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Amyloidosis 05 November 2004
Deposition of insoluble, fibrous amyloid proteins Unique morphology and secondary structure ie ß pleated sheet
Abbreviated Classification of Amyloid
Light Chain Amyloidosis (AL) commonest systemic amyloidosis <20% with AL have multiple myeloma 20% of multiple myeloma patients have amyloidosis lambda:kappa = 2:1 ; but myeloma has kappa:lamda = 2:1
Amyloid A Amyloidosis as complication of inflammatory disease
Heredofamilail Amyloidosis FMF FAP due to TTR; gelsolin; ApoA1
FMF autosomal recessive
FAP see FAP below AGel: lattice corneal dystrophy, peripheral neuropathy, cranial neuropathy, dystrophic skin changes, involvement of other organs
Clinical manifestations of amyloidosis renal cardiac liver skin gastrointestinal nervous system: both PNS & CNS endocrine joints & muscles respiratory hematologic
Treatment
Supportive: dialysis for renal failure pacemakers for CCF TPN for malnutrition
AL: prednisolone/melphalan/colchicine prolongs life stem cell transplant
FMF: colchicine
Familial Amyloid Polyneuropathy
Autosomal dominant disorder associated with mutant form of transthyretin (TTR) seen in less than 10% of patients with amyloidosis
Transthyretin (or pre-albumin) 127 amino acid single chain protein made predominantly in the liver also synthesized in choroid plexus, small intestine, retinal pigment epithelium tetrameric TTR caries thyroxine and retinoic acid in association with retinoic acid binding protein monomeric TTR has extensive ß pleated sheet in antiparallel configuration ie amyloid Val30Met mutation is the commonest mutant TTR can act as nidus for deposition of normal TTR deposition ie nucleation dependent polymerization particular TTR mutation determines pattern of organ involvement, age of onset & clinical outcome
Clinical begin 30-40 years of age painful peripheral neuropathy (as per multiple random lesion model or model of transport interference) autonomic neuropathy cardiomyopathy, conduction defects renal failure malnutrition vitreous opacities death within 7-10 years
Treatment
Supportive dialysis for renal failure pacemakers for CCF TPN for malnutrition all of the above do not improve mortality
Liver transplantation FAP does not cause cirrhosis and therefore easier to transplant TTR not detectable in serum after transplant neuropathy stabilizes and reported to improve in a proximal to distal fashion nutritional status improves BUT: cardiomyopathy hypertrophy can progress; maybe side effect of tacrolimus cardiomyopathy or conduction defect does not improve after transplant ocular dysfunction can progress failed to demonstrate improvement in mortality to date
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