FAST FACTS FAST “ A lovely balance of detail and simplicity ... a concise, comprehensive FAST FACTS and accessible update ....” Mr Leading Expert, Senior Director of Education and Training The American Society of Hematology, USA Pyruvate Kinase Deficiency Pyruvate Kinase FAST FACTS Deficiency Pyruvate Kinase Deficiency 7 Overview 16 Epidemiology and etiology Bertil Glader, Wilma Barcellini and Rachael Grace 20 Diagnosis 28 Differential diagnosis 47 Complications and monitoring 59 Supportive treatment 64 Future developments An independent publication developed by Health Press Limited and provided as a service to medicine. Supported by an educational grant from: ISBN 978-1-910797-43-3 the best offers are on fastfacts.com 9 781910 797433 FAST FACTS Fast Facts: Pyruvate Kinase Deficiency Bertil Glader MD Professor of Pediatrics Bass Cancer Center Lucile Packard Children’s Hospital Stanford Palo Alto, California, USA Wilma Barcellini MD PhD Associate Professor in Blood Diseases, Oncology and Rheumatology, University of Milan Director of Pathophysiology, Anemia Unit, Ospedale Maggiore Policlinico Foundation Milan, Italy Rachael Grace MD MMSc Physician, Pediatric Hematology Dana-Farber/Boston Children’s Cancer and Blood Disorder Center Harvard Medical School Boston, Massachusetts, USA Declaration of Independence This book is as balanced and as practical as we can make it. Ideas for improvement are always welcome: [email protected] Fast Facts: Pyruvate Kinase Deficiency First edition June 2018 Text © 2018 Bertil Glader, Wilma Barcellini, Rachael Grace © 2018 in this edition Health Press Limited Health Press Limited, Elizabeth House, Queen Street, Abingdon, Oxford OX14 3LN, UK Tel: +44 (0)1235 523233 Book orders can be placed by telephone or via the website. To order via the website, please go to: fastfacts.com For telephone orders, please call +44 (0)1752 202301 Fast Facts is a trademark of Health Press Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the express permission of the publisher. The rights of Bertil Glader, Wilma Barcellini and Rachael Grace to be identified as the authors of this work have been asserted in accordance with the Copyright, Designs & Patents Act 1988 Sections 77 and 78. The publisher and the authors have made every effort to ensure the accuracy of this book, but cannot accept responsibility for any errors or omissions. For all drugs, please consult the product labeling approved in your country for prescribing information. Registered names, trademarks, etc. used in this book, even when not marked as such, are not to be considered unprotected by law. A CIP record for this title is available from the British Library. ISBN 978-1-910797-88-4 Glader B (Bertil) Fast Facts: Pyruvate Kinase Deficiency/ Bertil Glader, Wilma Barcellini, Rachael Grace Medical illustrations by Graeme Chambers and Annamaria Dutto. Typesetting by Thomas Bohm, User Design, Illustration and Typesetting, UK. Printed in the UK with Xpedient Print. List of abbreviations 4 Glossary 4 Introduction 5 Overview 7 Epidemiology and etiology 16 Diagnosis 20 Differential diagnosis 28 Complications and monitoring 47 Supportive treatment 59 Future developments 64 Useful resources 67 Index 68 List of abbreviations 2,3-DPG: 2,3-diphosphoglycerate Ig: immunoglobulin AIHA: autoimmune hemolytic LDH: lactate dehydrogenase anemia NADH: nicotinamide adenine ATP: adenosine triphosphate dinucleotide – reduced CAD: cold agglutinin disease NADPH: nicotinamide adenine dinucleotide phosphate – reduced DAT: direct antiglobulin test NGS: next generation sequencing G6PD: glucose-6-phosphate dehydrogenase PK: pyruvate kinase GPI: glycosylphophatidyl-inositol PKD: pyruvate kinase deficiency Hb: hemoglobin PNH: paroxysmal nocturnal hemoglobinuria HMP: hexose monophosphate (shunt) RBC: red blood cell 4 Glossary Alloantibody: an antibody produced Erythropoietin: a glycoprotein following the introduction of hormone acting on bone marrow an antigen into the system of an stem cells to stimulate red blood cell individual lacking that particular production antigen Extramedullary hematopoiesis: the Anisocytosis: variation in the size formation of blood cells in locations of cells, especially red blood cells other than the bone marrow Aplastic crisis: a temporary cessation Flow cytometry: an analytic cell- of red blood cell production usually biology technique that utilizes light associated with infection with to identify, separate and characterize parvovirus B19 cells in a heterogeneous fluid mixture containing live cells. In addition, Cholecystectomy: surgical removal antibodies tagged with fluorescent of the gallbladder dyes, and raised against highly Compound heterozygote: an specific cell surface antigens (e.g. individual with a different mutation clusters of differentiation markers), in each copy of a gene can be used to better identify and separate subpopulations of cells Confounder: something that within a larger group confuses Gilbert syndrome: an inherited Direct antiglobulin (Coombs) test: abnormality resulting in the build test used in the differentiation of up of unconjugated bilirubin in the various types of hemolytic anemia; blood, leading to jaundice reveals the presence of anti-erythrocyte antibodies in Glucose-6-phosphate dehydro- red blood cells genase deficiency: the most common enzyme disorder of red Dysmyelopoiesis: impaired blood cells production of blood cells Glycolytic pathway: the ‘energy- Echinocyte: a red blood cell producing’ metabolic pathway in red with an abnormal cell membrane blood cells characterized by multiple small spiky projections Hematopoiesis: the formation of blood cells Erythropoiesis: formation of erythrocytes (also called Hemochromatosis: hereditary hematopoiesis) disorder of metabolism involving the build up of iron levels in the body 5 Hemolysis: the breaking up of red Poikilocytosis: the presence blood cells, liberating hemoglobin abnormally shaped red blood cells (poikilocytes) Hemolytic episode: an upsurge in hemolysis often triggered by acute Polychromatophilia: excessive infections, pregnancy, particular staining of a peripheral blood smear medicines or ingestion of certain as a result of increased numbers of foods such as fava beans reticulocytes Hemosiderosis: an increase in tissue Pyruvate kinase: an enzyme essential iron stores for the production of ATP (energy) by red blood cells Hepcidin: a hormone regulating the entry of iron into the circulation Reticulocytosis: an increase in the number of immature red blood Hexose monophosphate shunt: the cells (reticulocytes) in the blood, ‘protective’ metabolic pathway in red typically following hemorrhage or blood cells and their only source of accompanying hemolytic anemia the reduced form of nicotinomide adenine dinucleotide phosphate Splenectomy: surgical removal of the spleen Hydrops fetalis: gross edema of the body of a newborn Splenomegaly: enlargement of the spleen resulting from increased red Hyperbilirubinemia: excess bilirubin blood cell breakdown in the blood Thrombocytopenia: a persistent Missense mutation: a single decrease in the number of platelets nucleotide change that results in the in the blood production of a different amino acid Thromobcytosis: an (abnormal) Myelodysplastic syndrome: a rare increase in the number of platelets blood cancer characterized by a lack in the blood of healthy blood cells Thrombosis: the formation or Myelofibrosis: a rare disorder presence of a blood clot within affecting the bone marrow, resulting a blood vessel in disruption to the production of blood cells Next-generation sequencing: term used to describe a number of different gene sequencing technologies; also known as high-throughput sequencing 6 Introduction As an inherited disease manifesting as hemolytic anemia, pyruvate kinase (PK) deficiency is a lifelong condition, with symptoms that range from mild to severe. However, despite an ever-growing understanding of its pathophysiology, etiology and epidemiology, and an active research program, PK deficiency remains unfamiliar to many medical practitioners. Here, we provide a concise guide to PK deficiency for primary care providers, as well as hematologists, oncologists, pediatricians, internal medicine specialists, hematology nurses and medical students. As well as explaining the underlying defect, its mode of inheritance and how the condition manifests, we also discuss the diagnosis and differential diagnosis of PK deficiency, together with the complications that may arise and options for managing them. In the final chapter we look briefly at some of the emerging therapies under investigation. Each chapter is supported by key learning points and references for further reading, and we encourage you to take the free online FastTest that accompanies this resource at fastfacts.com to assess your understanding of this condition. We hope that this first edition of Fast Facts: Pyruvate Kinase Deficiency will be a useful resource for anyone who has an interest in learning more about this rare genetic blood disorder. 7 1 Overview Pyruvate kinase (PK) deficiency is the most common enzyme deficiency affecting the glycolytic pathway used by red blood cells (RBCs) to generate energy. PK is a tetrameric protein that catalyzes the conversion of phosphoenolpyruvate to pyruvate, one of two energy- generating steps in glycolysis. PK deficiency was first described in