Wilson's Disease¶

Chapter 427 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 427

Key Clinical Points¶

Autosomal recessive disorder of copper transport caused by loss-of-function variants in the ATP7B gene (a P-type ion-motive ATPase).
Kayser-Fleischer ring is a pathognomonic sign: present in 95% of patients with neurologic signs and ~2/3 of those with hepatic presentations.
Diagnosis confirmed by liver biopsy showing copper >200 μg per gram of dry weight (normal 20–50 μg) or via clinical, biochemical, and molecular features.
Treatment includes copper chelation (penicillamine, triethylene tetramine) or zinc salts to reduce gastrointestinal absorption.
Liver transplantation is indicated for end-stage liver disease or patients unresponsive to medical therapies.
Hemolytic anemia may occur due to direct toxic effects of copper on red blood cell membranes, often triggered by a sudden/catastrophic release of hepatic copper into circulation.
Neurologic signs reflect involvement of the basal ganglia (caudate, putamen).
Urinary copper excretion >100 μg/24 h is a key diagnostic indicator.
Wilson's disease must be ruled out in all teenagers and young adults with new-onset psychiatric symptoms.
Newborn screening may eventually utilize ATP7B peptides for presymptomatic diagnosis.

1. DEFINITION & OVERVIEW¶

• Definition: Wilson's disease (hepatolenticular degeneration) is an autosomal recessive inherited disorder of copper transport primarily impacting the liver and brain. • Molecular Mechanism: ◦ Caused by loss-of-function variants in ATP7B, a P-type ion-motive ATPase expressed primarily in liver and kidney. ◦ Normal Function: Mediates copper removal from the liver via biliary excretion → prevents brain copper accumulation. • Pathogenesis Cascade: 1. Loss of function → failure of biliary excretion → copper accumulates in liver (hepatotoxicity). 2. Excess copper released into circulation → causes hemolytic anemia. 3. Copper accumulates in the brain (basal ganglia) → neurologic dysfunction. 4. Copper deposits in the cornea (Descemet membrane) → Kayser-Fleischer ring. • Historical Context: ◦ 1912: First described by S.A.K. Wilson. ◦ 1948: J.N. Cumings linked it to copper overload. ◦ 1956: D-penicillamine introduced as preferred chelator over anti-lewisite. ◦ 1970s: Triethylene tetramine approved; first liver transplants performed. ◦ 1993: ATP7B gene identified. ◦ 1960s: Zinc salts recognized for reducing gastrointestinal copper absorption.

1.2 Phenotypes¶

• Clinical Presentation: Includes nonspecific liver disease, neurologic abnormalities, psychiatric illness, hemolytic anemia, renal tubular Fanconi syndrome, and skeletal abnormalities. • Age Correlation: ◦ Liver disease: Almost always <30 years of age. ◦ Neurologic/Psychiatric signs: Range from first to fifth decade. • Clinical Note: Must be differentiated from Parkinson disease or other movement disorders; must be excluded in all teenagers/young adults with new-onset psychiatric symptoms.

2. EPIDEMIOLOGY¶

• Prevalence: 1 in 7,000 to 1 in 30,000 (higher prevalence supported by genome-based data). • Global Considerations: ◦ HFE mutation: Northern European origin; rare in Asia. ◦ Non-HFE Hemochromatosis: Resulting from other genes; ubiquitous globally. ◦ African Iron Overload: Result of non-HFE genetic traits exacerbated by dietary iron loading.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Genetic Basis: Loss-of-function variants in ATP7B (e.g., H1069Q, M645R, R778L). ◦ Over 650 pathogenic or likely pathogenic variants identified. • Molecular Mechanism: ◦ ATP7B is a copper-transporting ATPase in liver and kidney. ◦ Failure of biliary excretion → hepatic accumulation → systemic circulation → brain/cornea deposition.

4. CLINICAL FEATURES¶

• Hepatic Presentation: ◦ Symptoms: Jaundice, hepatomegaly, edema, ascites, splenomegaly. ◦ Findings: Fatty liver, cirrhotic liver, hypoalbuminemia, elevated liver enzymes. • Neurologic Presentation (Movement Disorders): ◦ Signs: Dysarthria, facial grimace (risus sardonicus), drooling, dysphagia, dysgraphia, dystonia, tremor (wing-beating), ataxia, seizures (rare). ◦ Pathology: Reflects basal ganglia involvement (caudate, putamen). • Psychiatric Presentation: ◦ Symptoms: Personality changes (irritability, anger), mood disorders, schizophrenia. ◦ Demographic: Often presents in late teens or early twenties. • Ocular Manifestations: ◦ Kayser-Fleischer ring: Pathognomonic; copper deposition in Descemet membrane. ◦ Progression: Superior crescent → inferior → circumferential. ◦ Detection: Slit-lamp or optical coherent tomography (OCT) required for early detection. ◦ Prevalence: 95% of neurologic cases; ~2/3 of hepatic cases. • Other Manifestations: ◦ Renal: Fanconi syndrome (loss of amino acids, electrolytes, calcium, phosphorus, glucose). ◦ Skeletal: Osteoporosis, rickets, osteoarthritis (knees and wrists). ◦ Hemolytic Anemia: Result of direct copper toxicity on RBC membranes; often sudden/catastrophic due to massive hepatic copper release.

5. DIFFERENTIAL DIAGNOSIS¶

• Wilson's vs. Hemochromatosis: ◦ Hemochromatosis in heavy drinkers distinguished by C282Y mutation. ◦ Wilson's shows low serum copper/ceruloplasmin; Hemochromatosis does not. • Wilson's vs. Alcoholic Liver Disease: ◦ Alcohol reduces hepcidin → increased iron absorption (not seen in Wilson's). ◦ HFE mutations are uncommon in alcoholic liver disease.

6. INVESTIGATIONS & DIAGNOSIS¶

Biochemical Screening: • Serum ceruloplasmin: Low levels. • Serum copper: Low levels. • Urinary copper excretion: >100 μg/24 h (requires acid-washed containers). • Liver enzymes, hypoalbuminemia, and evidence of hemolytic anemia.
Specialized Diagnostic Tests: • Penicillamine Challenge: 500 mg oral dose → 12h interval → assess for several-fold increase in urine copper. • Radiolabeled ^{64}Cu Incorporation: Measure uptake into serum ceruloplasmin (low uptake is highly specific).
Gold Standard Confirmation: • Liver Biopsy: ICP mass spectrometry or atomic absorption spectrometry. • Threshold: >200 μg/g dry weight (Normal 20–50 μg).

6.3 Diagnostic Criteria Table¶

Table 427-1 Main Diagnostic Features of Wilson's Disease

Clinical Signs and Symptoms	Biochemical Findings	Molecular Findings
Hepatic: Jaundice, Anorexia, Vomiting, Ascites/edema, Splenomegaly, Fatty liver, Cirrhotic liver, Hemolytic anemia, Renal Fanconi syndrome	Low serum copper, Low serum ceruloplasmin, Increased urinary copper excretion, Elevated liver enzymes, Hypoalbuminemia, Increased liver copper	Variants in ATP7B on both chromosomes
Neurologic: Dysarthria, Facial grimace (risus sardonicus), Drooling, Dysphagia, Dysgraphia, Dystonia, Tremor (wing-beating), Ataxia, Seizures (rare)	Increased liver enzymes, Hypoalbuminemia, Increased liver copper	Variants or polymorphisms in other genes (e.g., CAT, SOD2, MTHFR) may influence clinical expression
Ocular: Kayser-Fleischer ring, Sunflower cataract (rare)	[Not specified]	[Not specified]
Psychiatric: Decline in school performance, Personality change, Mood disorder, Schizophrenia	[Not specified]	[Not specified]

7. MANAGEMENT & TREATMENT¶

Pharmacologic Therapy: • Chelation: Penicillamine, triethylene tetramine. • Absorption Reduction: Zinc salts (reduce gastrointestinal copper absorption). • Emerging Agents: Tetrathiomolybate (forms tripartite complex with copper and albumin); methanobactin (bacterial peptide traversing mitochondrial membranes).
Surgical/Procedural Management: • Liver Transplantation: Indicated for end-stage liver disease or patients unresponsive to medical therapies.
Monitoring & Outcomes: • Clinical: Fading and eventual disappearance of corneal copper. • Renal: Chelation may improve renal disturbances.

8. PROGNOSIS & COMPLICATIONS¶

• Hemolytic Anemia: Result of direct copper toxicity on RBC membranes; can be sudden/catastrophic. • Renal Failure: Fanconi syndrome leading to metabolic losses. • Skeletal Issues: Osteoporosis, rickets, osteoarthritis. • Neurologic Impairment: Crippling if untreated. • Prognosis: Early diagnosis and lifelong treatment prevent progression of hepatic and neurologic damage.

9. SPECIAL CONSIDERATIONS¶

• Age of Presentation: ◦ Liver: <30 years. ◦ Neuro/Psych: 1st to 5th decade. • Newborn Screening: Potential for presymptomatic diagnosis using ATP7B peptides.

10. KEY PEARLS & CLINICAL TRAPS¶

• Kayser-Fleischer ring: Pathognomonic; 95% of neuro cases, 2/3 of hepatic cases. • Diagnostic Thresholds: Urinary copper >100 μg/24 h; Liver copper >200 μg/g dry weight (Normal 20–50 μg). • Clinical Trap: Must rule out Wilson's in any teen/young adult with new-onset psychiatric symptoms (often mistaken for primary psych or substance abuse). • Mechanism: ATP7B mutation → failed biliary excretion → systemic copper toxicity.

Reference Tables¶

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

Harrison's 22e, p.3339

CLINICAL SIGNS AND SYMPTOMS	BIOCHEMICAL FINDINGS	MOLECULAR FINDINGS
Hepatic: Jaundice Anorexia Vomiting Ascites and/or edema Splenomegaly Neurologic: Dysarthria Facial grimace (risus sardonicus) Drooling Dysphagia Dysgraphia Dystonia Tremor (“wing-beating”) Ataxia Seizures (rare) Ocular: Kayser-Fleischer ring Sunflower cataract (rare) Psychiatric: Decline in school performance Personality change Mood disorder Schizophrenia	Low serum copper Low serum ceruloplasmin Increased urinary copper excretion Elevated liver enzymes Hypoalbuminemia Increased liver copper Fatty liver Cirrhotic liver Hemolytic anemia Renal Fanconi syndrome	Variants in ATP7B on both chromosomes Variants or polymorphisms in other genes (e.g., CAT, SOD2, MTHFR) may influence clinical expression of Wilson’s disease in some individuals