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1 Amyloidosis
2 CONTEMPORARY HEMATOLOGY Judith E. Karp, SERIES EDITOR For other titles published in this series, go to
3 Amyloidosis Diagnosis and Treatment Edited by Morie A. Gertz Mayo Clinic Rochester, MN S. Vincent Rajkumar Mayo Clinic Rochester, MN
4 Editors Morie A. Gertz Mayo Clinic 200 First Street SW Rochester, MN S. Vincent Rajkumar Mayo Clinic 200 First Street SW Rochester, MN ISBN e-isbn DOI / Springer New York Dordrecht Heidelberg London Library of Congress Control Number: Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, ), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (
5 Preface Amyloidosis is a term that represents a wide spectrum of protein folding disorders. The disease may be localized or systemic. The systemic amyloidoses can be either immunoglobulin light chain derived, related to the deposition of amyloid A protein in chronic inflammatory conditions, or an inherited disorder usually related to mutant transthyretin. Normal proteins are known to misfold into amyloid, the clinically most important being native transthyretin in the form of senile systemic amyloidosis. This text attempts to comprehensively provide a framework to clinicians seeing these patients and scientists studying the disorder, with an in-depth treatment of selected world s literature, as well as newest developments in the disorder. Because amyloidosis is so rare, many practicing clinicians are uncomfortable in the diagnosis, management, classification, prognostication, and therapy of the amyloidoses. This book calls on the clinical and scientific expertise of the world s noted experts in the protein folding disorders. To understand the protein folding disorders, knowledge of fibril structure and fibrillogenesis is essential. Drs. Martin, Randles, and Ramirez-Alvarado cover the essentials in the identification of amyloid fibrils, recognition of the kinetics of fibril formation, the issues associated with thermodynamic instability, and the mechanism by which the beta-pleated sheet forms. Whether it is the fully formed fibril or soluble oligomers which are responsible for the complications of the disease is also dealt with. Drs. Palladini, Merlini, and Perlini cover what is known about the in vivo imaging of amyloid fibrils. Unlike most hematologic disorders where sensitive imaging techniques exist to stage the extent of the disease, the identification and imaging of amyloid fibrils in vivo have been a challenge for four decades. The chapter covers radionuclide imaging with SAP, ultrasound, magnetic resonance imaging, and computerized tomography and its role in identifying amyloid deposits. Drs. Grateau and Stankovic review the diagnosis and classification of amyloidosis, reviewing correct nomenclature and clues to an appropriate clinical diagnosis. A review of available clinical techniques to establish the diagnosis, the pitfalls of histochemical staining, and the classification of the amyloidosis is dealt with. Drs. Lavatelli, Palladini, and Merlini review the pathogenesis of systemic amyloidosis, dealing with the cellular control mechanisms that regulate misfolding and the role of the non-fibrillar components of amyloid, including serum amyloid P, glycosaminoglycans, and the impact of molecular crowding. Drs. Lacy and Leung review supportive care for patients with amyloidosis, dealing with the role of cardiotropic agents, anti-arrhythmics, implantable defibrillators, and cardiac transplant. Renal involvement is dealt with in depth, using medical strategies v
6 vi Preface to reduce proteinuria, the role of renal transplant for amyloidosis, and the management of common complications such as pleural effusions that are recurrent. Dr. Dispenzieri discusses response assessment and prognosis in evaluating patients with immunoglobulin light chain amyloidosis, both in terms of the hematologic response and the role of the immunoglobulin free light chain, and defining organ response. The use of a clinically relevant staging system is presented. Since cardiac failure is the most common cause of death in systemic amyloidosis, special treatment is given to amyloid heart disease by Drs. Falk and Dubrey with specifics on the treatment of cardiac amyloidosis. Transthyretin-inherited cardiac amyloidosis and transthyretin senile systemic amyloidosis are treated independently and in depth. Drs. Bajwa and Kelly deal with the complex issues associated with amyloid neuropathy, clinical manifestations, differential diagnosis, and the role of the sural nerve biopsy. Dr. Gertz discusses the conventional treatment of immunoglobulin light chain amyloidosis from the first use of melphalan and prednisone through the use of the newest novel agents and their role in suppressing the light chain production by the clonal plasma cells responsible for the morbidity of the disease. Drs. Cohen and Comenzo deal with the increasingly important role of high-dose therapy with stem cell replacement in the management of amyloidosis, including the key issues of patient selection, risk-adapted therapy, and the role of post-transplant maintenance therapy. Dr. Zeldenrust deals with transthyretin amyloidosis, covering the diagnosis, the prognosis, and the available therapies with in-depth treatise on the use of liver transplantation to manage this devastating disorder. Dr. Benson draws on his in-depth experience with the rarest forms of amyloid, including apolipoprotein, lysozyme, and fibrinogen amyloidosis. Without awareness of these rare forms of amyloidosis, the diagnosis is frequently overlooked and the patient is not correctly managed. It is our hope that by comprehensively covering all forms of amyloidosis, from pathogenesis to therapy, this book can serve as a long-lasting reference volume for practicing physicians and scientists directly involved in the care of patients with amyloidosis, ultimately benefitting the patient population by shortening the diagnostic evaluation and allowing appropriate timing of necessary therapies. Rochester, Minnesota, Morie A. Gertz, MD S. Vincent Rajkumar, MD
7 Contents 1 Fibril Structure and Fibrillogenesis Douglas J. Martin, Edward G. Randles, and Marina Ramirez-Alvarado 2 ImagingofSystemicAmyloidosis Giovanni Palladini, Stefano Perlini, and Giampaolo Merlini 3 Diagnosis and Classification Gilles Grateau and Katia Stankovic 4 Pathogenesis of Systemic Amyloidoses Francesca Lavatelli, Giovanni Palladini, and Giampaolo Merlini 5 Supportive Care for Amyloidosis Martha Q. Lacy and Nelson Leung 6 Assessing Response and Prognosis in AL Amyloidosis Angela Dispenzieri 7 LocalizedAmyloidosis Francis Buadi 8 AmyloidHeartDisease Rodney H. Falk and Simon W. Dubrey 9 Renal Amyloidosis Laura M. Dember 10 Primary Systemic Amyloid Neuropathy Harman P.S. Bajwa and John J. Kelly 11 Conventional Treatment of Amyloidosis Morie A. Gertz and Francis Buadi 12 High-DoseTherapyinAmyloidosis Adam D. Cohen and Raymond L. Comenzo vii
8 viii Contents 13 Secondary, AA, Amyloidosis Helen J. Lachmann 14 ATTR: Diagnosis, Prognosis, and Treatment Steven R. Zeldenrust 15 OtherSystemicFormsofAmyloidosis Merrill D. Benson Index
9 Contributors Harman P.S. Bajwa, MD Department of Neurology, George Washington University, Washington, DC, Merrill D. Benson, MD Departments of Pathology and Laboratory Medicine, Medicine, and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, Francis Buadi, MB, ChB Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, Adam D. Cohen, MD Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, Raymond L. Comenzo, MD Blood Bank and Neely Cell Processing and Collection Center, Tufts Medical Center, Boston, MA, Laura M. Dember, MD Renal Section, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA, Angela Dispenzieri, MD Department of Medicine and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, Simon W. Dubrey, MD, FRCP Department of Cardiology, Hillingdon Hospital, Middlesex, UK Rodney H. Falk, MD, FACC Department of Medicine, Harvard Medical School, Cardiac Amyloidosis Program, Brigham and Women s Hospital, Harvard Vanguard Medical Associates, Boston, MA, MorieA.Gertz,MD Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, Gilles Grateau, MD Department of Internal Medicine, National Reference Center of Rare Diseases for Inflammatory Amyloidosis and Familial Mediterranean Fever, Hôpital Tenon, Assistance publique, Hôpitaux de Paris, Paris, France ix
10 x Contributors John J. Kelly, MD Departments of Neurology and Neurosurgery, School of Medicine and Health Care Sciences, The George Washington University, Washington, DC, Helen J. Lachmann, MD, FRCP Division of Medicine, UK National Amyloidosis Centre, University College London Medical School, London, UK Martha Q. Lacy, MD Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, Francesca Lavatelli, MD Biotechnology Research Laboratories, Biomedical Informatics Laboratory, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Amyloid Research and Treatment Center, University of Pavia, Pavia, Italy Nelson Leung, MD Department of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, Douglas J. Martin, BS Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, Giampaolo Merlini, MD Biotechnology Research Laboratories, Departments of Biochemistry and Internal Medicine, Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy Giovanni Palladini, MD, PhD Biotechnology Research Laboratories, Department of Biochemistry, Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy Stefano Perlini, MD Biotechnology Research Laboratories, Department of Biochemistry, Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy; Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy Marina Ramirez-Alvarado, PhD Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, Edward G. Randles, PhD Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, ; Laboratory for Neurophysics and Intelligence Modeling, Department of Biochemistry, Boston University School of Medicine, Boston, MA, Katia Stankovic, MD Department of Internal Medicine, National Reference Center of Rare Diseases for Inflammatory Amyloidosis and Familial Mediterranean Fever, Hôpital Tenon, Assistance publique, Hôpitaux de Paris, Paris, France Steven R. Zeldenrust, MD, PhD Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN,
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