Wilson's disease and alpha-1-antitrypsin deficiency - etiology, pathogenesis, and clinical manifestations.
Wilson's disease
Etiology
- Autosomal recessive genetic disorder.
- Mutation in ATP7B gene on chromosome 13.
- Defective copper-transporting ATPase → impaired copper incorporation into ceruloplasmin and decreased biliary copper excretion.
Pathogenesis
- Decreased hepatic copper excretion → copper accumulation in hepatocytes.
- Copper causes oxidative damage → hepatocyte necrosis and release of free copper into blood.
- Extrahepatic copper deposition:
- Brain (especially basal ganglia) → neuropsychiatric symptoms.
- Cornea → Kayser- Fleischer rings.
- Kidneys → tubular dysfunction.
Clinical manifestations
- Hepatic:
- Hepatitis, hepatomegaly.
- Chronic hepatitis → cirrhosis.
- Acute liver failure (especially in young patients).
- Neurological:
- Tremor, dystonia, dysarthria.
- Parkinsonian features.
- Psychiatric:
- Personality changes.
- Depression, psychosis.
- Ocular:
- Kayser- Fleischer rings (golden- brown ring at corneal margin).
Alpha- 1-antitrypsin (A1AT) deficiency
Etiology
- Autosomal codominant genetic disorder.
- Mutations in SERPINA1 geneon chromosome 14.
- Most severe variant: PiZZ genotype → misfolded A1AT protein.
Pathogenesis
- Abnormal A1AT protein misfolds → accumulates in hepatocyte endoplasmic reticulum → hepatocyte injury → hepatitis and cirrhosis.
- Reduced circulating A1AT → unopposed neutrophil elastase activity → alveolar wall destruction → panacinar emphysema, especially in lower lung zones.
Clinical manifestations
- Hepatic:
- Neonatal hepatitis with cholestatic jaundice.
- Chronic hepatitis in children or adults.
- Cirrhosis, risk of hepatocellular carcinoma.
- Pulmonary:
- Dyspnea on exertion.
- Chronic cough, wheezing.
- Early- onset emphysema (30–40s), especially in non- smokers.