AMYLOIDOSIS.ppt

AMYLOIDOSISAMYLOIDOSIS

Senior TalkSenior Talk

Collins Okolie PGY3Collins Okolie PGY3

OBJECTIVESOBJECTIVES

DefinitionDefinition Mechanism of formationMechanism of formation Characteristics common to all amyloid Characteristics common to all amyloid

subtypessubtypes ClassificationClassification Clinical Importance/SymptomsClinical Importance/Symptoms Diagnosis and TreatmentDiagnosis and Treatment Take home messageTake home message

DefinitionDefinition

A medical condition resulting from A medical condition resulting from aggregation of extracellularly aggregation of extracellularly deposited abnormal proteins called deposited abnormal proteins called amyloid fibrils that cause damage to amyloid fibrils that cause damage to organs and tissues. organs and tissues.

These fibrils are insoluble, linear, These fibrils are insoluble, linear, rigid and measures approximately rigid and measures approximately 7.5 to 10mm in width7.5 to 10mm in width

Mechanism of formationMechanism of formation Amyloid fibrils arise from misfolded Amyloid fibrils arise from misfolded

proteins. Alpha helix to beta pleated sheetproteins. Alpha helix to beta pleated sheet Proteins are deposited extracellularlyProteins are deposited extracellularly Proteins aggregate and form fibrils called Proteins aggregate and form fibrils called

amyloid fibrils.amyloid fibrils. Misfolded proteins may result from point Misfolded proteins may result from point

mutations.mutations. Deposited as localized vs systemicDeposited as localized vs systemic-localized; close to cells producing it.-localized; close to cells producing it.-Systemic; distant sites from these cells -Systemic; distant sites from these cells

producing these abnormal proteins.producing these abnormal proteins.

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

Characteristics common to all Characteristics common to all amyloid subtypesamyloid subtypes

Hematoxylin and Eosin (HE) staining Hematoxylin and Eosin (HE) staining results in results in amorphous eosinophilic amorphous eosinophilic appearanceappearance when viewed on light when viewed on light microscopy. microscopy.

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

www.emedicine.medscape.comwww.emedicine.medscape.com

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

Congo red staining of a cardiac biopsy specimen containing Congo red staining of a cardiac biopsy specimen containing

amyloid, viewed under polarized lightamyloid, viewed under polarized light Picture was adapted from Bruce A Baethge. Amyloidosis Overview. Picture was adapted from Bruce A Baethge. Amyloidosis Overview.

www.emedicine.medscape.comwww.emedicine.medscape.com

Electron microscopy shows Electron microscopy shows regular regular fibrillar structurefibrillar structure

X-ray diffraction shows X-ray diffraction shows beta beta pleated sheet structurepleated sheet structure

Classification:Classification: Historical vs Modern Historical vs Modern

Historical (Clinical): Primary, Secondary, Historical (Clinical): Primary, Secondary, multiple myeloma associated, Familial.multiple myeloma associated, Familial.

Modern (Biochemical): Since 1960’s based Modern (Biochemical): Since 1960’s based on ability to solubilize fibrils and on ability to solubilize fibrils and immunostain for protein subtypes.immunostain for protein subtypes.

23 different human subtypes named based 23 different human subtypes named based on A for amyloid followed the precursor on A for amyloid followed the precursor protein e.g AL, AH.protein e.g AL, AH.

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

Further Clinical ManifestationsFurther Clinical Manifestations CNS/Neuro: Neuropathy both autonomic and peripheral, CNS/Neuro: Neuropathy both autonomic and peripheral,

dementia. Corneal deposits also.dementia. Corneal deposits also. Cardiac: Cardiac: -Cardiomyopathy typically restrictive-Cardiomyopathy typically restrictive-Heart failure predominantly right sided-Heart failure predominantly right sided-Angina -Angina -Sudden death-Sudden death-Syncope/pre-syncope-Syncope/pre-syncope-ECG Abnormalities and Conduction disease-ECG Abnormalities and Conduction disease-Arrhythmia-Arrhythmia-Cardiac tamponade occasionally, though uncommon.-Cardiac tamponade occasionally, though uncommon.-Hypotension-Hypotension

CARDIAC AMYLOID

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

Pulmonary: Pulmonary: -P-Pleural effusionsleural effusions-Parenchymal nodules-Parenchymal nodules-Tracheal and bronchial infiltration causing -Tracheal and bronchial infiltration causing

hoarseness, airway obstruction and hoarseness, airway obstruction and dysphagia. dysphagia.

Renal: PRenal: Proteinuria, nephrotic syndrome, roteinuria, nephrotic syndrome, renal failure leading to kidney transplant renal failure leading to kidney transplant or dialysis.or dialysis.

Heme: Bleeding abnormalitiesHeme: Bleeding abnormalities Musc: Hypertrophy of muscles, Musc: Hypertrophy of muscles,

macroglossiamacroglossia Skin: Nodules, plaques, easy bruisingSkin: Nodules, plaques, easy bruising GI: Organomegaly (GI: Organomegaly (Hepatomegaly, Hepatomegaly,

splenomegaly), gastroparesis, abnormal splenomegaly), gastroparesis, abnormal bowel movement usually constipation, bowel movement usually constipation, malabsorptionmalabsorption

Liver amyloidLiver amyloid

Adapted from www.google.com/liver amyloid images

DiagnosisDiagnosis

Unexplained medical disorder and Unexplained medical disorder and you suspect amyloidosis: e.g heart you suspect amyloidosis: e.g heart failure, proteinuria, hepatic failure, proteinuria, hepatic dysfunctiondysfunction

Check ECG, TTE, BNP, UPEP, SPEPCheck ECG, TTE, BNP, UPEP, SPEP Ultimately, you need Tissue biopsy: Ultimately, you need Tissue biopsy:

Abd fat pad, rectal, salivary gland, Abd fat pad, rectal, salivary gland, endomyocardium.endomyocardium.

Bone marrow biopsyBone marrow biopsy

TreatmentTreatment

Treatment of this medical disorder is limited Treatment of this medical disorder is limited and research is still in progress.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 -High dose mephalan plus dexamethasone/prednisonedexamethasone/prednisone

-In selected candidates autologous stem cell -In selected candidates autologous stem cell transplant is an option.transplant is an option.

- The goal with treatment is to get rid of clonal - The goal with treatment is to get rid of clonal plasma cells that lead to immunoglobulin plasma cells that lead to immunoglobulin proteinprotein

AA: Treat the infection or chronic AA: Treat the infection or chronic inflammatory condition causing apo serum inflammatory condition causing apo serum A protein elevation. A protein elevation.

Familial Mediterranean fever: ColchicineFamilial Mediterranean fever: Colchicine Other conditions are treated Other conditions are treated

conservatively or require organ transplantconservatively or require organ transplant Prognosis is poor with this medical Prognosis is poor with this medical

disorder.disorder.

TAKE HOME MESSAGETAKE HOME MESSAGE

Can affect any organ system Can affect any organ system Hematoxylin and Eosin (HE) and Congo Hematoxylin and Eosin (HE) and Congo

stain only tells you these are amyloid stain only tells you these are amyloid fibrilsfibrils

Need to immunostain to determine Need to immunostain to determine subtypesubtype

Different subtypes are treated differently.Different subtypes are treated differently. A lot still have to be known about the A lot still have to be known about the

therapy as prognosis is poor for this therapy as prognosis is poor for this disease.disease.

ReferencesReferences Rajkumar, S. V. and M. A. Gertz. “Advances in the Treatment of Rajkumar, S. V. and M. A. Gertz. “Advances in the Treatment of

Amyloidosis.” Amyloidosis.” NEJM. NEJM. 2007. 356: 2413-2415 2007. 356: 2413-2415 Merlini G and V Bellotti. Molecular Mechanisms of Amyloidosis. New Merlini G and V Bellotti. Molecular Mechanisms of Amyloidosis. New

England Journal of Medicine 2003, August: 349:583England Journal of Medicine 2003, August: 349:583 Baethge B. Amyloidosis Overview. Baethge B. Amyloidosis Overview. www.emedicine.medscape.comwww.emedicine.medscape.com Bogov B, Lubomirova M and Kiperova B. Biopsy of subcutaneous fatty Bogov B, Lubomirova M and Kiperova B. Biopsy of subcutaneous fatty

tissue for diagnosis of systemic amyloidosis. tissue for diagnosis of systemic amyloidosis. Hippokratia.Hippokratia. 2008 2008 Oct;12(4):236-9.Oct;12(4):236-9.

Dember LM. Modern Treatment of Amyloidosis: Unresolved questions. Dember LM. Modern Treatment of Amyloidosis: Unresolved questions. J Am J Am Soc Nephrol.Soc Nephrol. 2008 Dec 10. 2008 Dec 10.

Gorevic, Gorevic, Shah, K. B., Shah, K. B., et al.et al. Amyloidosis and the Heart. Amyloidosis and the Heart. Archives of Internal Archives of Internal MedicineMedicine. 2006. 166: 1805-1813.. 2006. 166: 1805-1813.

P. D. An overview of amyloidosis. P. D. An overview of amyloidosis. UpToDate.comUpToDate.com J D Sipe and Alan Cohen. J D Sipe and Alan Cohen. AmyloidosisAmyloidosis. Harrison’s Principles of Internal . Harrison’s Principles of Internal

Medicine. Chapter 30, page 2024Medicine. Chapter 30, page 2024 Images and tables were obtained from Harrison’s, Archives of internal Images and tables were obtained from Harrison’s, Archives of internal

medicine, emedicine and google as sited on each image.medicine, emedicine and google as sited on each image.