- autosomal recessive
- 3 components
- Liver disease
- Keyser-Fleisher rings in cornea
- Degenerative changes in brain
- 1/30000 incidence
pathogenesis
genetics
- defective gene - ATB7B
- In chromosome 13q14.3
- copper transporting p type adinosine triphosphatase
- Used in biliary copper transport and copper excretion
- absence of this enzyme results in defective copper excretion
- accumulated copper is cytotoxic to liver and inhibits pyruvate oxidase in brain and ATPase in membranes
- pathogenic variations have disease onset as early as 3 years
- Milder variants can cause disease as late as 80 years
clinical manifestations
hepatic 40-60%
- asymptomatic elevation of liver enzymes
- Asymptomatic hepatomegaly with or without splenomegaly
- Acute liver failure - coagulopathy, jaundice, encephalopathy (females are 3 times more likely to develop ALF)
- Acute hepatitis - jaundice, abdominal pain
- Liver cirrhosis
neurological 40-50%
- involuntary movements - tremor, dyskinesia, ataxia, ballismus, chorea, parkinsonism
- Speech disturbances - dysarthria
- Dysphagia
- Autonomic disfunction - salivation, orthostatic hypotension
- Gait and balance distrubances
psychiatric 10-25%
- personality disorders
- Mood disorders
- Psychosis
- Cognitive impairment
ophthalmic 90-100% in neurological, 40-50% in hepatic
others
- renal - tubular disfunction, nephrolithiasis, hypercalciuria, hyperphosphaturia (fanconi’s)
- Bone - osteophorosis, chondrocalcinosis, joint pain
- Skin - hyperpigmentation, azure lunulae (sky blue moon) of the nails, xerosis, acanthosis nigricans, lipomas,
- Hematopoietic - thrombocytopenia, leukcytopenia, haemolytic anemia (can sometimes be the earliest presentation)
- Gynaecological - delayed puberty, abnormal menstruration
- Endocrine - glucose intolrerance, parathyroid insufficiency
pathology
- all grades of hepatic injury
- Earliest histological feature - steatosis
- Differential - non alcoholic fatty liver, steatohepatitis, autoimmune hepatitis
- Electron microscopy
- Primarily involve mitochondria
- Increased density of matrix material, inclusion of lipid and granular material, increased intracristal space with dilation of tips of cristae
Diagnosis
- decreased serum ceruloplasmin <20mg/dl
- Increased serum copper - >1.6 mcmol/24 hr in adult and >0.64 mcmol/24 hr in children
- increased urinary copper excretion 100-1000 mcg/day (normal <40)
- demonstration of KF ring
- Liver biopsy shows increase copper in tissue. >250 mcg/g of dry weight (Normal <10 mcg/g dry weight). To be done only if other investigations are inconclusive
- genetic analysis
- DNA gene analysis
- Linkage analysis
treatment
- limiting copper intake <1mg/day
- Initial (Copper chelating agents)
- Triethylene tetramine dihydrochloride 750-1500 mg/day in 2-3 divided doses
- Children dosing 20 mg/kg/day - D-penicillamine can be used as alternative 1000-1500 mg/day (20mg/kg/day in children) in 2-4 divided doses can be alternative
- Hypersensitive reaction can occur (good pasture syndrome, SLE, polymyositis) can occur in 10-20% of patient who take chelators
- Supplementation should be done for vitamin b6
- Ammonium tetrathiomolybdate 20 mg 6 times a day can also be used
- Side effects - anemia, leukopenia, thrombocytopenia, elevation of ALT and AST
- Zinc (impairs absorption of copper) 25-50 mg TDS
- Antioxidants - vitamin E, curcumin
- Pharmacological chaperones - 4-phenylbutyrate
- Liver transplant is curative