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Proteins Gone
Rogue
Benjamin L KitchensInternal Medicine PGY2
March, 9 2015
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53 y/o M with h/o bilateral carpal tunnel syndrome and no other PMH who presented to the ED with new onset chest discomfort and dyspnea.
PSH- bilateral median nerve decompression 4 years prior
FH- unremarkable SH- no tobacco, EtOH, or drugs ALL- NKDA Medications- none (including OTC)
Clinical Case- Mr. M
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Resp: Crackles over bilateral lung bases. Card: III/VI SEM over apex; no rubs or
gallups Abd: Soft, nt, nd, no masses, no
organomegaly, +BS MSK: 2+ bilateral lower extremity edema Neuro: A&Ox3. No focal neurologic deficits BNP- 1270
Physical Exam
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To define amyloidosis. Provide a brief overview of the disease’s
historical context. To understand its pathoneogenesis. To describe the presentation of amyloidosis. To focus on the specific case of cardiac
amyloidosis. To discuss diagnostic and imaging modalities. To provide a review of the current treatments
as well as recent developments.
Objectives
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Amyloidosis is a disorder of the secondary structure of protein that is synthesized and secreted from a cell as a soluble molecule and is then deposited as an insoluble molecule into tissue, forming a fibrous deposit.
This deposition leads to organ dysfunction.
Definition
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1639- Fontanus describes the “Sago spleen”
Historical Perspective
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1854- Virchow called material deposited in tissue “amyloid” based on a color reaction between iodine and sulphuric acid that was similar to starch (aka amylum).
1859- Friedreich and Kekule showed that this substance was protein.
1922- Bennhold first uses the Congo red stain to reveal these deposits.
1959- Cohen and Calkins describe the fibrillar structure of amyloid on EM.
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Most commonly presents with weakness and weight loss.
Purpura Swelling Neuropathy Syncope Arthralgias Myalgias
Symptoms
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Macroglossia
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AL Amyloidsosis Systemic AA Hereditary amyloidosis Senile systemic amyloidosis HD associated amyloidosis Isolated atrial amyloidosis
Types of Amyloid
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Most common form of amyloidosis. Associated with plasma cell dyscrasia. 2,000 to 2,500 new cases annually in the
US. Peak onset in sixth decade. Male:female 3:2 Heart is affected in 60-90% of cases Median survival is <6 months in untreated
patients.
AL Amyloidosis
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Monoclonal immunoglobulin light chains produced by plasma cells form the amyloid fibrils.
Consist of kappa or lambda light chains.
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Characterized by extracellular amyloid infiltration throughout the heart. Deposits occur in the:◦ ventricles and atria◦ perivascular tissue◦ conduction system
Results in biventricular wall thickening Leads to restrictive cardiomyopathy.
Cardiac Amyloidosis
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Dyspnea and chest discomfort Syncope Signs of right sided heart failure
◦ Peripheral edema◦ Elevated JVP◦ Mitral and tricuspid regurgitation murmurs◦ Narrow pulse pressure
Presentation
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Requires biopsy of evidence of amyloid tissue involvement + demonstration of a plasma cell clone.
Positive Congo Red stain and apple-green birefiringence under polarized light.
Diagnosis
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Pseudoinfarction in 46% of patients Low voltage in 47% of patients RBBB Bradycardia Arrhythmias
EKG Findings
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Elevated BNP NT-pro-BNP >152 pg/ml has 93% sensitivity
and 90% specificity. Elevated troponin Higher all cause mortality rate.
Cardiac Biomarkers
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Diastolic dysfunction is the earliest manifestation.
Ventricular thickening Granular “sparkling” of myocardium
Echocardiogram
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Transthoracic Echocardiogram
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Cardiac catheterization Hemodynamic assessment Endomyocardial biopsy
Nuclear studies Cardiac MRI
Other Diagnostic modalities
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Myocardial Biopsy
ElectronMicroscopy
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Cardiac MRI
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Heart failure management is challenging. Cornerstone of therapy is diuresis. Antihypertensives poorly tolerated. Bleeding/thromboembolic risk Arrythmia
Treatment
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Negative serum and urine for monoclonal protein
Normal free light chain ratio <5% bone marrow plasma cells
Goals of Chemotherapy
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Melphalan restuls with complete remission in 40% of patients.
Lenalidomide Melphalan + dexamethasone Thalidomide + dexamethasone Under investigation: deoxydoxorubicin and
interferon-alpha
Specific Agents
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Controversial at this time. Considered a palliative option in AL
amyloidosis. 39% survival at 4 years.
Heart Transplant
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Only effective in AL amyloidosis. Strict indications for transplant.
◦ Age <80 years, compensate CHF, EF >40%, no pleural effusions, SBP >90, O2 sat >95%
High dose melphalan + ASCT 67% complete hematologic response. 27% complete organ response. Overall survival rate of 75% Risks: PNA, arrhythmias, GI bleed,
thromboembolism, renal failure
Stem Cell Transplant
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EKG
Back to Mr. M
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Thickened intraventricular septum. LV and RV enlargement. EF- 35%. Mild MR. Global hypokinesis.
TTE
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Bone Marrow Bx
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Not a candidate for stem cell transplant. 8 cycles of melphalan. High dose dexamethasone. Failed this therapy. Brief trial of thalidomide limited by
intolerance. Underwent 12 week course of bortezomib.
Management
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Amyloidosis is a rare disease resulting from the production of abnormal protein that deposits in tissues resulting in end-organ dysfunction.
It is important to distinguish it from other entities, particularly when the heart is involved.
Biopsy is the gold-standard, but non-invasive methods are becoming more sensitive.
Prognosis continues to improve with therapies more specifically aimed at the underlying pathophysiology.
Conclusion