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Essential Fluid, Electrolyte and pH Homeostasis

Essential Fluid, Electrolyte and pH Homeostasis

Gillian Cockerill | Stephen Reed

The mechanisms of fluid, electrolyte and acid-base homeostasis are fundamental to normal cellular function. Students often struggle to understand these complex mechanisms and this book will prove invaluable in helping them get to grips with this difficult subject.

The book has been carefully structured to present topics in ‘bite-sized’ chunks of information supported by numerous self assessment exercises, clear diagrams and relevant case studies. This accessible, pocket-sized, self-directed learning guide details the chemical (mostly ionic) composition of body fluids, explains how abnormalities arise, what laboratory tests can be used to identify and analyse the cause of these disorders and shows how normality can be achieved to maintain health.

As such it will be essential reading for biomedical, pharmacology, medical and allied health students needing an understanding of how changes in fluid and key electrolytes affect the body in health and disease.

Gillian Cockerill, Reader in Vascular Biology, St George’s University of London, UKStephen Reed, Principal Lecturer, School of Life Sciences, University of Westminster, UK

O An accessible, pocket-sized introduction to fluid, electrolyte and acid-base homeostasis.

O Carefully structured to present topics in ‘bite-sized’ chunks with clear, straightforward diagrams.

O Includes numerous self-assessment questions and answers together with relevant case studies and clinical examples.

www.wiley.com/go/cockerill/fluid

Cockerill Reed

Essential Flu

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Essential Fluid, Electrolyteand pH Homeostasis


Essential Fluid, Electrolyteand pH Homeostasis

Gillian CockerillReader, Vascular Biology, St George’s London

Stephen ReedPrincipal Lecturer, School of Life Sciences,

University of Westminster

A John Wiley & Sons, Ltd., Publication


This edition first published 2012© 2012 by by John Wiley & Sons, Ltd.

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Library of Congress Cataloging-in-Publication Data

Cockerill, Gillian.Essential fluid, electrolyte, and pH homeostasis / Gillian Cockerill, Stephen Reed.

p.; cm.Includes index.ISBN 978-0-470-68306-4 (pbk.)1. Body fluids. 2. Acid-Base Equilibrium. 3. Water-electrolyte balance

(Physiology) I. Reed, Stephen, 1954- II. Title.[DNLM: 1. Body Fluids–chemistry. 2. Acid-Base equilibrium–physiology.

3. Body Fluid Compartments–physiology. 4. Water-Electrolyte Balance–physiology.5. Water-Electrolyte Imbalance. QU 105]

QP90.5.C55 2011612′.01522–dc23

2011015327

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

This book is published in the following electronic formats: ePDF 9781119971894;ePub 9781119973669; Wiley Online Library 9780470683064; Mobi 9781119973676

Set in 9/11pt Sabon by Aptara Inc., New Delhi, India.

First 2012

http://www.wiley.com/wiley-blackwell


In loving memory ofMW, EMS, IW and JFH


Contents

List of figures xiii

List of tables xvii

Preface xix

Acknowledgements xxi

Part 1: Background theory and basic concepts

Section 1.i Introduction and overview 3

Section 1.ii Water 8

Section 1.iii Solutions: concentrations and colligativeproperties of solutes 12

Section 1.iv Self-assessment exercise 1.1 16

Section 1.v Acids and bases 18

Section 1.vi Buffers and the Henderson-Hasselbalchequation 23

Section 1.vii Self-assessment exercise 1.2 26

Section 1.viii Body fluids and their composition:overview 28

Section 1.ix Fluid balance: (a) between fluidcompartments and (b) intake and loss 34

Section 1.x Ionic composition and electricalneutrality 39

Section 1.xi Water and ion distribution betweencompartments 1: Physical chemistry 43


viii Contents

Section 1.xii Water and ion distribution betweencompartments 2: Physiology 50

Section 1.xiii Osmoregulation: solvent and solutebalance 55

Section 1.xiv Self-assessment exercise 1.3 60

Section 1.xv Summary of Part 1 62

Answers to Part 1 self-assessmentexercises 63

Part 2: Fluid and electrolyte homeostasis

Normal physiology

Section 2.i Fluid translocation: plasma to ISF andISF to ICF 83

Section 2.ii Renal function: a brief overview 88

Section 2.iii Renal regulation of blood composition 93

Section 2.iv Self-assessment exercise 2.1 100

Section 2.v Minerals: key roles in physiology andmetabolism 102

Section 2.vi Sodium and potassium 106

Section 2.vii Sodium and water homeostasis: renalregulation of blood pressure and bloodvolume 109

Section 2.viii Calcium and magnesium 115

Section 2.ix Iron 123

Section 2.x Selected trace elements: Mn, Co, Se and S 128

Section 2.xi Anions: bicarbonate, chloride, phosphateand proteins 130

Section 2.xii Self-assessment exercise 2.2 132

Section 2.xiii Laboratory measurements 1: Osmometry 134


Contents ix

Section 2.xiv Laboratory measurements 2: Ion selectiveelectrodes (ISEs) 138

Section 2.xv Laboratory measurements 3: Calcium,magnesium, vitamin D, phosphate andiron 147

Section 2.xvi Laboratory measurements 4:Miscellaneous methods for clinicallyuseful analytes 150

Section 2.xvii Self-assessment exercise 2.3 154

Disorders of fluid and electrolyte balance

Section 2.xviii Introduction 157

Section 2.xix Principles of data interpretation 160

Section 2.xx Sodium, protein and water 167

Section 2.xxi Hypernatraemia 173

Section 2.xxii Hyponatraemia 179

Section 2.xxiii Disturbances of potassium homeostasis 184

Section 2.xxiv Hyperkalaemia 186

Section 2.xxv Hypokalaemia 189

Section 2.xxvi Disturbances of calcium or magnesiumbalance 193

Section 2.xxvii Disorders of iron homeostasis 200

Section 2.xxviii Self-assessment exercise 2.4 202

Section 2.xxix Summary of Part 2 207


Part 3: Acid-base homeostasis

Normal physiological processes

Section 3.i Acidity, pH and buffers: recap of somebasic chemistry 221


x Contents

Section 3.ii Some worked example calculations 224

Section 3.iii Self-assessment exercise 3.1 227

Section 3.iv Homeostasis and the ‘daily acidchallenge’ 228

Section 3.v Physiological buffering 232

Section 3.vi The role of the kidney in acid-basehomeostasis 237

Section 3.vii Respiration: gas pressures andbreathing 244

Section 3.viii The role of red cells: gas carriage byhaemoglobin 248

Section 3.ix Self-assessment exercise 3.2 253

Section 3.x The liver and gastrointestinal tract inacid-base homeostasis 254

Section 3.xi The ‘traditional’ versus the ‘modern’view of acid-base homeostasis 257

Section 3.xii Stewart’s three independent factors 262

Section 3.xiii Laboratory measurement of pH, PCO2

and bicarbonate 268

Acid-base disturbances

Section 3.xiv Classification of primary changes basedon pH and aetiology 273

Section 3.xv Overview of mechanisms 276

Section 3.xvi Physiological correction of primarydisturbances 279

Section 3.xvii Check the data 283

Section 3.xviii Self-assessment exercise 3.3 284

Section 3.xix Non-respiratory (metabolic) acidosis 287

Section 3.xx Metabolic acidosis: detailed case studies 293


Contents xi

Section 3.xxi Non-respiratory (metabolic) alkalosis:overview 297

Section 3.xxii Non-respiratory (metabolic) alkalosis:causes 299

Section 3.xxiii Self-assessment exercise 3.4 302

Section 3.xxiv Respiratory disorders: overview 303

Section 3.xxv Physiological consequences ofrespiratory disorders 305

Section 3.xxvi Respiratory disorders: case studies 307

Section 3.xxvii Summary of Part 3 312


Appendix 325

Index 329


List of figures

Figure Title Section Page

1.1 Transport processes 1.i 4

1.2 Ionic balance within and between compartments 1.i 5

1.3 Polarity of water 1.ii 9

1.4 Vapour pressure 1.iii 14

1.5 Acid-base behaviour of alanine 1.v 21

1.6 Total body water 1.viii 29

1.7 Body fluids are in dynamic flux 1.ix 35

1.8 Ionogram 1.x 40

1.9 Solvent, solute gradients 1.xi 44

1.10 Tonicity 1.xi 46

1.11 Gibbs-Donnan equilibrium 1.xi 48

1.12 Sodium pump 1.xii 51

1.13 Fluid movement between blood, ISF and ICF 1.xii 53

1.14 Starling’s hypothesis 1.xii 54

1.15 Osmosis 1.xiii 56

2.1 Starling’s forces 2.i 84

2.2 Drainage of ISF 2.i 86

2.3 Renal nephron 2.ii 89

2.4 Sodium gradient 2.ii 90


xiv List of figures

2.5 Kinetics of renal tubular transport 2.ii 91

2.6 ADH structure 2.iii 94

2.7 Relationship between ADH and osmolality 2.iii 95

2.8 Adrenal steroid synthesis 2.iii 96

2.9 Steroid structures 2.iii 97

2.10 Natriuretic peptide structure 2.iii 98

2.11 Renin-angiotensin-aldosterone cascade 2.vii 110

2.12 Renin and ACE produce angiotensin II 2.vii 111

2.13 Oedema 2.vii 113

2.14 Calcium distribution and turnover 2.viii 116

2.15 Vitamin D3 synthesis 2.viii 119

2.16 Control of vitamin D3 synthesis 2.viii 120

2.17 Iron uptake and distribution 2.ix 126

2.18 Cooling curves 2.xiii 135

2.19 Cryoscopy 2.xiii 136

2.20 Ion selective electrodes 2.xiv 140

2.21 Ionophores 2.xiv 141

2.22 Logarithmic response of an ISE 2.xiv 144

2.23 Fluid displacement by proteins and lipoproteins 2.xiv 145

2.24 Distribution of intravenous fluids 2.xviii 158

3.1 Lactate utilisation by liver 3.iv 230

3.2 Simplified diagram of the role of the nephron 3.vi 238

3.3 Ammonia and phosphate are bases 3.vi 239

3.4 Glutamine is a carrier of NH3 3.vi 242

3.5 Carbonic anhydrase and glutaminase 3.vi 243

3.6 Influence of arterial gas pressures onrespiratory rate 3.vii 245


List of figures xv

3.7 Gas diffusion in the lungs 3.vii 246

3.8 The oxygen dissociation curve 3.viii 249

3.9 Rapoport-Leubering shunt 3.viii 250

3.10 Bohr effect 3.viii 251

3.11 Role of red blood cells: chloride shift 3.viii 252

3.12 Cori cycle 3.x 255

3.13 Ketogenesis 3.x 256

3.14 Anion gap 3.xv 278

3.15 Compensation for respiratory acidosis 3.xvi 280

3.16 Compensation for respiratory alkalosis 3.xvi 281

3.17 Compensation for metabolic acidosis 3.xvi 281

3.18 Compensation for metabolic alkalosis 3.xvi 282

3.19 Overproduction of lactate 3.xix 289


List of tables

Table Title Section Page

1.1 Typical pKa values 1.v 20

1.2 Total body water 1.viii 29

1.3 Major Solutes 1.viii 30

1.4 Comparison of plasma and CSF 1.viii 32

1.5 Typical fluid balance 1.ix 36

1.6 Volumes of fluids and secretions 1.ix 36

2.1 Natriuretic peptides 2.iii 99

2.2 Minerals 2.v 103

2.3 Distribution of iron 2.ix 124

2.4 Electrometric methods 2.xiv 139

2.5 Factitious results 2.xix 161

2.6 Typical values for error 2.xix 165

2.7 Reference ranges 2.xix 166

2.8 Hyper-and hyponatraemia 2.xx 171

2.9 Hyper- and hypomagnesaemia 2.xxvi 198

3.1 Physiological compensation 3.xvi 280

3.2 Causes of metabolic acidosis 3.xix 288

3.3 Renal tubular acidoses 3.xix 290

3.4 Some common causes of respiratory disorders 3.xxiv 304

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Preface

‘All vital mechanisms, no matter how varied they may be, havealways but one end, that of preserving the constancy of theconditions of the internal environment.’

With these words, Claude Bernard in 1857 gave what was probablythe first definition of the process we now know as ‘homeostasis’, eventhough the term, derived from the Greek homoios meaning ‘the same’,was not coined until the 1920s.

Those events that collectively constitute ‘life’ can all be describedin terms of chemical and physical processes; cell biology in particularis chemistry in disguise! The purpose of this short text is to act as aprimer for students meeting key topics for the first time, but sectionsof this book will also be useful as a quick revision guide for moreadvanced students. The text, supported by diagrams, aims to explainphysiochemical processes related to the homeostatic maintenance of:

(i) electrochemical neutrality (anion/cation balance);(ii) osmotic balance (regulation of the concentrations of solutes in-

side and outside cells, and(iii) hydrogen ion balance.

The mechanisms of fluid, electrolyte and acid-base homeostasis arefundamental to normal cellular function and therefore have a majorimpact on the health of the individual, and an imbalance may leadto a life-threatening situation. Processes of fluid, electrolyte and acid-base regulation that are physiologically interrelated are the ones whichstudents often find most difficult to understand, partly because of theircomplexity.

This introductory text is divided into three main Parts dealing ini-tially with basic physicochemical concepts, then aspects of normal andabnormal physiology. Each part is presented as a number of Sections

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xx Preface

which are essentially ‘bite-sized chunks’ of key information. The bookis designed such that it may be read as continuous prose, or, andbecause each Section more or less stands alone, the reader may dipinto the text for the purposes of review or revision of particular topics.Some concepts are described in several sections to ensure that relevantsections are fairly self-contained, but will also allow the reader theopportunity to revisit and consolidate essential material. The contentscovered range from basic chemistry and physiology to more advancedconcepts which are applied to clinically relevant situations. Selectedaspects of analysis and discussion of some of the pitfalls of interpreta-tion of laboratory data are also to be found. There are numerous SelfAssessment Exercises based on understanding of key concepts, data-handling problems and case studies for reinforcement of the learningprocess. We hope the text will be of value to laboratory staff and ward-based staff in endeavouring to understand what many see as a ‘verydifficult’ topic area.

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Acknowledgements

Our thanks go to the production and editorial staff at John Wiley;Nicky McGirr, Fiona Woods, Izzy Canning and Celia Carden, LizRenwick and Samantha Jones. To several colleagues especially, DavidGaze and Dr Nawaf Al-Subaie (both St George’s) for help with casestudies, and Alison Boydell (Westminster) who offered constructivecomment on the manuscript.

Also, to Colin Samuell, a valued colleague who provided some ofthe case histories, and more importantly an inspiring teacher who hasmade many difficult concepts understandable to countless numbers ofstudents (including SR).

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PART 1

Background theory andbasic concepts

Overview

The purpose of Part 1 is to review some important concepts of physicalchemistry and to introduce key ideas of physiology, all of which willprovide underpinning knowledge for deeper study in Parts 2 and 3.Although some understanding of solutions, acids, bases, pH andbuffers may have been acquired from previous studies, these top-ics are included here for revision; some readers may choose to omitcertain sections.

An overview is given of body fluid compartments, their volumesand their chemical compositions. Importantly, concepts relating toosmotic balance and electrical neutrality of physiological fluids arealso discussed.

Essential Fluid, Electrolyte and pH Homeostasis, First Edition. Gillian Cockerill and Stephen Reed.© 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

1


SECTION 1.i

Introduction andoverview

The human body is, by weight, predominantly water: the total vol-ume1 being distributed into two major compartments. The largerproportion is located inside cells (intracellular fluid, ICF) with asmaller volume occurring as extracellular fluid (ECF). To functioneffectively, cells must maintain correct fluid volume balance, ionicbalance, osmotic balance and acid-base balance. Two fundamentalphysicochemical phenomena, namely electroneutrality and osmosis(‘osmoneutrality’), have significant effects on cellular function. Home-ostatic mechanisms operate to maintain physiological steady-state con-ditions of ionic and solute concentrations.

Body fluids are complex ‘cocktails’ of various chemicals such as(a) ions (electrolytes), notably sodium, potassium, calcium, chloride,phosphate and bicarbonate, (b) small molecular weight metabolitessuch as glucose, urea, urate (uric acid) and creatinine, and (c) largermolecular weight compounds, for example, proteins and lipoproteincomplexes.

Qualitatively, the chemical composition of most body fluids is sub-stantially the same, but quantitatively, the chemical content of thedifferent body fluids varies considerably. Overall, the total volume ofwater in our bodies does not vary greatly, and nor does the overallchemical composition of the fluids, as both volume and compositionare carefully regulated to maintain homeostasis. However, as is of-ten the case in physiological systems, there is at the molecular level a

1One should always refer to fluids (i.e. liquids and gases) in terms of volumerather than amount.

Essential Fluid, Electrolyte and pH Homeostasis, First Edition. Gillian Cockerill and Stephen Reed.© 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

3


4 Background theory and basic concepts

Key: membrane-bound transport protein

Cell membrane

High Low

ATP

ADP + Pi

Passive diffusion via pores

Carrier mediated diffusion

Active carrier mediated transport

concentration gradient across membrane

Figure 1.1 Membrane transport. Passive osmotic, passive mediatedand active mediated mechanisms

dynamic state of flux and continual change occurring, with fluid andsolutes moving between compartments. These movements are drivenby physicochemical gradients which arise due to osmotic, electro-chemical and concentration2 differences across cell membranes. Fluidmovement between the intracellular and extracellular compartmentsis directed by osmosis (a particular form of passive diffusion), but be-cause the outer plasma membrane of cells is relatively impermeable tomost solutes, especially ions, active or passive carrier mechanisms arerequired to transport such components between compartments.

2Strictly speaking, it is thermodynamic ‘activity’ rather than concentrationgradients which determine the dynamic flux of molecules across a membrane.


Introduction and overview 5

Electrochemical gradients across cell membranes arise due to thenumber and nature (principally their size and charge) of the solutesdistributed on either side of the membrane. An imbalance in electricalcharge across certain membranes is physiologically essential for exam-ple to allow nerve impulse conduction and for the initiation of musclecontraction, for example. However, for most cells, an equal distribu-tion of total number of anions and cations is the norm. In addition tothe necessity for electrical neutrality across a membrane, i.e. betweencompartments, the numbers of negative and positive charges within aparticular compartment or body fluid must also be equivalent.

Normal hydrogen ion concentration in most body fluids is verylow, in the nanomolar range, compared with concentrations of otherions such as sodium and potassium which are present at millimolarconcentrations. Homeostatic mechanisms that regulate hydrogen ionbalance are of necessity very sensitive to avoid the wide fluctuations inpH which might seriously impair enzyme function, leading to conse-quent cell dysfunction.

Physiological control of body fluid volumes and their chemicalcomposition is fundamental to the health and wellbeing of cells, tis-sues and whole organisms, and as such represents a major purpose ofhomeostasis. Several physiological systems are involved with normalfluid and electrolyte homeostasis, and thus disorders of the kidneys,liver, endocrine system and gut can all lead to fluid, electrolyte orpH imbalance.

compartment 1 compartment 2

[A ]−1

[C ]+1

[A ]−2

[C ]+2

Electrical Neutrality.

The numerical product of the cations and ions in compartment 1 = the product of cations and anions in compartment 2; [C ] × [A ] = [C ] × [A ] +

1−

1+

2−

2

Total cation concentration in compartment 1 = Total anion concentration in compartment 1, ([C ] ) = ([A ] ). Similarly for compartment 2. +

1−

1

The specific nature of anions and cations in the two compartments may differ.

Figure 1.2 Ionic balance within and between compartments


6 Background theory and basic concepts

The organs that play the most significant role in fluid and electrolytehomeostasis are the kidneys, which process approximately 140 litresof fluid containing a significant quantity of solutes, including elec-trolytes, each day. Thus, it is not surprising that renal disease is oftenassociated with serious fluid and electrolyte imbalances. Mechanismsfor the normal renal handling of water, sodium and potassium, andcalcium, in particular, are controlled by the endocrine system via theactions of anti-diuretic hormone (also called vasopressin), aldosteroneand parathyroid hormone respectively. Endocrinopathy of the pitu-itary, adrenal cortex or parathyroid glands will therefore result influid and electrolyte imbalance. Renal regulation of proton excre-tion and bicarbonate reabsorption is a crucial aspect of pH home-ostasis but, in contrast to water and electrolyte balance, is not underhormonal control.

The gastrointestinal tract secretes and subsequently reabsorbs alarge volume of electrolyte-rich fluid on a daily basis, hence condi-tions leading to severe vomiting or diarrhoea can also result in signif-icant losses of water, electrolytes or acid-base disturbances. Indeed,fatalities due to cholera infection are invariably due to dehydrationas a result of the action of a microbial toxin interfering with normalwater and electrolyte reabsorption in the colon. Additionally, the liver,one of the gastrointestinal-associated organs, contributes to acid-basebalance through its role in ammonia metabolism and urea synthesis.

Changes in fluid balance, within an individual, can also occur fre-quently even in times of good health. Many of us suffer the side-effects,notably headache, of periods of especially underhydration, causing tis-sue cells to shrink, due simply to deficient fluid intake even thoughwe are in all other respects ‘well’. Cellular overhydration resulting incellular swelling is much more likely to be due to a homeostatic ab-normality, but headache is also an early sign of fluid overload. Severechanges in hydration may occur after physical trauma resulting in in-jury to the body; this includes major surgery, so during the ‘post-op’recovery period, surgeons and intensive-care physicians monitor fluidand electrolyte balance very carefully in their patients.

It is not only volume changes across cell membranes that are asso-ciated with pathology. If the volume of blood in the veins and arteriesincreases, the individual will suffer from high blood pressure (hyper-tension), a state which can have serious effects on, for example, thecardiovascular system, leading possibly to a stroke. Kidney damagecan be either the cause or effect of hypertension. Conversely, if blood

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