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NEW DEVELOPMENTS IN MEDICAL RESEARCH
AMYLOIDOSIS
RISK FACTORS, TREATMENT
OPTIONS AND CLINICAL ASPECTS
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NEW DEVELOPMENTS IN
MEDICAL RESEARCH
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NEW DEVELOPMENTS IN MEDICAL RESEARCH
AMYLOIDOSIS
RISK FACTORS, TREATMENT
OPTIONS AND CLINICAL ASPECTS
RAQUEL WATTS
EDITOR
New York
Copyright © 2017 by Nova Science Publishers, Inc.
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ISBN: H%RRN
Library of Congress Control Number: 2016947175
Published by Nova Science Publishers, Inc. † New York
CONTENTS
Preface vii
Chapter 1 Amyloid Cardiomyopathy 1
Tomas Pika and Jiri Vymetal
Chapter 2 Novel Therapies for Amyloidosis in the Era of
RNAi and Immunotherapy 29
Sandy W. Wong and Raymond L. Comenzo
Chapter 3 Clinical Management of Amyloidosis:
Genetic Counseling as an Important Component of
the Treatment Algorithm 51
Jennifer Davey, Jen Bevilacqua, Andrew Hesse and
Honey V. Reddi
Chapter 4 Tissue Examination in a Diagnostic Procedure 73
Pavla Flodrova, Tomas Pika and Patrik Flodr
Chapter 5 Protein Studies in Light-Chain Amyloidosis 91
Pavel Lochman
Bibliography 107
Related Nova Publications 125
Index 129
PREFACE
Amyloidosis is a result of the abnormal deposition of ‘amyloid’ resulting
in the disruption of organ and tissue function, which can be localized or
systemic, with the kidney being most frequently affected. This book discusses
the risk factors, treatment options and clinical aspects of amyloidosis. Chapter
One explores amyloid cardiomyopathy. Chapter Two summarizes current
investigations utilizing RNAi and immunotherapy to target the amyloid
protein itself. Chapter Three reviews genetic counseling as an important
component of the treatment algorithm for amyloidosis. Chapter Four discusses
tissue examination in a diagnostic procedure. Chapter Five reviews protein
studies in light-chain amyloidosis.
Chapter 1 - Light-chain amyloidosis (AL), hereditary transthyretin
amyloidosis and senile systemic amyloidosis are the most common
amyloidoses with cardiac involvement. Cardiac involvement is present in more
than 60% of patients with light-chain amyloidosis, and symptomatic heart
failure is a dominant symptom in 35% of patients. In hereditary transthyretin
amyloidosis, clinical symptoms depend on the type of mutations in the
transthyretin gene. Patients with dominant cardiac involvement usually carry
the Val122Ile mutation.
Advanced stage clinical finding includes symptoms of right-sided heart
failure caused by restrictive and hypertrophic cardiomyopathy with initial
diastolic dysfunction, followed by a relatively rapid progression to global form
of heart failure. Chronic hypotension with ortostatic syncope is often present
with autonomous nervous system involvement. A sudden death due to
arrhythmogenic causes and a chronic refractory heart failure are the most
common causes of death.
Raquel Watts
viii
Cardiac biomarkers assay is an essential part of diagnostic algorithm for
patients with AL amyloidosis. Usually, serum levels of troponins and N-
terminal pro-brain natriuretic peptide are evaluated. The values determined at
the time of diagnosis of the disease serve as a prognostic parameter, and also
enable an effective stratification of patients within the Mayo Clinic staging
system. Typical ECG findings include reduced voltage in the extremity leads
under 5 mm and the presence of QS in the chest leads (pseudoinfarct pattern).
At present, echocardiography is crucial for the diagnosis and monitoring of
cardiac involvement in amyloidosis. The criterion of impairment is concentric
hypertrophy of left ventricle with end-diastolic thickness of the
interventricular septum in excess of 12 mm. Echocardiography, along with the
cardiac biomarkers assay, are crucial for the evaluation of organ treatment
response or disease progression. Magnetic resonance examination of the heart
allows morphological and functional imaging. The use of gadolinium contrast
examination enables evaluation of the extent of myocardial imbibition by
amyloid masses, using the phenomenon of “delayed enhancement”.
Endomyocardial biopsy is indicated in case of suspected heart condition when
non-targeted biopsies are negative. Cardiac amyloidosis therapy focuses on
influencing the principal process leading to amyloid production, and on the
treatment of cardiac failure.
Chapter 2 - Abnormal fibrillar deposition of protein causing organ failure
characterizes all forms of amyloidosis. Amyloidosis was uniformly a rapidly
fatal disease without effective treatment options around 20 years ago. Multiple
advances especially in light chain (AL) amyloidosis have occurred since, first
with the advent of melphalan-based autologous stem cell transplant and then
the introduction of bortezomib-based treatment. Both of these treatment
modalities, derived from multiple myeloma research, kill the clonal cells
producing immunoglobulin light chains. While research continues in search of
cytotoxic therapies for AL, current studies are directed at the production,
stability and clearance of light-chains as well as other types of amyloid
proteins. The authors summarize the current investigations utilizing RNAi and
immunotherapy to target the amyloid protein itself.
Chapter 3 - Amyloidosis is a result of the abnormal deposition of
‘amyloid’ resulting in disruption of organ and tissue function, which can be
localized or systemic, with the kidney being most frequently affected.
Clinically, the presence of proteinuria, renal insufficiency, heart failure,
orthostatic hypertension, peripheral neuropathy, or unexplained kidney, heart
or systemic disease is suggestive of amyloidosis. Presentation includes a
spectrum of symptoms varying from asymptomatic to fatigue, extremity