Overview
Definition:
Wilson disease (WD) is an autosomal recessive genetic disorder characterized by impaired biliary copper excretion, leading to copper accumulation in the liver, brain, eyes, and other organs
In children, it often presents with hepatic or neuropsychiatric manifestations.
Epidemiology:
WD affects approximately 1 in 30,000 to 1 in 40,000 live births worldwide
It is caused by mutations in the ATP7B gene on chromosome 13, encoding a copper-transporting ATPase
Carriers are estimated to be 1 in 90 individuals.
Clinical Significance:
Early diagnosis and treatment are crucial to prevent irreversible organ damage and improve prognosis
Untreated WD can lead to severe liver failure, cirrhosis, and debilitating neurological and psychiatric symptoms, making it a critical topic for pediatricians preparing for DNB and NEET SS examinations.
Clinical Presentation
Symptoms:
Hepatic symptoms: Jaundice
Abdominal distension
Ascites
Easy bruising
Fatigue
Nausea and vomiting
Loss of appetite
Hepatomegaly
Splenomegaly
Neuropsychiatric symptoms: Tremors
Dysarthria
Dystonia
Drooling
Behavioral changes
Depression
Psychosis
School performance decline
Ocular findings: Kayser-Fleischer rings (golden-brown corneal copper deposits)
Sunflower cataracts.
Signs:
Hepatomegaly
Splenomegaly
Jaundice
Spider angiomas
Palmar erythema
Ascites
Signs of chronic liver disease
Neurological signs: Parkinsonism
Gait disturbances
Speech difficulties
Psychiatric manifestations.
Diagnostic Criteria:
Diagnosis is based on a combination of clinical findings, laboratory tests (low serum ceruloplasmin, elevated urinary copper excretion, elevated liver copper content), genetic testing, and sometimes ophthalmological examination for Kayser-Fleischer rings
Specific scoring systems exist to aid diagnosis.
Diagnostic Approach
History Taking:
Detailed family history of liver or neurological disease
Onset and progression of symptoms
Nutritional history
Exposure to copper-containing products
Prior hepatitis or liver disease
Any previous unexplained liver enzyme elevations.
Physical Examination:
Thorough abdominal examination for hepatomegaly, splenomegaly, and ascites
Neurological examination to assess for tremors, rigidity, dystonia, and coordination
Ocular examination for Kayser-Fleischer rings
Skin examination for signs of chronic liver disease.
Investigations:
Serum ceruloplasmin: Typically < 20 mg/dL (normal 20-40 mg/dL)
Low levels are highly suggestive, especially in symptomatic patients
However, it can be normal in some early or asymptomatic cases or elevated in inflammatory conditions
24-hour urinary copper excretion: Elevated (> 100 µg/day)
Liver biopsy with quantitative copper analysis: Elevated liver copper content (> 250 µg/g dry weight) is diagnostic, particularly in cases with borderline serum ceruloplasmin
Serum copper: Often low or normal
Kayser-Fleischer rings: Best visualized with a slit lamp examination
ATP7B gene sequencing: Confirmatory for genetic diagnosis
Liver function tests: AST, ALT, bilirubin, albumin, prothrombin time may be abnormal.
Differential Diagnosis:
Other causes of chronic liver disease in children: Viral hepatitis (Hepatitis A, B, C)
Autoimmune hepatitis
Non-alcoholic fatty liver disease (NAFLD)
Alpha-1 antitrypsin deficiency
Biliary atresia
Genetic hemochromatosis
Other metabolic disorders presenting with liver dysfunction
Neurological disorders with movement abnormalities.
Management
Initial Management:
In patients with symptomatic WD or those with advanced hepatic disease, immediate management focuses on stabilization and initiation of copper-reducing therapy
Liver transplantation may be indicated in fulminant hepatic failure or decompensated cirrhosis unresponsive to medical management.
Medical Management:
Copper-chelating agents: Penicillamine (initial dose 10-20 mg/kg/day in 2-4 divided doses, max 1 g/day)
Side effects include rash, fever, bone marrow suppression, and renal involvement
Trientine dihydrochloride (initial dose 750-1500 mg/day in 2-3 divided doses)
Generally better tolerated than penicillamine, especially for neuropsychiatric symptoms
Zinc therapy: Recommended as maintenance therapy after initial chelation or for asymptomatic patients
It blocks intestinal copper absorption by inducing metallothionein
Doses: 50-150 mg elemental zinc daily in 3 divided doses.
Surgical Management:
Liver transplantation is reserved for patients with irreversible liver disease, including acute liver failure or decompensated cirrhosis with a poor prognosis despite optimal medical therapy
Pre-transplant chelation is generally continued until the procedure.
Supportive Care:
Nutritional support is vital
Patients should avoid copper-rich foods (e.g., shellfish, nuts, chocolate, mushrooms, liver)
Regular monitoring of liver function tests, renal function, blood counts, and copper levels is essential
Neurological and psychiatric assessments should be ongoing
Genetic counseling for affected families.
Complications
Early Complications:
Worsening liver dysfunction after initiating chelation therapy (a transient phenomenon in some cases)
Neurological deterioration (rare, can occur early in chelation)
Hematological abnormalities (anemia, leukopenia, thrombocytopenia) due to penicillamine.
Late Complications:
Cirrhosis and portal hypertension
End-stage liver disease requiring transplantation
Irreversible neurological damage
Osteoporosis
Renal dysfunction
Hemolytic anemia
Increased risk of hepatocellular carcinoma.
Prevention Strategies:
Early diagnosis through screening of at-risk individuals (e.g., siblings of affected patients) and prompt initiation of therapy can prevent the development of severe complications and improve long-term outcomes.
Prognosis
Factors Affecting Prognosis:
Age at diagnosis and treatment initiation is the most critical factor
Patients diagnosed and treated before significant organ damage have an excellent prognosis
Presence and severity of neurological or hepatic manifestations at diagnosis
Compliance with therapy
Development of drug side effects.
Outcomes:
With timely and consistent treatment, the accumulation of copper can be prevented, leading to stabilization or improvement of symptoms and a near-normal life expectancy
Untreated disease is fatal.
Follow Up:
Lifelong monitoring is required
This includes regular clinical assessments, laboratory tests (serum ceruloplasmin, urinary copper, liver function tests), and monitoring for drug side effects
Patients may transition to maintenance therapy with zinc once copper levels are normalized and symptoms are controlled.
Key Points
Exam Focus:
Low serum ceruloplasmin is a hallmark, but not diagnostic alone
Elevated liver copper content is definitive
Treatment involves chelating agents (penicillamine, trientine) and zinc
Genetic testing is important for family screening.
Clinical Pearls:
Always consider WD in children with unexplained liver enzyme abnormalities, especially if accompanied by neurological or psychiatric symptoms
Kayser-Fleischer rings are highly suggestive but may be absent in early disease or some hepatic forms
Zinc therapy is crucial for long-term management and prevention of copper re-accumulation.
Common Mistakes:
Diagnosing WD based solely on low ceruloplasmin without corroborating evidence
Delaying treatment in symptomatic patients
Underestimating the importance of lifelong adherence to therapy
Not screening siblings of diagnosed children.