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Contents
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dilo,<I." of th ...n i ... nd f.,in. live, 111
~. Morpho'ogk.1 <I."ificotion of bili.ry di •• ,d ... J.nnv A C"",IM, John M. Cullm.
'"gil.
or III . ..n l". on<! r.lineIM, 61 1<Ii S. G. A M. wm dm rom Van Vlintl<.
fod S. G. A M. van rkn iIIgh. John M. Cullen, Vol." J. On",.,
Dovid C. TWftll Ta .. Ibn I\'inllo, lUI• ., J. Dt5lll<l
Jan IfO'h"U •• In</"" 12S
WSAVA Liver Standardization Group
The WSAVA Liver Standardization Group during one of the working meetings, early spring 2003 in
Utrecht. Left to right: Ted van den Ingh, David Twedt, John Cullen, Jan Rothuizen, Valeer Desmet,
Susan Bunch, Tom Van Winkle, Jenny Charles, Robert Washabau. Absent: Viktor Szatmári.
ix
Preface and acknowledgements
Jan Rothuizen
This book is the result of the joint efforts of many been able to complete the first standardization
people and it has been written for use by those exercise with his help. The authors are glad that
working in veterinary practice, by veterinary Brovida keeps representing the board, because he
pathologists, and by scientists in academia. has initiated the standardization iniative. The con-
This is the first world standard for the definition tinuous setting and updating of world standards
and nomenclature of diseases in small animal med- has become a key activity of the WSAVA which will
icine, and the authors hope this joint international enable our group to update the present book.
initiative will be the start of many comparable Thanks also go to a special member of the Liver
efforts to bring veterinarians from all over the Standardization Group, Professor Valeer Desmet
world to consensus. Bearing in mind that standards from the Medical School of Leuven, Belgium. Pro-
will need to be updated, we expect that within 3 fessor Desmet has been engaged with all the
to 4 years, it will be necessary to publish an human liver standardization exercises over the past
updated world standard for the diagnosis of liver 30 years or more, and he can really be considered
diseases. The authors of this book invite readers to to be one of the co-founders of modern human
support this standardization by supplying them liver pathology. The presence of such a great expert
with new information that may lead to the defini- in our group has been, and will remain to be, cru-
tion of new diseases or re-definition of existing cially stimulating. He is a pure scientist who is open
ones. The authors are also open to any comment to any scientific argument, and he takes an active
on the content of this book. part in the often sharp, but never personal or
The group owes a special word of gratitude to unfriendly debates about the issues under discus-
those who have made this book possible. First of sion. It is a strength of the group that it was pos-
all, to Dr Claudio Brovida, President of the sible for arguments to be open, direct, and always
WSAVA until October 2002, who had the vision scientific; and when the veterinarians could not
to help this book come to fruition, and in the reach agreement it was always the expert in human
process, hopefully to set the stage for world-wide pathology who helped to find the way out. We as
professional cooperation in many other areas of veterinarians cannot overestimate the value of his
veterinary medicine. The veterinary world owes contribution, which he gave freely, without any
Claudio lasting recognition for his vision, and our personal remuneration.
specialist group feels it has been a privilege to have
xi
Foreword
The aim of the WSAVA is to promote continuing company in seeing this 2-year project to comple-
education and to enhance standards of veterinary tion. The enrichment and lenghtening of the
education throughout the world. The hepatic stan- special relationships between people and pets is the
dardization project developed as a concept in July mission statement of Hill’s Pet Nutrition and this
2000 following discussions with Dr Jan Rothuizen project has contributed to both this mission state-
of the Utrecht Veterinary School about a wide- ment and to knowledge and welfare throughout
spread disparity in the diagnostic reporting of the the veterinary world.
pathology of liver disease. It was a strange fact that This initiative has been so well received by vet-
in this modern world, international experts on the erinary educators that it has been followed by a
five continents used differing terminologies to second project working with international gas-
describe the pathological changes taking place in troenterologists who will be reporting at the
the liver. Prague WSAVA Congress in 2006 on the stan-
An international committee of world-renowned dardization of the nomenclature of the pathology
specialists was convened and the result is seen in of gastrointestinal disease.
this publication which will contribute enormously
to the diagnosis of hepatic disease, and it is hoped, Claudio Brovida DVM Hein Meyer DVM,
become the standard subject text of the future. PhD, Dipl-ECVIM
The WSAVA has worked closely with Hill’s Pet Past president, WSAVA Director, Hill’s Pet
Nutrition on many projects and has been fortunate Nutrition, Inc.
to have had, once again, the full support of this
1
1
Chapter
Introduction – background, aims
and methods
Jan Rothuizen
This book is for use in veterinary practice and
CHAPTER CONTENTS pathology as an aid in making and understanding
the diagnosis of all liver diseases known to date, in
Background 1
dogs and cats. It is also meant to be a guide for the
Examination 2
veterinary profession in the standardized diagnos-
Aims 3
tic approach and nomenclature of liver diseases.
Methods 3
The liver study group 3
BACKGROUND
The diagnosis of liver diseases depends on the
interpretation of the outcome of a number of
examinations. Central to the diagnostic process is
the interpretation of the liver histology examina-
tion, and for most liver diseases, this is the essen-
tial step in making a good diagnosis. Clinicians and
pathologists, therefore, need to cooperate closely
in order to understand each other’s input in
making decisions about the true diagnosis.
In general, and certainly also in the histopatho-
logical evaluation of liver disorders, there tends to
be a large variation in the interpretation of a
particular tissue by different pathologists. Samples
from one case may produce up to six different diag-
noses when evaluated by ten pathologists. Such
large interobserver variations do also exist for many
other observations made during the diagnostic
process. However, since the histopathological eval-
uation is critical for the diagnosis of liver diseases,
this aspect is a cornerstone of our attempt to set
up a world standard for diagnostic criteria of liver
diseases of companion animals.
The apparent lack of standard criteria for
defining the diagnosis has had serious
consequences.
2 WSAVA STANDARDS FOR CLINICAL AND HISTOLOGICAL DIAGNOSIS OF CANINE AND FELINE LIVER DISEASE
Firstly, in everyday practice there must have with the result that differences in nomenclature
been many cases in which the diagnosis was not seem to have occurred between the different con-
correct, with the result that clinicians have treated tinents. Because the standardization process in this
many dogs and cats with the wrong medication. book has been performed by specialists from all
Many veterinarians have the impression that liver over the world, it has been possible, where appli-
diseases are difficult to treat, but this is in fact not cable, to propose one standard name where differ-
true for the vast majority of these diseases. A solid ent names exist for one disease.
diagnosis might usually be followed by successful
therapy, but it may also make clear that there is no
treatment possible. A solid diagnosis is therefore
Examination
the basis for all logical and evidence-based veteri-
nary interventions. Pathomorphological examination is important, but
Secondly, on reading the scientific literature it it is only part of the diagnostic process for liver dis-
becomes clear that reports on a particular disease eases. One of the most important advances in the
cannot be compared with reports on the same past decade has been the complete incorporation
disease in other publications, simply because the of ultrasonography into veterinary medicine; and
criteria are different; it is also not unusual to find certainly for the diagnostic process of liver diseases,
that different diseases are reported under the same ultrasound examination has become an indispensa-
name. This may make it very hard to compare the ble tool. The generally accepted parameters for
results and conclusions of one publication with evaluation by ultrasonography are summarized in
those of another and such confusion hinders the Chapter 2 along with techniques for liver biopsy.
potential progress of veterinary medicine because Although the Liver Study Group has primarily
it takes much time and many studies before the focused on the role of pathological interpretation
truth becomes apparent and generally accepted. and its interaction with clinical hepatology includ-
Good comparability of different publications on a ing clinical pathology, it was felt that limiting eval-
particular disease is not the only profit to be uation to this approach in this way would give rise
gained. The development of rationally validated to incomplete standards for the diagnosis of all
treatments has been largely hampered by the lack other diseases. In the vascular liver diseases,
of solid diagnostic criteria. When reviewing the lit- particularly, ultrasonographic examination is an
erature, it is apparent that there are very few, if any, essential cornerstone in combination with clinical
medications of liver diseases that have been tested pathological and histological examination; there-
in double-blind, placebo-controlled studies. Such fore, Dr Viktor Szatmári (Universtity of Utrecht),
studies are required to make decisions about the who had developed and published standard proto-
best treatment regimes for diseases, and to decide cols for ultasonographic evaluation of vascular liver
about the added value of newly developed treat- diseases, was invited to write a chapter on this
ments in the future. Given the caseload of most subject. For these diseases, standard protocols are
specialized clinics, controlled studies of the thera- described in Chapter 3, which permits the location
peutic effect of drugs can only be performed of portosystemic shunts and other vascular changes
during a reasonable time span with the cooperation with a large degree of certainty.
of different centers in each study (multicenter Hematological and biochemical examinations
studies). It is now time to make progress in this are an integral part of the diagnostic process for
direction, but it is only possible when different par- liver diseases. However, most of these examinations
ticipating centers can use solid and undisputed are not a decisive factor in the diagnosis of a liver
diagnostic criteria. disease, but serve only to differentiate liver disease
Thirdly, confusion has increased even further from other diseases with similar symptoms and
owing to the fact that certain diseases have been signs. As soon as the presence of a liver disease has
given more than one name. There has been insuf- been demonstrated (e.g. by elevated liver enzymes
ficient reference to the existing literature and lack or bile acids in plasma, or clinical icterus) the role
of scientific discussion to prevent this happening, of the blood examination in making a decision on
INTRODUCTION – BACKGROUND, AIMS AND METHODS 3
the diagnosis is very weak for most liver diseases, of debate on difficult topics. The Liver Standard-
except in the vascular disorders. Therefore the ization Group was not only formed under the aus-
reader will find little information about blood pices of the WSAVA, but also supported by the
examinations that is not essential in the diagnostic boards of the European and American Colleges
process. of Veterinary Internal Medicine (ECVIM and
This book starts at the point where the presence ACVIM). The expert group was composed as
of a liver disease is apparent through the finding of follows:
elevated plasma enzymes, bile acids, or the pres- Dr S. Bunch (USA), clinical hepatologist (North
ence of icterus. Carolina State University); Dr J. A. Charles
(Australia), liver pathologist (University of
Melbourne); Dr J. Cullen (USA), liver pathologist
AIMS (North Carolina State Univesity); Dr V. J. Desmet
(Belgium, Europe), human liver pathologist (Uni-
The main aim of this book is to describe world- versity of Leuven); Dr T. S. G. A. M. van den Ingh
wide-accepted standards and criteria for the diag- (Netherlands, Europe), liver pathologist (Univer-
nosis of all known liver diseases of dogs and cats. sity of Utrecht); Dr T. Van Winkle (USA), liver
Pathologists and clinicians will find well-defined pathologist (University of Pennsylvania); Dr D. C.
histological diagnostic criteria and precise defini- Twedt (USA), clinical hepatologist (Colorado
tions of chronicity stages. The variations with State University); Dr R. J. Washabau (USA), gas-
which diseases may present are described and troenterologist/hepatologist (University of Min-
examples are given. In addition, unified nomencla- nesota); Dr J. Rothuizen (Netherlands, Europe),
ture is proposed if a disease has been given differ- clinical hepatologist, coordinator of the group
ent names in the past; and clearly descriptive names (University of Utrecht).
are proposed. The necessary combination of diag- This group has met twice a year over a 3-year
nostic methods and their relative roles is given in period. Each year there was a meeting during the
tables, so that the reader will have an immediate American ACVIM forum and one during the
review of the essentials of the diagnostic process. European ECVIM congress. The agreements on
The reader will find all the relevant technical details standardization reached in the previous period
about the diagnostic procedures used by clinicians, were presented at the specialist meetings of the two
pathologists, and ultrasonographers. congresses, so that the reactions of the veterinary
We have attempted to give relevant pictures of specialists in the field could be incorporated in the
all liver diseases and their variations in dogs and final standards developed. The pathologists of the
cats. group have also presented the consensus diagnos-
tic criteria at the American and European Veteri-
nary Pathology congresses.
METHODS The liver diseases were divided into four groups:
The liver study group
1. Vascular liver disorders
In cooperation with and under the auspices of 2. Biliary tract disorders
the Board of the World Small Animal Veterinary 3. Parenchymal disorders including stellate cells
Association (WSAVA), an international Liver and Kupffer cells
Standardization Group was formed, consisting of 4. Neoplasia.
internationally recognized scientists in hepatogas-
troenterology. Pathologists who specialize in the An exhaustive list was made of all liver diseases
liver and expert clinicians were invited from the in the four groups, and cases were collected in all
USA to become part of the group, Europe, and centers participating in the standardization group.
Australia. In addition, one of the top human liver In several publications, veterinarians from practice
pathologists was invited as an independent back-up or academia were also invited to submit samples or
and to help in making decisions during the course other contributions.
4 WSAVA STANDARDS FOR CLINICAL AND HISTOLOGICAL DIAGNOSIS OF CANINE AND FELINE LIVER DISEASE
Two months before the meeting the patholo- cases per disease), so that it was possible to evalu-
gists had exchanged representative samples of ate them in the months before the meeting, and to
tissue of all these diseases. All veterinary patholo- start to discuss them over the telephone and e-mail
gists had selected three cases of each of the diseases in preparation for the meeting. This culminated
of which they had paraffin-embedded liver tissue in the production of hundreds of slides by all
available. They selected those cases based on their pathologists.
feeling that they were representative for the During the meeting the members of the Liver
disease. If appropriate, they also selected represen- Standardization Group evaluated all slides and the
tative cases of acute, subacute, and chronic stages, relevant clinical aspects of the diseases. Although
or mild, moderate, and severe stages. Since there there was a lot of discussion about the cases, it was
should be the possibility for each pathologist to not hard to reach consensus. A smaller selection
make specific stains of liver slides, each participat- was made from all slides that were considered to
ing center submitted four unstained slices of each represent the typical features for all diseases. Ted
selected tissue. Each pathologist thus possessed an van den Ingh has made a collection of the typical
identical set of slides of all diseases (ten or more slides for all diseases for publication in this book.
