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Proteins Gone Rogue Benjamin L Kitchens Internal Medicine PGY2 March, 9 2015

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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