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Clinicopathologic principles for

veterinary medicine

Clinicopathologic

principles for

veterinary

medicine

Edited by

WAYNE F. ROBINSON and

CLIVE R. R. HUXTABLE

School of Veterinary Studies, Murdoch University

Murdoch, Western Australia

The right of the

University of Cambridge

to print and sell

all manner of books

was granted by

Henry VIII in 1534.

The University has printed

and published continuously

since 1584.

CAMBRIDGE UNIVERSITY PRESS

Cambridge

New York New Rochelle Melbourne Sydney

PUBLISHED BY THE PRESS SYNDICATE OF THE UNIVERSITY OF CAMBRIDGE

The Pitt Building, Trumpington Street, Cambridge, United Kingdom

CAMBRIDGE UNIVERSITY PRESS

The Edinburgh Building, Cambridge CB2 2RU, UK

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477 Williamstown Road, Port Melbourne, VIC 3207, Australia

Ruiz de Alarcon 13,28014 Madrid, Spain

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http://www.cambridge.org

© Cambridge University Press 1988

This book is in copyright. Subject to statutory exception

and to the provisions of relevant collective licensing agreements,

no reproduction of any part may take place without

the written permission of Cambridge University Press.

First published 1988

First paperback edition 2003

A catalogue record for this book is available from the British Library

Library of Congress cataloguing in publication data

Clinicopathologic principles for veterinary medicine / edited by Wayne

F. Robinson and Clive R. R. Huxtable.

p. cm.

Includes index.

ISBN 0 521 30883 6 hardback

I. Veterinary clinical pathology. I. Robinson, Wayne F.

II. Huxtable, Clive R.R.

[DNLM: 1. Pathology, Veterinary. SF 769 C641]

SF772.6.C57 1988

636.089'607-dcl9

DNLM/DLC

for Library of Congress 87-32006 CIP

ISBN 0 521 30883 6 hardback

ISBN 0 521 54813 6 paperback

Contents

Contributors

Preface

Acknowledgements

1 The relationship between

pathology and medicine

Wayne F. Robinson and

Clive R. R. Huxtable

2 The immune system

page vi

vii

viii

1

4

9

10

11

The urinary system

Clive R. R. Huxtable

The endocrine glands

Wayne F. Robinson and

Susan E. Shaw

The skin

Clive R. R. Huxtable and

Susan E. Shaw

W. John Penhale

3 The hematopoietic system 38

Jennifer N. Mills and V. E. O. Valli

4 Acid-base balance 85

Leonard K. Cullen

5 The respiratory system 99

David A. Pass and John R. Bolton

6 The cardiovascular system

Wayne F. Robinson

122

7 The alimentary tract 163

John R. Bolton and David A. Pass

8 The liver and exocrine pancreas 194

Clive R. R. Huxtable

216

249

275

12 The skeletal system 298

Wayne F. Robinson,

Robert S. Wyburn and John Grandage

13 The nervous system 330

Clive E. Eger, John McC. Howell

and Clive R. R. Huxtable

14 Muscle 378

Wayne F. Robinson

15 Metabolic disease 389

David W. Pethick

16 The reproductive system 399

Peter E. Williamson

Index 419

Contributors

John R. Bolton, B.V.Sc., Ph.D.,

M.A.C.V.Sc. Senior Lecturer in Large

Animal Medicine

Leonard K. Cullen, B.V.Sc, M.A., M.V.Sc,

Ph.D., D.V.A., F.A.C.V.Sc. Senior Lecturer

in Anesthesiology

Clive E. Eger, B.V.Sc, M.Sc, Dip. Sm. An.

Surg. Senior Lecturer in Small Animal

Medicine and Surgery

John Grandage, B.Vet.Med., D.V.R.,

M.R.C.V.S. Associate Professor of Anatomy

John McC. Howell, B.V.Sc, Ph.D.,

D.V.Sc, F.R.C Path., M.A.C.V.Sc,

F.A.N.Z.A.A.S., M.R.C.V.S. Professor of

Pathology

Clive R. R. Huxtable, B.V.Sc, Ph.D.,

M.A.C.V.Sc Associate Professor of Path￾ology

Jennifer N. Mills, B.V.Sc, M.Sc, Dip. Clin.

Path. Senior Lecturer in Clinical Pathology

David A. Pass, B.V.Sc, M.Sc, Ph.D., Dip.

Am. Coll. Vet. Path. Associate Professor of

Pathology

W. JohnPenhale,B.V.Sc,Ph.D.,Dip. Bact.,

M.R.C.V.S. Associate Professor of Micro￾biology and Immunology

David W. Pethick, B.Ag.Sc, Ph.D. Lecturer

in Biochemistry

Wayne F. Robinson, B.V.Sc, M.V.Sc,

Ph.D., Dip. Am. Coll. Vet. Path,

M.A.C.V.Sc. Associate Professor of Path￾ology

Susan E. Shaw, B.V.Sc., M.Sc.,F.A.C.V.Sc.,

Dip. Am. Coll. Int. Med. Senior Lecturer in

Small Animal Medicine

V. E. O. Valli,* D.V.M., M.Sc, Ph.D., Dip.

Am. Coll. Vet. Path. Professor of Veterinary

Pathology

Sheila S. White, B.V.M.S., Ph.D.,

M.R.C.V.S. Senior Lecturer in Anatomy

Peter E. Williamson, B.V.Sc, Ph.D. Senior

Lecturer in Reproduction

Robert S. Wyburn, B.V.M.S., Ph.D.,

D.V.R., F.A.C.V.Sc, M.R.C.V.S. Associate

Professor of Veterinary Medicine and Surgery

(Radiology)

Department of Veterinary Pathology, University of

Guelph, Guelph, Ontario, Canada NIG 2WI

Except where otherwise stated, all contributors are faculty members of the School of Veterinary Studies, Murdoch University, Murdoch WA 6155, Australia.

VI

Preface

This book is written for veterinary medical stu￾dents as a primer for their clinical years and

should also be of benefit beyond graduation.

As the title suggests, our aim is to highlight

the essential relationship between tissue dis￾eases, their pathophysiologic consequences

and clinical expression. The book is designed

to emphasize the principles of organ system

dysfunction, providing a foundation on which

to build.

The basis of the book is an integrated course

in systemic pathology and medicine taught at

this school, and it is a source of satisfaction

that all but one of the contributors teach in the

course. The approach taken is similar in many

respects to the pattern followed in other

schools throughout the world. Our experience

and no doubt that of many others is that the

two disciplines of pathology and medicine are

enriched by such integration, a merger rather

than a polarization. We have endeavoured to

encapsulate these views in the first chapter of

the book entitled The relationship between

pathology and medicine'.

To our co-authors we extend our heartfelt

thanks. Their contributions of time and

expertise are greatly appreciated.

January 1987 W. F. Robinson

C. R. R. Huxtable

Perth, Australia

VII

Acknowledgements

We are indebted to a number of dedicated

helpers who do not appear in name elsewhere.

Sue Lyons with her trusty word processor has

typed and corrected numerous chapter drafts

with dedication, speed and accuracy. Hers was

a most onerous task carried out with cooper￾ation and willingness. Pam Draper and Diane

Surtees were also of immense help with some

of the chapter typing. The creativity and

expertise of Gaye Roberts, whose line draw￾ings and diagrams are of the highest quality,

are evident throughout the book. Geoff

Griffiths lent his able photographer's eye to

the printing of the graphic artwork and

Jennifer Robinson dealt swiftly with the split

infinitive and other grammatical trans￾gressions. To all, our profound gratitude is

extended.

We also wish to express our deep appreci￾ation to the publisher, Cambridge University

Press, and especially to Dr Simon Mitton, the

editorial director, who enthusiastically sup￾ported the initial idea and helped throughout

the writing and production phases. Finally, we

would like to thank both the School of Veter￾inary Studies and Murdoch University for

grants to complete the graphic artwork.

VIM

Wayne F. Robinson and

Clive R. R. Huxtable

1 The relationship

between pathology

and medicine

The aim of this book is to assist the fledgling

clinician to acquire that 'total view' of disease

so essential for the competent diagnostician.

The typical veterinary medical student first

encounters disease at the level of cells and

tissues, amongst microscopes and cadavers

and then proceeds rather abruptly to a very

different world of lame horses, vomiting dogs,

panting cats, scouring calves, stethoscopes,

blood counts, electrocardiographs and

anxious owners. In this switch from the funda￾mental to the business end of disease, the link

between the two is often obscured. It is easy to

forget that all clinical disease is the result of

malfunction (hypofunction or hyperfunction)

within one or several organ systems, and that

such malfunction springs from some patho￾logic process within living tissues.

Although some disease processes are purely

functional, in most instances the pathologic

events involve structural alteration of the

affected organ, which may or may not be

reversible or repairable. At least one of the

basic reactions of general pathology, such as

necrosis, inflammation, neoplasia, atrophy or

dysplasia, will be present.

The expert clinician, having recognized

functional failure in a particular organ as the

cause of a clinical problem, is easily able to

conjure up a mental image of the likely under￾lying lesion and take effective steps to charac￾terize it. This characterization of the under￾lying disease opens the way for establishing

the etiology and appropriate prognosis and

management. By contrast, the novice tends to

stop short at the stage of identifying organ

malfunction, neglecting the important step of

characterizing and comprehending the nature

of the tissue disease. A good example is pro￾vided by the clinical state of renal failure,

recognized by a number of characteristic

clinical findings. This failure may result from a

diversity of pathologic states, some readily

reversible, some relentlessly progressive. The

need to accurately characterize the tissue dis￾ease is appreciated by the expert, but fre￾quently neglected by the novice.

The diagnostic process must therefore com￾bine clinical skills with a sound understanding

of pathology. Lesions causing tissue destruc￾tion will only become clinically significant

when the functional reserve of the affected

organ has been exhausted. This fact clearly

establishes the important principle that tissue

disease does not necessarily induce clinical dis￾ease, and that many quite spectacular struc￾tural lesions have no functional significance.

The critical factor is the erosion of functional

reserve capacity or, conversely, the stimu￾lation of significant hyperfunction.

Modern veterinary medicine provides an

expanding battery of clinical diagnostic aids,

by which organ function may be assessed and

tissue disease processes characterized. This

happy situation catalyzes the fusion of the

clinical sciences and tissue pathology. Whilst

we cannot promise diamonds, we hope that

the veterinary student will find a crystalline

1

The relationship between pathology and medicine

and easily digestible fusion in the chapters of

this book.

These introductory remarks pave the way

for the enunciation of some general principles.

The limited nature of clinical and

pathologic responses

The clinical signs resulting from malfunction

of a particular organ may be likened to the

themes and variations of a particular musical

composition. Regardless of variations induced

by different etiology and pathogenesis, the

thread of the basic theme is always apparent to

the thoughtful investigator. In the case of

renal failure, for example, two basic themes -

failure of urinary concentration and elevation

of non-protein nitrogenous compounds in the

plasma - are always present. Variations are

provided by items such as large or small urine

output, large or small urinary protein concen￾tration and few or numerous inflammatory

cells in the urine. Particular patterns of vari￾ations based on the common theme provide

opportunity for differentiating types of disease

processes.

Pathologic responses are limited in scope

and modified by the differing characteristics of

various organs. Ultimately all lesions can only

fall into those basic categories defined in gen￾eral pathology, such as inflammation/repair,

proplasia/retroplasia, neoplasia, developmen￾tal anomaly, degeneration/infiltration, circu￾latory malfunction or non-structural bio￾chemical abnormality. The most important

modifying factors are the developmental age

of the affected tissue and its intrinsic regener￾ative ability.

The progression of the diagnostic

process

The clinician's initial contact with a patient

usually occurs when the owner reports the

recognition of an abnormality. Through

further questioning and a physical examin￾ation of the animal, the recognition of abnor￾mality is further refined to a localization of the

problem to a particular organ or tissue, and

often the 'single' problem may prove to be a

plethora of problems. The next step is usually

confirmation of suspicions by the use of

appropriate clinical aids such as radiography

and the taking of blood and tissue samples.

Then follows characterization, directly or by

inference, of the underlying pathologic pro￾cess. This is ideally accompanied by identifi￾cation of the specific cause, by further testing

or by inference from previous experience. The

culmination of all these steps and procedures

is the prediction of the outcome of the process.

This method of investigation has widespread

acceptance and again demonstrates the

inextricable link between the clinical appear￾ance of the disease and the underlying

pathology. Recognition, localization and con￾firmation are the essence of clinical skill,

whereas characterization and identification

involve knowledge of tissue reactions. The last

and most important step of prediction is a

combination of the two disciplines.

Disease versus failure

The prevalence of disease far outweighs the

prevalence of tissue or organ failure. A certain

threshold must be reached before an organ

system fails. This varies greatly from organ to

organ and the interpretation of failure must

necessarily be broad. The concept of organ

failure applies well to the heart, lungs,

kidneys, liver, exocrine pancreas and some

endocrine organs. In these organs, failure

implies an inability to meet the metabolic

needs of the body. Organ failure in this sense

cannot be applied so strictly to organs such as

the brain, muscle, bone, joints and skin. These

rarely fail totally, but rather produce severe

impediments to normal function when focally

damaged.

However, the overriding concept remains,

that disease does not necessarily equate with

failure. A lesion may be visible grossly in an

organ, leaving no doubt that disease is pres￾ent, but organ function may not be impaired.

Conversely, comparatively small lesions may

Reversible versus irreversible disease 3

be of great clinical significance when they are

critically located, or have a potent metabolic

effect. The skilled and experienced observer

will be able to assess the type and character of

any lesion and decide if it has nil, moderate or

marked effect on organ function.

Reversible versus irreversible disease

One of the central features of the clinician's

skill is the ability to estimate the outcome of a

disease process. While a number of factors

need to be considered, the two most important

are the conclusions reached about the nature

of the disease process and the inherent ability

of a particular tissue to replace its specialized

cells.

The nature of the disease process may, for

example, be a selective degeneration and

necrosis of specialized cells. This may be

caused by a number of agents and may be

accompanied by an inflammatory process. If

the offending cause is removed or disappears

and the architectural framework remains, a

number of organs have the capacity to replace

the lost cells. Prominent in this regard are the

skin, liver, kidney, bone, muscle and most

mucosal lining cells. However, tissues such as

the brain, spinal cord and heart muscle have

little or no capacity for regeneration.

Sometimes, when a disease process is highly

destructive, it matters little if the organ has the

capacity to regenerate and the only savior in

the circumstances is the ability of some

systems to compensate. The remaining

unaffected tissue undergoes hypertrophy or

hyperplasia and to some extent increases its

efficiency. An example of this is the ability of

one kidney to enlarge and compensate when

the other is lost because of a disease such as

chronic pyelonephritis.

Another factor that needs to be taken into

account is the potential reversibility of the

disease process itself. There are numerous

examples of chronic diseases in which there is

little hope of reversal. A number of the

inherited or familial diseases fit this pattern, as

do many malignant neoplastic diseases. In

these cases, a disease may be recognized in its

early stages, but there is an inexorable pro￾gression. It is important to characterize the

nature of the disease as quickly as possible so

that suffering by the animal and emotional and

monetary costs to the owner can be

minimized.

W. John Penhale

2 The immune system

Knowledge of immunology has now become

essential for the comprehension of many dis￾ease processes. In addition to the awareness of

an expanding spectrum of diseases which have

at their core immunologic mechanisms, basic

information is also required on the cells of the

immune system and their interactions and

effector mechanisms.

The immune system is extremely complex,

performing a variety of activities directed

towards maintaining homeostasis. It consists

of an intricate communications network of

interacting cells, receptors and soluble factors.

As a consequence of this complex organiz￾ation, it is immensely flexible and is able

greatly to amplify or markedly to diminish a

given response, depending upon the circum￾stances and momentary needs of the animal. A

normally functioning immune system is an

effective defense against the intrusion of

noxious foreign materials such as pathogenic

microbial agents, toxic macromolecules and to

some extent against endogenous cells which

have undergone neoplastic transformation.

However, by virtue of its inherent complexity,

the system has the potential to malfunction

and, since it also has the ability to trigger effec￾tor pathways leading to inflammation and cell

destruction, may then cause pathologic effects

ranging from localized and mild to generalized

and life threatening.

The intensity of a particular immune

response depends on many factors, including

genetic constitution, and hormonal and

external environmental influences. Amongst

these, it is now becoming clear that genetic

background plays a highly influential role, and

to a significant extent, therefore, immuno￾pathologic events are a reflection of geneti￾cally determined aberrations in immune

regulation.

This chapter is designed to bridge the inter￾face between immunology and disease and will

be concerned largely with the involvement of

immunologic processes in disease patho￾genesis. Accordingly, emphasis will be placed

on the effector pathways and regulating

mechanisms and detailed accounts will not be

given of the organization of the system as a

whole or of its primary role in host defense.

The organization and regulation of the

immune system

In the absence of immune function, death

from infectious disease is inevitable. In order

to counteract infectious agents, the system has

evolved to recognize molecular conformations

foreign to the individual (antigenic determi￾nants) and to promote their elimination. To

accomplish this effectively, the system is

ubiquitously distributed throughout body

tissues and has as basic operational features:

molecular recognition, amplification and

memory, together with a range of effector

pathways by which foreign material may be

eliminated. The last of these can be divided

Organization and regulation

broadly into the humoral and cell-mediated

immune responses.

In addition, such a system requires precise

regulation in order to avoid excessive and

hence wasteful responses, and also potentially

dangerous reactivity to self components.

These diverse activities are performed by a

limited number of morphologically distinct

cell types which are capable of migrating

through the organs and tissues, performing

their functions remote from their sites of origin

and maturation. In this section, the chief

features and interactions of these cells where

considered germane to the main theme of this

chapter will be reviewed briefly.

Cells of the immune system

The ability of the individual to recognize and

respond to the intrusion of foreign macro￾molecules resides in cells of the lymphoid

series. Lymphoid cells are distributed

throughout the body both in circulating fluids

and in solid tissues. In the latter, they occur

either diffusely or in aggregates of varying

degrees of organization. In strategic regions of

the body, they collectively form discrete

encapsulated lymphoid organs such as the

spleen and lymph nodes.

The central cell of lymphoid tissues is the

immunocompetent lymphocyte. These cells

have receptor molecules on their cytoplasmic

antigenic stimulation

resting

lymphocyte effector

cells

(B or T)

blast transformation proliferation

Fig. 2.1. Resting lymphocytes following contact with

an appropriate antigen undergo blast transformation

followed by proliferation and further differentiation.

membranes which enable them to recognize,

and to interact with, complementary anti￾genic, as well as endogenously derived physio￾logic molecules.

Lymphocytes are activated by contact with

appropriate antigenic determinants and then

undergo transformation, proliferation and

further differentiation (Fig. 2.1). Ultimately,

one or more effector pathways are initiated

and the antigen concerned may then be elimin￾ated. Activated cells secrete a variety of bio￾logically active effector molecules which are

responsible both for cellular regulation and

effector functions. In addition, a proportion of

the expanded cell population remains dor￾mant as memory cells and accounts for the

augmented secondary response on re￾exposure to the same antigen.

Lymphocytes are divided into B and T

cell classes on the basis of ontogeny and

function. Functionally, B lymphocytes are

responsible for humoral, and T lymphocytes

for cell-mediated immune responses. These

cells also differ in their distribution within

lymphoid tissues and in their expression of cell

surface molecules (markers). Thus the

immune system can be regarded as a system

composed of dual but interacting compart￾ments.

The B lymphocyte

Cells of this lineage are the progenitors of anti￾body-secreting plasma cells and in mammals

develop initially from stem cells situated in the

bone marrow by a process of antigen-indepen￾dent maturation. Subsequently, after

migration to peripheral lymphoid tissues, they

undergo further differentiation induced by

antigen contact and mature to plasma cells.

Depending on the nature of antigen con￾cerned, B cell activation may require the

cooperation of a subpopulation of T cells (T

helper cells). Generally, small asymmetric

molecules such as polypeptides will not stimu￾late B cells directly, and require T cell cooper￾ation, whilst many polysaccharides are

capable of causing a direct (but limited) B cell

response. The antibodies generated may exist

The immune system

in several different molecular types or classes

(immunoglobulins (Ig) A, D, E, G and M).

The first antibodies generated are often of

IgM class and later, particularly after re￾stimulation, a switch in production to IgG, and

less frequently to IgA and IgE classes, occurs.

The functional activities of B cells depend

on an array of cell surface receptor molecules,

including Ig receptors for antigen, histocom￾patibility markers, receptors for the Fc region

of IgG and for complement (C3b component).

The T lymphocyte

T lymphocytes which undergo maturation in

the thymus are key cells in the expression of

many facets of immunity, where they perform

a variety of functions essentially concerned

with immune regulation and the elimination of

abnormal cells.

T cells orchestrate the immune response by

modulating the activities of both B and other T

cells. Regulation may be either positive or

negative. So, T cells are involved in initiating

immune responses (T helper cells) and also

terminating them (T suppressor cells). T cells

are also the principal cells involved in initiat￾ing cellular immune events which include such

phenomena as delayed hypersensitivity

reactions and allograft rejection.

Another facet of cell-mediated immunity is

cytotoxicity, executed by T cells having the

capacity to kill other cells, as exemplified in

the destruction of virus-infected cells and in

the rejection of allografts.

These various functions are performed by

major subsets of T lymphocytes which have

distinctive surface markers and which appear

to belong to different T cell lineages. Two

major subsets are now well defined both func￾tionally and phenotypically. T helper/inducer

cells cooperate in the production of antibodies

by B cells and with other T cells in cellular

immune reactions. They also act as inducers of

cy totoxic/suppressor cells. Helper/inducer

cells may be identified serologically by the

presence of the CD4 marker (defined by a

monoclonal antibody) on their surfaces. Cy to￾toxic/suppressor T lymphocytes are involved

in the suppression of immune responses and in

the killing of virus-infected and other abnor￾mal cells. They also express a specific cell

marker, CD8, on their cell membrane.

Antigen recognition by T lymphocytes

In major contrast to B cells, T cells recognize

antigen only when it is presented on a cell sur￾face. Furthermore, the antigen-presenting cell

must be of histocompatibility type identical

with that of the T cell concerned. Thus, in this

instance, antigen recognition is restricted and

can only be accomplished in the context of an

appropriate histocompatibility molecule. The

latter occurs in several different classes and it

is now clear that the major subsets of T cells

described above, recognize antigen in associ￾ation with different histocompatibility classes.

Thus helper/inducer cells are restricted to the

recognition of antigen on cells bearing the

class II molecules (immune-associated anti-

( T helper V< cell-' . ^ (CD4+

8") '

mr<

*W4

cell membrane

T cytotoxic >/-/ cell /\ /

y (CD4"8+

) I

0

Fig. 2.2. Antigen (Ag) recognition by T lymphocytes

involves an appropriate histocompatibility molecule

(CD4 and CD8 in diagram), and a combination of the T

cell receptor, the antigen and an appropriate histo￾compatibility product (class I or class II) on the pre￾senting cell. MHC, major histocompatibility complex.