AMYLOIDOSIS Senior Talk Collins Okolie PGY3

OBJECTIVES Definition Definition Mechanism of formation Mechanism of formation Characteristics common to all amyloid subtypes Characteristics common to all amyloid subtypes Classification Classification Clinical Importance/Symptoms Clinical Importance/Symptoms Diagnosis and Treatment Diagnosis and Treatment Take home message Take home message

Definition A medical condition resulting from aggregation of extracellularly deposited abnormal proteins called amyloid fibrils that cause damage to organs and tissues. A medical condition resulting from aggregation of extracellularly deposited abnormal proteins called amyloid fibrils that cause damage to organs and tissues. These fibrils are insoluble, linear, rigid and measures approximately 7.5 to 10mm in width These fibrils are insoluble, linear, rigid and measures approximately 7.5 to 10mm in width

Mechanism of formation Amyloid fibrils arise from misfolded proteins. Alpha helix to beta pleated sheet Amyloid fibrils arise from misfolded proteins. Alpha helix to beta pleated sheet Proteins are deposited extracellularly Proteins are deposited extracellularly Proteins aggregate and form fibrils called amyloid fibrils. Proteins aggregate and form fibrils called amyloid fibrils. Misfolded proteins may result from point mutations. Misfolded proteins may result from point mutations. Deposited as localized vs systemic Deposited as localized vs systemic -localized; close to cells producing it. -Systemic; distant sites from these cells producing these abnormal proteins.

In 1854 Rudolph Virchow named it amyloid based on color after staining these proteins with iodine and sulfuric acid. Meaning cellulose or starch In 1854 Rudolph Virchow named it amyloid based on color after staining these proteins with iodine and sulfuric acid. Meaning cellulose or starch

Characteristics common to all amyloid subtypes Hematoxylin and Eosin (HE) staining results in amorphous eosinophilic appearance when viewed on light microscopy. Hematoxylin and Eosin (HE) staining results in amorphous eosinophilic appearance when viewed on light microscopy.

Amorphous eosinophilic interstitial amyloid observed on renal biopsy Amorphous eosinophilic interstitial amyloid observed on renal biopsy Picture was adapted from Bruce A Baethge. Amyloidosis Overview. Picture was adapted from Bruce A Baethge. Amyloidosis Overview.

Congo red staining results in bright green fluorescence/birefringe apple green color when viewed under polarized light. Congo red staining results in bright green fluorescence/birefringe apple green color when viewed under polarized light.

Congo red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light Congo red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light Picture was adapted from Bruce A Baethge. Amyloidosis Overview. Picture was adapted from Bruce A Baethge. Amyloidosis Overview.

Electron microscopy shows regular fibrillar structure Electron microscopy shows regular fibrillar structure X-ray diffraction shows beta pleated sheet structure X-ray diffraction shows beta pleated sheet structure

Classification: Historical vs Modern Historical (Clinical): Primary, Secondary, multiple myeloma associated, Familial. Historical (Clinical): Primary, Secondary, multiple myeloma associated, Familial. Modern (Biochemical): Since 1960s based on ability to solubilize fibrils and immunostain for protein subtypes. Modern (Biochemical): Since 1960s based on ability to solubilize fibrils and immunostain for protein subtypes. 23 different human subtypes named based on A for amyloid followed the precursor protein e.g AL, AH. 23 different human subtypes named based on A for amyloid followed the precursor protein e.g AL, AH.

Table was adapted from Harrison's principles of internal medicine 16 th edition vol II, chapter 310-Amyloidosis

Further Clinical Manifestations CNS/Neuro: Neuropathy both autonomic and peripheral, dementia. Corneal deposits also. CNS/Neuro: Neuropathy both autonomic and peripheral, dementia. Corneal deposits also. Cardiac: Cardiac: -Cardiomyopathy typically restrictive -Heart failure predominantly right sided -Angina -Sudden death -Syncope/pre-syncope -ECG Abnormalities and Conduction disease -Arrhythmia -Cardiac tamponade occasionally, though uncommon. -Hypotension

CARDIAC AMYLOID Adapted from K. Shah et al, Archives of internal medicine 2006.

Pulmonary: Pulmonary: -P leural effusions -Parenchymal nodules -Tracheal and bronchial infiltration causing hoarseness, airway obstruction and dysphagia. Renal: P roteinuria, nephrotic syndrome, renal failure leading to kidney transplant or dialysis. Renal: P roteinuria, nephrotic syndrome, renal failure leading to kidney transplant or dialysis.

Heme: Bleeding abnormalities Heme: Bleeding abnormalities Musc: Hypertrophy of muscles, macroglossia Musc: Hypertrophy of muscles, macroglossia Skin: Nodules, plaques, easy bruising Skin: Nodules, plaques, easy bruising GI: Organomegaly ( Hepatomegaly, splenomegaly), gastroparesis, abnormal bowel movement usually constipation, malabsorption GI: Organomegaly ( Hepatomegaly, splenomegaly), gastroparesis, abnormal bowel movement usually constipation, malabsorption

Liver amyloid Adapted from amyloid imageswww.google.com/liver

Diagnosis Unexplained medical disorder and you suspect amyloidosis: e.g heart failure, proteinuria, hepatic dysfunction Unexplained medical disorder and you suspect amyloidosis: e.g heart failure, proteinuria, hepatic dysfunction Check ECG, TTE, BNP, UPEP, SPEP Check ECG, TTE, BNP, UPEP, SPEP Ultimately, you need Tissue biopsy: Abd fat pad, rectal, salivary gland, endomyocardium. Ultimately, you need Tissue biopsy: Abd fat pad, rectal, salivary gland, endomyocardium. Bone marrow biopsy Bone marrow biopsy

Treatment Treatment of this medical disorder is limited and research is still in progress. Treatment of this medical disorder is limited and research is still in progress. Treatment differs depending on subtype. Treatment differs depending on subtype. AL and AH AL and AH -High dose mephalan plus dexamethasone/prednisone -In selected candidates autologous stem cell transplant is an option. - The goal with treatment is to get rid of clonal plasma cells that lead to immunoglobulin protein

AA: Treat the infection or chronic inflammatory condition causing apo serum A protein elevation. AA: Treat the infection or chronic inflammatory condition causing apo serum A protein elevation. Familial Mediterranean fever: Colchicine Familial Mediterranean fever: Colchicine Other conditions are treated conservatively or require organ transplant Other conditions are treated conservatively or require organ transplant Prognosis is poor with this medical disorder. Prognosis is poor with this medical disorder.

TAKE HOME MESSAGE Can affect any organ system Can affect any organ system Hematoxylin and Eosin (HE) and Congo stain only tells you these are amyloid fibrils Hematoxylin and Eosin (HE) and Congo stain only tells you these are amyloid fibrils Need to immunostain to determine subtype Need to immunostain to determine subtype Different subtypes are treated differently. Different subtypes are treated differently. A lot still have to be known about the therapy as prognosis is poor for this disease. A lot still have to be known about the therapy as prognosis is poor for this disease.

References Rajkumar, S. V. and M. A. Gertz. Advances in the Treatment of Amyloidosis. NEJM : Rajkumar, S. V. and M. A. Gertz. Advances in the Treatment of Amyloidosis. NEJM : Merlini G and V Bellotti. Molecular Mechanisms of Amyloidosis. New England Journal of Medicine 2003, August: 349:583 Merlini G and V Bellotti. Molecular Mechanisms of Amyloidosis. New England Journal of Medicine 2003, August: 349:583 Baethge B. Amyloidosis Overview. Baethge B. Amyloidosis Overview. Bogov B, Lubomirova M and Kiperova B. Biopsy of subcutaneous fatty tissue for diagnosis of systemic amyloidosis. Hippokratia Oct;12(4): Bogov B, Lubomirova M and Kiperova B. Biopsy of subcutaneous fatty tissue for diagnosis of systemic amyloidosis. Hippokratia Oct;12(4): Dember LM. Modern Treatment of Amyloidosis: Unresolved questions. J Am Soc Nephrol Dec 10. Dember LM. Modern Treatment of Amyloidosis: Unresolved questions. J Am Soc Nephrol Dec 10. Gorevic, Shah, K. B., et al. Amyloidosis and the Heart. Archives of Internal Medicine : Gorevic, Shah, K. B., et al. Amyloidosis and the Heart. Archives of Internal Medicine : P. D. An overview of amyloidosis. UpToDate.com P. D. An overview of amyloidosis. UpToDate.com J D Sipe and Alan Cohen. Amyloidosis. Harrisons Principles of Internal Medicine. Chapter 30, page 2024 J D Sipe and Alan Cohen. Amyloidosis. Harrisons Principles of Internal Medicine. Chapter 30, page 2024 Images and tables were obtained from Harrisons, Archives of internal medicine, emedicine and google as sited on each image. Images and tables were obtained from Harrisons, Archives of internal medicine, emedicine and google as sited on each image.