University:
Boston University
Course:
CAS BI 108 | Biology 2
Academic year:

2023
Views:

329

Pages:

19
Author:

Triston Franco

Diagnostic Evaluation Diagnostic Evaluation Tissue biopsy to diagnose amyloid deposits Fat aspirate Involved organ Gingival tissue or minor salivary gland Sural nerve Amyloid Typing AL Bone marrow biopsy with immunohistochemistry for clonal plasma cells Serum free light chain assay Serum and urine immunofixation electropheresis ATTR DNA sequencing AA Immunohistochemistry Identification of underlying infection, inflammatory disease Tissue biopsy Light microscopy (H&E): amorphous, eosinophilic, hyaline, extracellular substance Deposits induce pressure atrophy Peripheral nerve Wallerian Degeneration Distal degeneration of axon & myelin sheath Proximal axonal degeneration to next node Cell body swells, nucleus is peripheralized Congo red stain: apple-green birefringence Tissue Biopsy Nerve involvement Intraneural amyloid AL amyloidosis cannot be differentiated from TTR amyloidosis on basis of biopsy Immunohistochemistry with specific Abs Helpful for differentiation Not completely reliable Sural Nerve Biopsy Vascular deposits No intraneural deposits seen Spotty nature of deposits does not exclude nerve involvement Congo red staining Cross links within fibrils Polarized light Apple green birefringence Commercial DNA Testing Available for TTR Full TTR DNA testing if mutation unknown Specific TTR sequence testing if mutation known Not available for: ApoAI Gelsolin Treatment Treatment Goals Treatment Nonspecific Specific Nonspecific Treatment Treat painful neuropathic symptoms Agents: Gabapentin Amitryptyline Pregabalin Duloxetine Tricyclic antidepressants, may exacerbate orthostasis Opioid analgesics Response to drug may change as disease progresses Specific Treatment: TTR-FAP Orthotopic liver transplantation Remove mutant TTR, synthesized in liver Val30Met mutation best prognosis: 80% 5 year survival Other mutations: 55-60% 5 year survival Some evidence of efficacy for ApoAI Vitrectomy for corneal amyloid deposits Small molecules to stabilize the normal TTR tetramer Diflunisal (NSAID) Tafamidis Specific Treatment: Gelsolin Lattice corneal dystrophy Method: Corneal transplantation Cutis laxis & blepharochalasis (resultant from facial palsy) Method: Plastic surgery Note: Gelsolin is essential protein of actin function Rx aimed to eliminate production will likely not be tolerated Specific Treatment: AL Anti-plasma cell chemotherapy Oral melphalan chemotherapy (relatively ineffective) High dose IV melphalan and autologous stem cell transplantation New agents Bortezomib, proteasome inhibitor Lenalidomide, immunomodulator Others Summary Summary: Overview TTR-FAP ApoA1 AL Age at Onset 30s-70s 30s-40s Usually older pts Gender M>F M=F M>F Associated Systems Sensorimotor Weight loss Heart failure Increased ICP Corneal Dystrophy Sensorimotor Weight loss Renal Failure Sensorimotor Weight loss Heart Failure Renal Failure Family History Yes Yes No Cause of Death Heart failure, wasting syndrome Renal failure Heart failure, arrhythmia, bleeding Summary: Clinical Findings Summary: Diagnosis & Treatment Take Home Points Amyloidosis should not be considered a single disease All amyloid has a similar structure of β-sheet fibrils Amyloid is either misfolded normal protein or mutant protein. Both deposit extracellularly and disrupt adjacent normal tissue function Neuropathy occurs with AL and AF, particularly ATTR Biopsy is required for diagnosis of systemic amyloidosis, following by genetic, hematologic, immunochemical, and proteomics for typing Treatment methods are both nonspecific and specific