Wilson's Disease

Front 1

WD history

Back 1

autosomal recessive disorder that was localized to c13

encodes ATP7b a cation-transporting R type ATPase

Front 2

Coper metabolism

Back 2

copper is essential trace element that permits the transfer of electrons by a diverse group of coproenzymes

Oxidizes copper, required for cellular resp, iron oxidation, pigment formation, neurotransmitters, antioxdiants, peptide amidation, connective tissue formation

Front 3

Normal cu metabolism

Back 3

dietary copper intake far exceeds the trace amt required

copper is absorbed in the upper intestines

stored and processed by liver

serum copper bound by ceruloplasmin and 5% bound to AAs

Front 4

Liver steps

Back 4

excretion of copper into bile by the hepatocytes is essentially the only mechanism for eliminations

disease completely reversed in OLT

hepatocyte can rapidly increase biliary excretion of copper in response to increases in systemic copper

unusual to be overloaded

no enterohepatic cu circulation

Front 5

Copper cell biology

Back 5

three pathways for copper; excertion into bile, secertion into serum, cuproprotein synthesis

metallothionenin are proteins that are capable of binding metal ions and protecting intracellular proteins for copper tox

Atox1= essential metallochaperone involved in trafficking copper into its secertory pathways, delivers copper directly to ATP7b located on trans golgi network

Front 6

ATP7b

Back 6

8 transmembrane domain protein

6 cu binding sites

cation channel and phosphorylation domain on TD6, ATP binding site near TD7

ATPb7 functions orchestrates excretion of Cu into bile through CMOAT transport on canicular membrane

orchestrates Cu bound secetion to ceruloplasmin

Front 7

wilsons disease genetics

Back 7

1 in 30,000 live births

prevelance is 15-25 million

carrier rate is 1-100

tons of mutations

Front 8

ATP7b mutations

Back 8

causes loss of function and defective holoceruloplasmin biosynthesis and biliary copper secertion

copper overload in hepatocytes with induced oxidative damage, activation of cell death pathways leakage of copper into plasma, eventual copper overload in most tissues

Front 9

clinical present

Back 9

2 main presentations hepatic and neuro

age of onset is 3-45

hepatic usually precedes neuro

hepatic presents; cirrhosis, chronic active hep picture, fulminant liver failure, more common in children then adults

WD considered for any child with fatty liver, hepatomegaly, elevated LFTs, self limiting illness resmebling hepatitis

Self limited jaundice due to hemolysis, WD may be indistinguishable form autoimmune hepatitis, fatigue arthopathy, rash, elevated gamma globulins, ANA+ and Anti smooth mus +

fulminant liver failure; non autoimmune hemolytic anemia, female 2:1 low AP, high urinary copper

Front 10

Neuro symptoms

Back 10

tends to be in 2nd and 3rd decades

generally have hepatic disease already

two main patterns of neuro involvement, movement disorders = tremors poor coordination loss of fine motor control

rigid dystonia = masklike facies rgidity gait disturbances, drooling dysphagia

psych symp are variable depression is common neurotic and compulsive behaviors

Front 11

ocular signs

Back 11

KFR is caused by copper deposition in Descemets membrane at the limbus cornea

KFR (kayser fleischer ring) are seen on direct inspection only when iris pigmentation and copper depo is heavy

careful slit lamp exam necessary

Front 12

KFR rings

Back 12

absent in 15-50% with only hepatic involvement

absent in only 5% who have neurologic issues

may be found due to other diseases

Front 13

other organs

Back 13

coombs negative hemolytic anemia

renal

large joint arthritis

cardiomyopathy, arrhythmia

Front 14

Dx

Back 14

KFR

chronic liver disease

tremor or dystonia

high index of suspicion is necessary

cerulplasmin is less than 20 mg in about 90% of patients with WD, but some Wd heterozygotes have reduced levels with no symptoms looking into screening potentil no

Front 15

Ceruloplasmin

Back 15

catalyzes the oxidation of a number of different reactions, no path in WD

ferroxidase is important of mobilizing iron from tissues

measured via immunologic or oxidase assay, can be false positive and negative

Front 16

Total copper

Back 16

usually low in parallel with low ceruloplasmin

non ceruloplasmin bound copper is elevated calculated by total serum copper

slit lamp

Front 17

Rx

Back 17

liver transplant for fulminant

avoid copper rich foods and use chelators

penicillamine (chelator that increases urinary excretion of copper, inhibits collagen cross-linking and has some immunosuppresant prop.) , trien (also a chelator) and zinc (competes with oral absorption and induce enterocyte metallothionein)