 Neurological Disorders¶

Distinguish from Parkinson’s disease, Huntington’s disease, and other movement disorders using clinical presentation and diagnostic tests.

6. INVESTIGATIONS & DIAGNOSIS¶

Diagnosis of Wilson’s disease combines clinical suspicion, biochemical tests, imaging, and genetic analysis. Key diagnostic tools include urinary copper excretion, Kayser-Fleischer rings, liver biopsy, and ATP7B mutation analysis.

6.1 Biochemical Tests¶

Low serum copper and ceruloplasmin, elevated urinary copper (>100 µ g/24h), and elevated liver enzymes are critical. Radiolabeled 64Cu incorporation into ceruloplasmin is highly specific.

6.2 Imaging and Liver Biopsy¶

Liver biopsy with inductively coupled plasma mass spectrometry (ICP-MS) measures hepatic copper (>200 µ g/g). Slit-lamp examination detects Kayser-Fleischer rings.

6.3 Genetic Testing¶

ATP7B mutation analysis confirms the diagnosis. Over 650 pathogenic variants are cataloged, with geographic and ethnic variations in allele frequencies.

7. MANAGEMENT & TREATMENT¶

Treatment of Wilson’s disease includes zinc (first-line), copper chelators (penicillamine, trientine, tetrathiomolybdate), and liver transplantation for end-stage disease. Lifelong monitoring is essential to prevent complications.

7.1 Pharmacologic Therapy¶

Zinc (50–100 mg/day) reduces intestinal copper absorption. Copper chelators (penicillamine, trientine) bind and excrete excess copper. Tetrathiomolybdate is a newer chelator with fewer side effects.

7.2 Liver Transplantation¶

Liver transplantation is indicated for end-stage liver disease or refractory cases. It corrects hepatic and neurological complications but requires lifelong immunosuppression.

7.3 Monitoring¶

Regular monitoring of serum copper, ceruloplasmin, and urinary copper is required. Neurological and hepatic function should be assessed periodically.

8. PROGNOSIS & COMPLICATIONS¶

Early diagnosis and treatment significantly improve prognosis. Untreated Wilson’s disease leads to progressive liver failure, neurodegeneration, and renal failure. Complications include hepatic encephalopathy, hemolytic anemia, and osteoporosis.

8.1 Long-Term Outcomes¶

With treatment, most patients achieve remission. Untreated cases have a 50% mortality rate within 10 years. Lifelong management is required to prevent relapse.

8.2 Complications¶

Liver failure, neurological decline, renal Fanconi syndrome, and osteoporosis are major complications. Copper toxicity can be fatal if left untreated.

9. SPECIAL CONSIDERATIONS¶

Wilson’s disease requires tailored management in specific populations. Pregnancy, pediatric, and elderly patients may require adjustments in treatment and monitoring.

9.1 Pregnancy¶

Zinc is safe during pregnancy. Copper chelators may require dose adjustments. Fetal copper accumulation is rare with proper treatment.

9.2 Pediatrics¶

Early diagnosis in children is critical. Neurological and psychiatric symptoms may be subtle, requiring careful evaluation.

9.3 Elderly Patients¶

Elderly patients may present with atypical symptoms (e.g., psychiatric changes). Liver function tests and imaging are essential for diagnosis.

10. KEY POINTS & CLINICAL PEARLS¶

Wilson’s disease is a treatable autosomal recessive disorder caused by ATP7B mutations. Early diagnosis is critical to prevent irreversible organ damage. Key diagnostic features include Kayser-Fleischer rings, low ceruloplasmin, and elevated urinary copper. Zinc is first-line therapy, while chelators are used for severe cases. Liver transplantation is reserved for end-stage disease. Lifelong monitoring is required to prevent complications.