WILSON'S DISEASE A Clinician 's Guide to Recognition,

Diagnosis, and Management

WILSON'S DISEASE A Clinician 's Guide to Recognition,

Diagnosis, and Management

By

George J. Brewer University of Michigan Medical School

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

Library of Congress Cataloging-in-Publication Data

Brewer, George J., 1930-Wilson's disease: a clinician's guide to recognition, diagnosis, and management / by

George 1. Brewer. p. ;cm.

lncludes bibliographical references and index. ISBN 978-1-4613-5657-8 ISBN 978-1-4615-1645-3 (eBook) DOI 10.1007/978-1-4615-1645-3

1. Hepatolenticular degeneration. 1. Title. (DNLM: 1. Hepato1enticular Degeneration---<iiagnosis. 2. Hepatolenticular

Degeneration-therapy. WI 740 B847w 2001) RC394.H4 B74 2001 616.3 '99---<ic21

2001023682

Copyright © 2001 Springer Science+Business Media New York Originally published by Kluwer Academic Publishers in 2001 Softcover reprint ofthe hardcover lst edition 2001 AII rights reserved. No part ofthis publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo-copying, recording, or otherwise, without the prior written permission ofthe publisher,Springer

Science +Business Media, LLC.

Printed an acid-free paper.

Dedication

I dedicate this mono graph to patients with Wilson's disease, particularly those I have had the opportunity to work with, and who have provided inestimable help in our joint efforts to improve the diagnosis and management of this disease. I dedicate it also to the Wilson's Disease Association, which contributes invaluable assistance through its pro grams designed for patients and their families.

Chapter Guide

Chapter 1. Overview of the Disease for the Clinieian ....................... 1

Chapter 2. The Clinician's Challenge: Reeognizing Wilson's Disease ........................................................... 9

Chapter 3. Simple Approaehes to Screening and Definitive Diagnosis ...................................................... 29

Chapter 4. Deseription ofthe Anticopper Drugs Whieh are Used in Wi1son's Disease Therapy .............................. ..49

Chapter 5. Overview of Management for the Clinieian: What' s Important and What's Not.. ................................. 69

Chapter 6. Initial Treatment ofPatients Who Present with Liver Disease .................................................. 79

Chapter 7. Initial Treatment of Patients Who Present with Neurologie andlor Psychiatrie Disease .................... 97

Chapter 8. Maintenanee Therapy ............................................ 105

Chapter 9. Therapy of the Presymptomatie, the Pediatrie, and the Pregnant Patient ............................................. 117

Chapter 10. Risk Faetors During Maintenanee Therapy and Prognosis ..................................................... 127

Chapter 11. Disease Pathogenesis and Genetics ............................ 135

Chapter 12. Disease Patho10gy ................................................ 149

Chapter 13. History, Important Milestones, and the Future ............... 157

Table of Contents

List of Figures ....................................................................... xvii

List of Tables .......................................................................... xix

Forward ............................................................................... xxi

Preface ............................................................................... xxiii

Acknowledgments ................................................................. xxvii

1. Overview ofthe Disease for the Clinician ..................................... 1

Introduction .................................................................... 1 Cause ofWilson's disease ................................................... 2 Inheritanee ..................................................................... 3 Clinieal Presentations ......................................................... 3 Reeognition Problem ......................................................... 4 Some Screening Tests are Accurate ....................................... .5 Diagnosis is Usually Straightforward ....................................... 5 Treatment and Management Coneepts ..................................... 6 Monitoring and Complianee ................................................. 6 Prognosis ....................................................................... 7

2. The Clinician's Challenge: Recognizing Wilson's Disease ................ 9

Introduetion .................................................................... 9 The Neurologieal Presentation ............................................. 10

IfYour Patient Has Movement Disorder-Type Neurologieal Symptoms (Important Ones Are Dysarthria, Tremor, Dystonia, and Ineoordination) .................................. .10

Disasters and Near Disasters Caused by Clinieians FaiIing to Diagnose Wilson's Disease Patients with aNeurologie

Presentation .................................................... 14 Full-blown Neurologie Syndrome Unreeognized .................. 14 Tremor Unreeognized .................................................. 15 Parkinsonism-like Syndrome, Unreeognized at First. ............. 15

The Hepatic Presentation .................................................. 16 Hepatitis and Episodie Hepatitis ...................................... 16 Cirrhosis ................................................................. 17 Hepatie Failure .......................................................... 18

Severe Hepatie Failure ............................................ 19 Mild Hepatie Failure ............................................. .20

x Wilson's Disease

Intermediate Hepatic Failure ...... , ..................... , ... , .. 21 Disasters Caused by Clinicians Failing to Diagnose

Wilson's Disease Patients with Hepatic Presentations ........ 21 Chronic Hepatitis and Liver Failure Unrecognized ........... 21 Cirrhosis, Hepatic Failure, and Family

History Unrecognized ................................... 21 The Behavioral Change Presentation .......................................... 21

Recognition ofWilson's Disease by Psychiatrists-The Good, and the Bad ................................................ 24

The Presymptomatic Patient ................................................... .24 Disasters Related to Screening Presymptomatic Patients ............. .25

A Partial Disaster When a Physician Ignores Wilson's Disease Screening Data ........................................... 25

Two Deaths, at Least One ofThem Unnecessary .................. 25 Other Situations in Which Wilson's Disease May be Present. ............ .26 Key Points with Respect to Recognition of Possible

Wilson's Disease ............................................................ 27

3. Simple Approaches to Screening and Definitive Diagnosis •............. 29

Introduction ....................................................................... 29 Screening Tests and Procedures ................................................ 29

The 24-Hour Urine Copper Assay ......................................... 29 Kayser-Fleischer Ring Examination ...................................... .34 Serum Ceruloplasmin Assay .............................................. .34 Not Very Useful and/or Confusing Tests ................................ .35

How to Screen Patients for Wilson's disease ................................ 36 NeurologiclPsychiatric Presentation ...................................... 36 Hepatic Presentation ......................................................... 38 Presymptomatic Patients ................................................... 39

Making a Definitive Diagnosis ofWilson's Disease ........................ .42 Definitive Diagnosis Without a Liver Biopsy .......................... .42 Liver Biopsy with Measurement of Quantitative Copper ............. .42 Diagnostic Dilemmas ...................................................... .44

Long-Standing Hepatic Failure or Obstruction .................... .44 Other Diagnostic Dilemmas .......................................... .47

Disasters and Near Disasters Re1ated to Screening and Diagnostic Tests ............................................................. .47 Serum Copper Levels Misinterpreted .................................... .47 Liver Copper Assay in Error .............................................. .48 DNA Mutation Test, Misinterpreted ..................................... .48

Contents xi

4. Description ofthe Anticopper Drugs Which are Used in Wilson's Disease Therapy ........•........•...........................•....•........•.... 49

Introduetion ....................................................................... 49 Zine ................................................................................ 49

Meehanism of Anticopper Action of Zinc ............................... .49 Main U ses of Zine in Wilson' s Disease ................................. .51 Evidenee ofUniform Effieaey of Zinc in Wilson's Disease ........... 53

An Unusual Case ofNon-Complianee With Maintenanee Zine Therapy ............... , ...................................... .55

Toxieity of Zine .............................................................. 56 Monitoring Zinc Therapy ................................................... 57

Trientine ........................................................................... 59 Meehanism of Anticopper Action ofTrientine .......................... 59 Main Uses ofTrientine in Wilson's Disease ............................. 59 Evidence ofUniform Efficacy ofTrientine in Wilson's Disease ...... 59 Toxieity ofTrientine ......................................................... 60 Monitoring Trientine Therapy ............................................. 61

Tetrathiomolybdate .............................................................. 62 Meehanism of Anticopper Action ofTetrathiomolybdate (TM) ... , .. 62 Main Use ofTetrathiomolybdate in Wilson's Disease .................. 63 Evidence ofEfficacy ofTetrathiomolybdate in the Initial

Treatment ofNeurologie Wilson's Disease ......................... 63 Toxicity ofTetrathiomolybdate ............................................ 64 Monitoring Tetrathiomolybdate Therapy ................................ 65

Penicillamine ...................................................................... 65 Mechanism of Anticopper Action ofPenicillamine ..................... 62 Main Uses ofPenicillamine in Wilson's Disease ....................... 62 Evidenee ofUniform Effieaey ofPenicillamine in

Wilson's Disease ........................................................ 66 Toxicity ofPenieillamine ................................................... 67 Monitoring Penicillamine Therapy ........................................ 68

Other Anticopper Drugs ......................................................... 68

5. Overview ofManagement for the Clinician: What's Important and What's Not •.•......•....•.•..................•..•...••........ 69

Introduction ....................................................................... 69 Anticopper Drug Therapy Overview-Important.. .......................... 70

Keys to Successful Initial Therapy ........................................ 70 Drug Choiee ............................................................. 70 Drug Dose and Direetions for Use .................................... 70 Monitoring for Drug Toxieity ......................................... 70 Monitoring for Copper and/or Zine Response (Complianee) ..... 71

xii Wilson's Disease

Keys to Sueeessful Maintenanee Therapy ................................ 71 Drug Choiee ............................................................. 71 Drug Dose and Direetions for U se .................................... 71 Monitoring for Drug Toxieity ......................................... 72 Monitoring for Copper Response (Complianee) .................... 72

Diet-Generally Not Important ................................................ 73 Drinking Water-Oeeasionally Important .................................... 74 Patients Signs and Symptoms-Always Important .......................... 74

Hepatie Complieations and Symptomatology ........................... 74 Neurologie Complieations and Symptomatology ....................... 76 Psychiatrie Complieations and Symptomatology ........................ 77

6. Initial Treatment of Patients Who Present With Liver Disease ........ 79

Introduetion ........................................................................ 79 Initial Therapy ofPatients With Hepatie Failure ............................. 79

Review of Severe, Intermediate, and Mild Hepatie Failure ......... 79 Triaging Patients for Hepatie Transplantation Versus

Initial Medieal Therapy ................................................ 81 Hepatie Transplantation in Wilson's Disease ............................ 85

Indieations for Hepatie Transplantation .............................. 85 Non-indications for Hepatie Transplantation ........................ 86 Anticopper Therapy While Awaiting Transplantation ............ 88

Medieal Therapy for Mild Hepatie Failure .............................. 89 Medieal Therapy for Intermediate Hepatie Failure ...................... 91

A Disaster Resulting From a Failure to Adequately Reevaluate the Status of a Patient with Intermediate Hepatie Failure During Medieal Therapy .......................................... 93

Initial Therapy ofPatients With Hepatitis .................................... 94 Initial Therapy ofPatients With Cirrhosis ................................ 95

7. Initial Treatment of Patients Who Present With N eurological andlor Psychiatrie Disease ..................................................... 97

Introduetion ....................................................................... 97 Neurologieal Worsening ofPatients With Initial

Penicillamine Therapy ...................................................... 98 Reeommended Therapy-Tetrathiomolybdate ............................... 99

Method ofTherapy .......................................................... 99 Results in an Open Study ................................................. 100 Potential for Aeeessing Tetrathiomolybdate Therapy ................. 101

Alternative Therapies ................ '" ........................................ 102 Zine ........................................................................... 102 Trientine ..................................................................... 102

Contents xiii

8. Maintenance Therapy ......................................................... 1 05

Introduction ...................................................................... 105 Definition of Maintenance Therapy ..................................... 105 Objectives ofMaintenanee Therapy ..................................... 105

Reeommended Maintenanee Therapy-Zine ............................... 106 Method of Therapy ......................................................... 106

Dietary Reeommendations ........................................... 107 Monitoring Zine Therapy ............................................. 108 Zine Side Effeets ...................................................... 109 Overtreatment ......................................................... 109

Results of Zine Therapy in a Large Series of Patients ................ 110 Alternative Maintenanee Therapy ............................................ 114

Trientine ..................................................................... 114 Penieillamine ............................................................... 115

9. Therapy ofthe Presymptomatic, the Pediatric, and the Pregnant Patient .......................................................... 117

Therapy for the Presymptomatie Patient. ................................... 117 Definition of Presymptomatie Patient ................................... 117 Usual Methods of Aseertaining Presymptomatie Patients ............ 117 Recommended Therapy for the Presymptomatie Patient-Zine ..... 118 Alternative Therapy for the Presymptomatie Patient ................. 118 Near Disaster and a Disaster Using Penicillamine

Therapy in Initial Therapy ofPresymptomatie Patient. .......... 120 Therapy for the Pediatrie Patient. ............................................ 121

Introduetion ................................................................. 121 Evidenee for Early Disease and Therefore a Rationale for

Early Treatment. ...................................................... 121 Need to A void Overtreatment with Antieopper Agents in

Children with Wilson's Disease ..................................... 122 Reeommended Therapy for the Pediatrie Patient-Zine .............. 122 Alternative Therapy for the Pediatrie Patient ........................... 122

Therapy for the Pregnant Patient ............................................. 123 N eed to Maintain Therapy During Pregnancy .......................... 123 Teratogenieity of Anticopper Therapy .................................. 124 Reeommended Therapy for the Pregnant Patient-Zine ....... " ..... 124 Alternative Therapy for the Pregnant Patient-Trientine ............ 124

10. Risk Factors During Maintenance Therapy and Prognosis .......... 127

Introduetion ...................................................................... 127 A General Risk Faetor-Poor Complianee .................................. 127

xiv Wilson's Disease

Disasters Related to Poor Compliance With Anticopper Therapy .. 130 Hepatic RiskFactors ........................................................... .131

Variceal Bleeding ............ " ., .......................................... 131 Hepatic Failure ............................................................. 132

Neurological Risk Factors ..................................................... 132 Aspiration ................................................................... 132 Infection ..................................................................... 133 Accidents .................................................................... 133

Psychiatrie Risk Factors ....................................................... 133 Suicide ....................................................................... 133

Prognosis ......................................................................... 133

11. Disease Pathogenesis and Genetics .•......•.••.....••...•..•.............. 135

Introduction ...................................................................... 135 Does Copper Toxicity Cause Wilson's Disease? .......................... 135 Normal Copper Handling ...................................................... 136 Defective Biliary Excretion ofCopper in Wilson's Disease ............. .136 The Genetics ofWilson's Disease ........................................... .137

Gene Defect in Wilson's Disease ....................................... .139 From Gene Defect to Copper Accumulation, Organ Damage,

and Symptoms ................................................................ 143 Important Pathogenic Questions .......................................... 144

Animal Models ................................................................... 146 Summary of Our Knowledge of Pathogenesis .................... " ........ 147

12. Disease Pathology ............................................................. 149

Introduction ........................... , ......................................... .149 The Nature of Copper Toxicity ............................................... .149 Liver Pathology .......................................................... , ... '" .151 Brain Pathology .................................................................. 152 Pathology in Other Organs ......... , .......................................... .153

The Female Reproductive System ....................................... 153 The Skeletal System ....................................................... 153 The Kidneys .............................. , ........ , ................. , ...... .154 The Eyes ..................................................................... 155 The Heart ................................................................... .155

Summary ......................................................................... 155

13. History, Important Milestones, and the Future ......................... 157

Introduction ...................................................................... 157 History ofWilson's Disease ................................................... 157 Historical Milestones in Wilson's Disease .................................. 160

Contents xv

Future Challenges ............................................................... 160 Recognition .................................................................. 160 Better Screening Methods ................................................. 162 Improved Compliance ..................................................... 163 Improved Therapy ......................................................... 163 Improved Understanding of Gene Function ............................ 164 Summary .................................................................... .164

List of Figures

Figure 301A

Figure 301B

Figure 302 Figure 303

Figure 601A

Figure 601B

Figure 801

Figure 802

Figure 803

Figure 8.4

Figure Bol

Figure 1302

Initial 24-hour urine copper data on 90 Wilson's disease patients who presented with neurologie Wilson's disease (po 33)

Initial 24-hour urine copper data on 17 Wilson's disease patients who presented with liver disease (po 33)

Illustration ofhaplotype analysis in a pedigree (po 40) Distribution of urine copper levels in unaffeeted and

presymptomatie affeeted siblings ofWilson's disease patients (po 41)

Retrospeetive data from Nazer et al. showing the predietive eapability ofthe Nazer prognostie index (po 82)

Prospeetive data from Nazer et alo showing the predietive eapability ofthe Nazer prognostie index (po 82)

Mean 24-hour urine copper and zine values in patients followed for several years on zine maintenanee therapy after TM therapy (po 111)

Mean noneeruloplasmin serum copper and serum zine values in patients followed for several years on zine maintenanee therapy after initial TM therapy (po 112)

Mean neurological and speech funetion scores in patients followed for several years on zine maintenanee therapy after initial TM therapy (po 112)

Mean values ofliver funetion tests in patients with mild to intermediate liver failure treated with trientine and zine for four to six months, then zine maintenanee therapy (po 113)

Funneling effeet of inereasing physieian specialization leading to eoneentration ofWilson's disease patients seen by speeialists (p. 162)

Classifieation seheme for disability severity in Wilson's disease patients (po 165)

List of Tables

Table 1.1

Table 2.1

Table 2.2 Table 2.3

Table 2.4

Table 2.5

Table 2.6.

Table 3.1 Table 3.2 Table 3.3 Table 3.4 Table 4.1 Table 4.2 Table 4.3

Table 4.4 Table 4.5 Table 4.6 Table 4.7 Table 4.8

Table 6.1

Table 6.2

Table 6.3 Table 6.4

Table 6.5

Table 6.6

Table 6.7

Table 7.1 Table 7.2

Guidance to the Clinician on How to Use this Book Efficiently (p. 1)

Neurological Signs and Symptoms That May be Present in Wilson's Disease (p. 12)

Neurologic Abnonnalities Not Present in Wilson's Disease (p. 14) What Types of Liver Disease Patients Should be Screened for

Wilson's Disease? (p. 17) Typical Laboratory and Clinical Findings in Mild, Intennediate, and

Severe Liver Failure in Wilson's Disease (p. 20) Behavioral Changes Seen at Time ofPresentation in Wilson's

Disease Patients (p. 23) Additional Clinical Presentations or Events That May Precede (As

WeIl As Accompany) the N eurologic, Hepatic, or Behavioral Presentations ofWilson's Disease (p. 26)

Values or Findings in Screening Tests for Wilson's Disease (p. 31) Usefulness ofScreening Tests for Wilson's Disease (p. 32) Recommended Screening Tests (p. 37) Diagnostic Scenarios Not Requiring a Liver Biopsy (p. 43) Anticopper Drugs Used in Wilson's Disease (p. 51) Anticopper Drugs ofChoice for Various Types ofPatients (p. 52) Types ofEvidence to Establish Unifonn Efficacy of Anticopper

Drugs (p. 54) Monitoring Anticopper Therapy with Zinc (p. 58) Toxicities ofTrientine (p. 61) Recommended Strategy for Monitoring Trientine Therapy (p. 62) Toxicities ofPenicillarnine (p. 67) Recommended Strategy for Monitoring Penicillarnine Therapy

(p.68) Typical Laboratory Findings in Mild, Intennediate, and Severe

Liver Failure in Wilson's Disease (p. 80) Prognostic Index ofNazer et al. (66) (Modified with Perrnission)

(p. 81) Child-Turcotte-Pugh Scoring System (Partial) (p. 84) Indications and Non-Indications for Hepatic Transplantation in

Wilson's Disease (p. 86) Recommended Anticopper Therapy While Awaiting Hepatic

Transplantation (89) Recommended Initial Anticopper Medical Therapy for Patients in

Mild to Intennediate Hepatic Failure and in Other Cases of Hepatic Presentation (p. 90)

Pros and Cons ofHepatic Transplantation Versus Medical Therapy for Intennediate Liver Failure in Wilson's Disease (p. 92)

Method ofInitial Therapy with Tetrathiomolybdate (TM) (p. 100) Priorities for Anticopper Drugs for Initial Treatment of

Neurologically and/or Psychiatrically Presenting Patients (p.102)

xx Wilson's Disease

List of Tables continued

Table 8.1 Table 8.2 Table 9.1

Table 9.2 Table 11.1 Table 13.1

Objeetives ofMaintenanee Antieopper Drug Therapy (p. 106) Method ofMaintenanee Therapy with Zine (p. 107) Method of Maintenanee (and Presymptomatie) Therapy with Zine

(p. 119) Reeommended Doses of Zine for Pediatrie Patients (p. 123) Observations on ATP7B Mutations in Various Populations (p. 142) Historieal Milestones in Wilson's Disease (p. 161)

Forward

George J. Brewer, M.D. has made enormous contributions to the field of Wilson's disease. He has accumulated more than 250 patients, most ofwhom have been, or are currently, treated with zinc acetate. Zinc acetate achieved FDA approval as maintenance therapy for Wilson's disease in 1997. It is also popularly used in pregnant patients, pediatric patents and asymptomatic patients. Large strides have been made in obtaining FDA approval of zinc acetate (Galzin) for these indications, so that they may be added to the approval for the maintenance indication. Dr. Brewer's ongoing studies have accumulated more scientific information about the benefits, the doses, and the side effects of zinc acetate than were ever achieved for penicillamine or trientine.

In addition, Dr. Brewer has made giant steps towards the approval of a new drug, tetrathiomolybdate, for the treatment of new onset neurological and even hepatic Wilson's disease. Thus far, in more than 60 patients, he has shown it to be almost completely free of the serious side effects of neurological worsening, which are very common and often irreversible when penicillamine is the drug chosen for initial treatment. The research on tetrathiomolybdate, as weIl as the research resulting in the approval of zinc acetate, were funded in part by the Food and Drug Administration's Orphan Product Grant Pro gram.

For his ongoing dedication and achievements in Wilson's disease, Dr. Brewer has been honored with the creation of a professorship in Human Genetics at the University of Michigan to which he is the first designee. His other academic and scientific accomplishments are too numerous to list here. He is a humanist, dedicated to his family, his friends, his colleagues, and his patients. He is not only concerned with arresting their disease, but also with improving their lives, both physical and emotional. Remarkably, he answers his own phone and frequently talks at length with his patients. He is a professor who makes himself available nights, weekends, and even goes to the hospital while on vacation to help patients requiring care.

In this book, Dr. Brewer reaches out to physicians to help them achieve the best possible resuIts for Wilson's disease patients. He provides the scientific background and the details of treatment. The Wilson's Disease Association is grateful to Dr. Brewer for his efforts. He provides direction, counsel, lectures, and he comes to any meetings we request he artend. He was the impetus to reviving the Association in 1994 as an instrument fostering the health and well-being of Wilson's disease patients. Dr. Brewer's ongoing dedication to his patients is reflected in the fact that he has had the foresight and feIt the responsibility to create a Wilson's disease clinic at the University of Michigan, staffed by knowledgeable physicians, to continue patient care and research in Wilson's disease when he retires. There have been other Wilson's disease experts, but none has created an ongoing arrangement such

xxii Wilson's Disease

as Dr. Brewer has undertaken. George J. Brewer, M.D., personifies physician excellence. He has embraced many aspects of the ideal physician "caring, research, service, education, commitment, imagination, perseverance, and foresight. "

H. Ascher SeHner, M.D. President, Wilson's Disease Association

Preface

Movement disorder specialists, general neurologists, hepatologists, general gastroenterologists, and psychiatrists are the specialists who will most likely see some Wilson's disease patients during their careers. General intemists, too, especially those who tend to get referred difficult diagnostic cases, will see their share. See them-yes. Recognize and diagnose them­maybe. If you are in one of these specialties, and a patient with tremor, hepatitis, cirrhosis, apparent Parkinsonism, or mood disorder, is referred to you, will you appropriately recognize the possibility that the underlying diagnosis may be Wilson's disease? If you think of Wilson's, do you know how to screen for the disease? Most physicians think "measure ceruloplasmin," not realizing that serum ceruloplasmin measurement alone is a totally inadequate screening test. If you do have positive or suggestive screening results, or if the doctor on the phone calling you in consultation thinks he or she has, do you know how to make a definitive diagnosis of Wilson's disease? It must be definitive, if you are going to subject a patient to a lifetime of anticopper treatment. And speaking of treatment, do you know the treatment options available today? Don't rely on your textbook-it was out of date on this subject when it was written.

If you are in one of the above specialties, you are going to see and be referred patients who may have Wilson's disease, and it is critically important that you recognize the possibility of the diagnosis, and know how to screen for and diagnose it. Critically important-because more than probably any other chronic disease in your practice, it is treatable, and reversible. It is a tragedy when the physician fails to make the diagnosis of Wilson's disease, and a patient is condemned to needless suffering, and eventual death, unless some other clinician, sharper and more up-to-date than the one who missed the diagnosis, comes through for the patient.

Physicians, even specialists and super-specialists, can't be expected to keep all the critical information they need for every disease they will see in their heads. This monograph on Wilson's disease was designed to make it as simple as possible for the busy clinician to easily access all the information necessary to recognize, diagnose, and treat Wilson's disease. In the recognition chapter (Chapter 2), helpful guidelines are consolidated into tables-reminding you of the type of patient with which to be vigilant. One example-a key reminder is to be aware of the role of relative youth in thinking ofthe disease. A 25-year-old carrying the label of essential tremor is vastly different, in terms of risk of Wilson's disease, than a 60 year old carrying that label.

Similarly, in the diagnosis chapter (Chapter 3), simple tables clarify diagnostic constellations. For example, if the patient presents neurologically, a somewhat different set of procedures/tests can make the diagnosis for you, compared to a hepatic presentation. Similarly, the management and treatment

xxiv Wilson's Disease

chapters are all carefully organized, and summary tables provided, to guide you to treatment options depending upon the type of patient you have. Treatment is a little different now than it was a decade ago, when we had essentially only one drug, penicillamine, with which to treat this disease. In fact, penicillamine is now outdated, and I no longer recommend its use in Wilson's disease. If that's a surprise to you, be sure to read the treatment chapters!

Once a patient is on treatment, how do you monitor progress? What's the prognosis with various kinds of patients? Should I put my patient on a low­copper diet? What is a low-copper diet? Should I check my patient's drinking water for copper levels? What risks, if any, do I need to warn my patient about? All of these questions are important, and the answers to these questions, and countless more, are provided and easily accessible in this mono graph.

This book is written for clinicians. This is obvious by observing that chapters 1-10, the first three quarters of the book, deal with c1inical topics. Chapters 11-13 are there to provide more detail and referencing for those who choose to delve into a particular topic in more depth, but unlike all previous books and monographs on Wilson's disease, these chapters are at the end, rather than at the beginning, so that they will not get in the way of the c1inician's ability to go straight to the material that answers hislher urgent c1inical question.

I chose to write this book because in seeing and caring for over 300 patients with Wilson's disease during the last 20 years, I suspect I have seen in my patients' histories most of the mistakes, at least by type, that can be made. By the nature of the treatment research I've done, I have had unparalle1ed long-term experience with my patients. These experiences have taught me much about the disease, and I have shared those experiences in numerous publications of original research and reviews. But these writings, and those of my fellow researchers, have been aimed more at advancing information for those already rather knowledgeable about the disease. In other words, the experts have been writing far each other. As I looked at the mi stakes by clinicians piling up in the histories of my patients, I came to realize that somebody needed to write a "user-friendly" book for the clinician. So, Doctor, this book is for you. I would hope you might read, or at least skim, the whole book. But if you are not yet caring for a Wilson's disease patient, and want to limit your time on this effort, focus on the overview and recognition chapters (Chapters 1 and 2). You don't really need the rest ofthis book until you use the recognition guides to identify one or more patients who may have the disease. Once you have recognized one or more patients as possibly having Wilson's disease, you can then go on to Chapter 3, which presents tests used for screening. And if you have a positive screening, Chapter 3 then teIls you how to make a definitive diagnosis. Once you have diagnosed a patient (or have been referred a diagnosed patient), one or more

Preface xxv

of the management and treatment chapters, depending on the type of patient you have just diagnosed or been referred, become relevant.

Most symptomatic patients with Wilson's disease respond beautifully, in terms of recovery, with appropriate treatment. There is nothing more rewarding than seeing a frightened patient, bewildered by an array of strange symptoms, recover and resume anormal life. I've been rewarded in this manner countless times, and I hope this book helps numerous other physicians share in that pleasure.

Acknowledgements

I never would have wandered into Wilson's disease research in the first place if I had not been fortunate enough to be a faculty member in a department (Human Genetics) and at a university (The University of Michigan) where one is encouraged to follow his or her research leads, even though they stray through disciplinary boundaries. I am grateful not only to the University, but to my colleagues, both inside and outside the institution, who have contributed greatly to my work on Wilson's disease. I am particularly grateful to Dr. Ananda Prasad of Wayne State University, who first stimulated my interest in trace metal research.

I have dedicated this book to patients with Wilson's disease, and here I wish to acknowledge that obviously none of my clinical research on Wilson' s disease could have been done without their help and cooperation. In the early days, many patients provided weeks of their time to participate in copper balance studies, which allowed us to proceed, safely, with the development of zinc acetate as a recognized and approved therapy. This is but one example of the sacrifices made by so many patients to facilitate the progress of our Wilson's disease work.

The book is also dedicated to the Wilson's Disease Association (WDA). I owe a great deal to the WDA, and the two WDA presidents I have worked with, Ms. Carol Terry and Dr. Ascher Sellner. The WDA has always been available to help facilitate not only good patient care, but appropriate patient participation in the research necessary to advance patient care. That latter concept is important if progress is to be made, and the WDA has been a strong supporter of advancing knowledge through research.

Acknowledgement of three additional groups, both extremely important to me and my research on Wilson's disease, must be made. The first is my laboratory staff, particularly Ms. Virginia (Ginger) Johnson, and Mr. Robert (Bob) Dick. Ginger has been the heart and soul of our patient-related activities, coordinating admissions, visits, data collection, and myriads of other tasks critical to the success of a large clinical research activity. She has been the patients' "friend," helping countless patients navigate their way through a complex disease and clinical research process. Bob has provided the laboratory excellence that has made the quality of much of our research outstanding. Our copper balance work was exquisitely sensitive and highly accurate, mostly due to Bob. Our copper assays carried out on 10-20 mg of liver tissue from a needle biopsy are the most accurate in the world, again thanks to Bob. The same can be said for our plasma and urine copper, zinc, and more recently, molybdenum, assays, yes again thanks to Bob.

The second group that deserves accolades and acknowledgement is the staff of the General Clinical Research Center (GCRC) of the University of Michigan Hospital. Those copper balances mentioned earlier-they wouldn't have been "exquisitely sensitive and highly accurate" without the quality

xxviii Wilson's Disease

control on the diet of the dietitians and on the meticulous stool and urine collections of the nurses. The nurses and physician assistants have also provided wonderful clinical care for the patients, many of them quite ill. Beyond this, the nursing staff and administrative staff ofthe GCRC have been extremely supportive and helpful to our project. In summary, the people of the GCRC, collectively have been the key to getting our work with patients done, and without that work, this mono graph wouldn't exist.

The third group I'd like to acknowledge rarely gets the credit they deserve, or any credit, for that matter. This is the Institutional Review Board, the group of faculty members and laypersons who selflessly give of their time to make sure patient's rights aren't violated, and that the research meets ethical standards. While sometimes clinical investigators complain about the amount of work they have to do to put in the !RB application, file reports, answer !RB questions, etc., I think we all recognize what an important role they fill. It is their ongoing review of our projects which gives our work the ethical credibility that is so important when doing research with human subjects and patients, and I extend my personal thanks to the University of Michigan Institutional Review Board.

The grant pro gram of the Orphan Products Office of the FDA has provided extremely helpful grant support for both the development of zinc acetate (Grant #FD-R-000179) and ammonium tetrathiomolybdate (Grant #FD-U-000505) as therapies for Wilson's disease. I also wish to acknowledge the Lemmon Company, later acquired by Gate Pharmaceutical, for adopting zinc acetate as an orphan therapy and pursuing it until a New Drug Application was approved by the FDA. Special thanks are due to Stanley Schiendlin, who first approached us about such sponsorship, and shepherded the drug (now known as Galzin®) through much of its regulatory pathway. I also thank Charles Krippendorf of Gate Pharmaceutical, who helped in the later stages. I also acknowledge the Gastrointestinal Division of the FDA, led at the time by Dr. Stephen Fredd, for their timely approval of Galzin®.

Finally, I wish to acknowledge the people who helped with this manuscript. Many people, including Dr. Fred Askari, Dr. Martha Carlson, Dr. John K. Fink, Dr. Peter Hedera, Ms. Karen Kluin, Dr. Peter LeWitt, Dr. Michael Schilsky, and Dr. Ascher Sellner have read all or parts of it, and made useful comments. Ms. Joanne Tracy, of Kluwer Publishing, originally approached me to write such a mono graph, and has shepherded the project ever since, including providing helpful critiques. I'm very grateful to Joanne for all her help and support. FinaIly, Ms. Nancy Shefferly has gone weIl beyond the usual in physically putting together this mono graph. She has made many important contributions to the layout and design of key elements, and I thank Nancy for all her contributions.

George J. Brewer