Marshall / Lapsley / Day Clinical Biochemistry E-Book

Metabolic and Clinical Aspects
3. Auflage 2014
ISBN: 978-0-7020-5478-5
Verlag: Elsevier HealthScience EN
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 996 Seiten

Essential reading for candidates for the MRCPath examination and similar postgraduate examinations in clinical biochemistry. The book gives an overview of the acquisition of data, as well as concentrating on clinical aspects of the subject, giving detailed coverage of all conditions where clinical biochemistry is used in diagnosis and management. In common with other diagnostic specialties clinical biochemistry now uses an increasing number of techniques involving the 'new biology': these are covered in this book. It is also increasingly common for medically qualified clinical biochemists to become involved in the clinical management of patients (eg nutritional support) and material on this will be included.

From the author of the popular Clinical Chemistry medical student textbook.

Although there are many competing texts on clinical chemistry, the vast majority concentrate on the technology; this book concentrates on the clinical.

Ideally suited for preparation for the MRCPath and similar examination.

• Significant changes to content to reflect changes in how clinical chemistry services are organised and to reflect the advent of metabolic medicine as a recognised specialty.
• Chapter on Clinical biochemistry of nutrition to include new information on regulation of appetite and the clinical management of obesity.
• New chapter to bring together information on inborn errors of metabolism affecting adults.
• New chapter on clinical biochemistry of cardiovascular disease.
• The diabetes chapter has been split into two separate chapters to allow more detailed description of the practical clinical management of the disease.

Autoren/Hrsg.

Marshall, William J.

Lapsley, Márta

Day, Andrew

Ayling, Ruth

Inhaltsverzeichnis

1;Front Cover;1
2;Clinical Biochemistry: Metabolic and clinical aspects;4
3;Copyright;5
4;Contents;6
5;Preface;8
6;Contributors;9
7;Chapter 1: Uses of biochemical data in clinical medicine;12
7.1;Introduction;12
7.2;Specific uses of biochemical tests;13
7.2.1;Diagnosis;13
7.2.2;Management;14
7.2.2.1;Assessment of disease severity;14
7.2.2.2;Prognosis;14
7.2.2.3;Monitoring the progression of disease;14
7.2.3;Screening;15
7.2.3.1;Population screening;15
7.2.3.2;Selective screening;15
7.2.3.3;Individual screening;15
7.2.4;Other uses of biochemical investigations;16
7.3;Conclusion;16
7.4;Further reading;16
8;Chapter 2: Acquisition and interpretation of biochemical data;17
8.1;Introduction;17
8.2;The Test Request;17
8.3;Factors Affecting Test Results;18
8.3.1;Preanalytical factors;18
8.3.1.1;Technical factors;18
8.3.1.2;Biological factors;18
8.3.1.2.1;Endogenous factors;19
8.3.1.2.1.1;Age;19
8.3.1.2.1.2;Sex;19
8.3.1.2.1.3;Ethnic origin;19
8.3.1.2.1.4;Body mass;19
8.3.1.2.2;Exogenous factors;19
8.3.1.2.2.1;Time-dependent changes;19
8.3.1.2.2.2;Stress;20
8.3.1.2.2.3;Posture;20
8.3.1.2.2.4;Food intake;20
8.3.1.2.2.5;Drugs;20
8.3.1.2.2.6;Other factors;20
8.3.1.2.3;Intrinsic biological variation;20
8.3.1.2.4;Analytical range;21
8.3.1.2.5;Accuracy and bias;21
8.3.1.2.6;Precision;22
8.3.1.2.7;Specificity and interference;22
8.3.1.2.8;Practicalities: what is desirable performance?;22
8.3.1.2.9;Analytical goals;23
8.3.2;Analytical factors;21
8.3.3;Postanalytical factors;23
8.4;Interpretation of Results;24
8.4.1;Normal and abnormal;24
8.4.2;The meaning of normal;24
8.4.3;Reference values;25
8.4.3.1;Problems with reference intervals;25
8.4.4;Comparison of observed results with reference limits;26
8.4.5;Comparison of results with previous values;26
8.5;The Predictive Value of Tests;27
8.5.1;Introduction;27
8.5.1.1;Definitions;27
8.5.1.2;Example;28
8.5.2;Prevalence and predictive value;29
8.5.3;Practical applications of the predictive value model;30
8.5.4;Receiver operating characteristic curves;30
8.5.5;Likelihood ratios;30
8.6;Conclusion;31
8.7;Acknowledgement;31
8.8;Further reading;31
9;Chapter 3: Quality aspects of laboratory medicine;32
9.1;Introduction;32
9.2;What is quality?;32
9.3;Quality standards;32
9.3.1;Quality assurance;32
9.3.2;Regulation of laboratories;33
9.3.2.1;Quality management systems;33
9.3.3;Personnel;33
9.3.4;Premises and environment;33
9.3.5;Information systems;34
9.3.5.1;Evaluation and audit;34
9.4;Clinical quality indicators;35
9.4.1;Clinical effectiveness;35
9.4.2;Key performance indicators;35
9.4.3;Demand management;36
9.5;Evidence-based clinical biochemistry;36
9.6;Point-of-care testing;36
9.7;Conclusion;37
9.8;Further Reading;37
10;Chapter 4: Sodium, water and potassium;38
10.1;Physiology;38
10.1.1;Introduction;38
10.1.2;Extracellular fluid and sodium;39
10.1.2.1;Renal control of sodium output;39
10.1.2.1.1;Intrinsic renal control of tubular reabsorption of sodium;39
10.1.2.1.2;Renin–angiotensin–aldosterone axis;39
10.1.2.1.3;Natriuretic peptides;40
10.1.2.2;Sodium appetite;41
10.1.3;Intracellular fluid and water;41
10.1.3.1;Control of renal water output;41
10.1.3.1.1;Osmoregulation;41
10.1.3.1.2;Non-osmotic control of arginine vasopressin;42
10.1.3.1.3;Renal responsiveness to arginine vasopressin;42
10.1.3.2;Control of water intake;42
10.1.3.2.1;Osmoregulation;42
10.1.3.2.2;Non-osmotic control of thirst;43
10.1.4;Extracellular fluid, intracellular fluid and potassium;43
10.1.4.1;Extracellular and intracellular fluid distribution of potassium;43
10.1.4.2;Renal control of potassium output;44
10.1.4.2.1;Intrinsic tubular control;44
10.1.4.2.2;Aldosterone;44
10.2;Disorders of sodium metabolism;44
10.2.1;Sodium deficiency;44
10.2.1.1;Clinical presentation;44
10.2.1.2;Causes of sodium deficiency;44
10.2.1.2.1;Extrarenal sodium loss;45
10.2.1.2.2;Primary renal sodium loss;45
10.2.1.2.3;Secondary renal sodium loss;46
10.2.1.3;Laboratory investigation of sodium deficiency;46
10.2.1.4;Management of sodium deficiency;47
10.2.2;Sodium excess;47
10.2.2.1;Clinical presentation;47
10.2.2.2;Causes of sodium excess;48
10.2.2.2.1;Sodium excess with oedema;48
10.2.2.2.2;Pregnancy;48
10.2.2.2.3;Menstrual cycle;49
10.2.2.2.4;Idiopathic oedema;49
10.2.2.2.5;Sodium excess without oedema;49
10.2.2.3;Laboratory investigation of sodium excess;50
10.2.2.4;Management of sodium excess;50
10.3;Disorders of water metabolism;50
10.3.1;Polyuria;50
10.3.1.1;Primary polyuria with secondary polydipsia;50
10.3.1.2;Pregnancy and polyuria;52
10.3.1.3;Polyuria secondary to primary polydipsia;52
10.3.1.4;Laboratory investigation and treatment of polyuria;52
10.3.1.4.1;Water deprivation test;53
10.3.1.4.2;Hypertonic saline infusion;53
10.3.1.5;Management of polyuria;53
10.3.2;Nocturnal polyuria;54
10.3.2.1;Laboratory investigation and treatment of nocturnal polyuria;54
10.3.3;Hypernatraemia;55
10.3.3.1;Water deficiency with thirst;55
10.3.3.2;Water deficiency without thirst;55
10.3.3.3;Management of hypernatraemia;56
10.3.3.3.1;Management of hypodipsic hypernatraemia syndromes;56
10.3.4;Hyponatraemia;57
10.3.4.1;Acute dilutional hyponatraemia;57
10.3.4.2;Chronic dilutional hyponatraemia;58
10.3.4.2.1;The syndrome of inappropriate antidiuretic hormone secretion;59
10.3.4.2.2;Sick cell syndrome;60
10.3.4.3;Low osmotic load hyponatraemia;60
10.3.4.4;Cerebral salt wasting;61
10.3.4.5;Laboratory investigation of hyponatraemia;61
10.3.4.6;Management of hyponatraemia;62
10.3.4.6.1;Recommended management of symptomatic acute dilutional hyponatraemia;62
10.3.4.6.2;Recommended management of chronic dilutional hyponatraemia;62
10.4;Disorders of potassium metabolism;63
10.4.1;Hypokalaemia;63
10.4.1.1;Causes of hypokalaemia;63
10.4.1.1.1;Redistribution hypokalaemia in vitro;63
10.4.1.1.2;Redistribution hypokalaemia in vivo;63
10.4.1.1.3;Hypokalaemic periodic paralysis;63
10.4.1.1.4;Extrarenal causes of potassium depletion;64
10.4.1.1.5;Renal causes of potassium depletion;65
10.4.1.1.6;Renal hypokalaemic acidosis;65
10.4.1.1.7;Renal hypokalaemic alkalosis;66
10.4.1.1.8;Renal hypokalaemia without specific acid–base disorder;67
10.4.1.2;Laboratory investigation of hypokalaemia;67
10.4.1.3;Management of hypokalaemia;68
10.4.2;Hyperkalaemia;68
10.4.2.1;Causes of hyperkalaemia;69
10.4.2.1.1;Redistribution hyperkalaemia in vitro;69
10.4.2.1.2;Redistribution hyperkalaemia in vivo;69
10.4.2.1.3;Hyperkalaemic periodic paralysis;70
10.4.2.1.4;Potassium retention;70
10.4.2.1.5;Syndromes of hypoaldosteronism;70
10.4.2.2;Laboratory investigation of hyperkalaemia;71
10.4.2.3;Management of hyperkalaemia;72
10.5;Conclusion;72
10.6;Further reading;72
10.7;Appendix 4.1. Formulae;73
10.7.1;(a)
Estimate of reduction in ECF volume from rise in haematocrit (HCT) when no blood loss has occurred;73
10.7.2;(b)
Estimate of sodium deficit in patients with hypovolaemic hyponatraemia;73
10.7.3;(c)
Estimate of water deficit in hypernatraemia;73
10.7.4;(d)
Estimate of the expected sodium depression in hyperglycaemia-induced hyponatraemia;73
10.7.4.1;Reference;73
10.7.5;(e)
Calculation of serum osmolality;73
10.7.5.1;Reference;73
10.7.6;(f)
Calculation of osmolal gap;73
10.7.7;(g)
Estimate of sodium required in acute water intoxication;73
10.7.8;(h)
Calculation of the transtubular potassium gradient (TTKG);73
10.7.8.1;Reference;74
10.8;Appendix 4.2. Dynamic function tests;74
10.8.1;(a)
Water deprivation test;74
10.8.1.1;Notes;74
10.8.1.2;Vasopressin test;74
10.8.1.3;Interpretation;74
10.8.1.4;Reference;74
10.8.2;(b)
Hypertonic saline infusion;74
10.8.2.1;Pre-infusion preparation;74
10.8.2.2;Infusion protocol;74
10.8.2.3;Notes;74
10.8.2.4;Reference;75
10.8.3;(c)
Water load test;75
10.8.3.1;Interpretation;75
10.8.3.2;Reference;75
11;Chapter 5: Hydrogen ion homoeostasis and tissue oxygenation and their disorders;76
11.1;Introduction;76
11.2;The physiological role of hydrogen ions;76
11.2.1;Definitions;76
11.3;Hydrogen ion homoeostasis;77
11.3.1;Buffering;77
11.3.1.1;Bicarbonate;77
11.3.1.2;Phosphate;78
11.3.1.3;Haemoglobin;78
11.3.1.4;Other proteins;78
11.3.1.5;Ammonia;78
11.3.2;Hydrogen ion turnover;79
11.3.3;Hydrogen ion production;79
11.3.3.1;Carbon dioxide;79
11.3.3.2;Incomplete metabolism of glucose: glycolysis and lactate metabolism;79
11.3.3.3;Incomplete metabolism of triglycerides: ketogenesis;80
11.3.3.4;Complete oxidation of glucose and triglycerides;80
11.3.3.5;Amino acid metabolism;80
11.3.4;Hydrogen ion excretion;81
11.3.4.1;Carbon dioxide;81
11.3.4.2;Hydrogen ions;81
11.3.4.2.1;Bicarbonate reabsorption;81
11.3.4.2.2;Acidification of the urine;81
11.3.4.2.3;The role of urinary ammonium excretion;82
11.3.4.2.4;The role of the liver in hydrogen ion homoeostasis;83
11.3.5;Summary;84
11.4;The assessment of acid–base status;84
11.4.1;Clinical assessment;84
11.4.2;Laboratory assessment;84
11.4.2.1;Hydrogen ion concentration and PCO2 ;84
11.4.2.2;Derived variables;84
11.4.2.3;Anion gap;85
11.4.2.4;Other investigations;85
11.5;Disorders of hydrogen ion homoeostasis;85
11.5.1;Introduction;85
11.5.2;Non-respiratory acidosis;85
11.5.2.1;Compensatory responses in non-respiratory acidosis;85
11.5.2.1.1;Buffering;85
11.5.2.1.2;Hyperventilation;85
11.5.2.1.3;Renal hydrogen ion excretion;86
11.5.2.2;Biochemical characteristics of non-respiratory acidosis;86
11.5.2.3;Systemic effects of acidosis;86
11.5.2.3.1;The cardiovascular system;86
11.5.2.3.2;Oxygen delivery to tissues;87
11.5.2.3.3;The nervous system;87
11.5.2.3.4;Potassium homoeostasis;87
11.5.2.3.5;Bone;87
11.5.2.3.6;Other effects;87
11.5.2.4;Management of non-respiratory acidosis;87
11.5.2.5;Specific causes of non-respiratory acidosis;87
11.5.2.5.1;Ketoacidosis;87
11.5.2.5.2;Other acid–base disturbances associated with alcohol;88
11.5.2.5.3;Lactic acidosis;88
11.5.2.5.4;Dilutional (expansion) acidosis;89
11.5.2.5.5;Acidosis in renal disease;89
11.5.3;Respiratory acidosis;91
11.5.3.1;Compensatory responses in respiratory acidosis;91
11.5.3.1.1;Buffering;91
11.5.3.1.2;Hyperventilation;92
11.5.3.1.3;Renal hydrogen ion excretion;92
11.5.3.2;Biochemical characteristics of respiratory acidosis;92
11.5.3.3;Systemic effects of respiratory acidosis;92
11.5.3.4;Management;92
11.5.4;Non-respiratory alkalosis;93
11.5.4.1;Compensation for non-respiratory alkalosis;93
11.5.4.1.1;Buffering;93
11.5.4.1.2;Hypoventilation;93
11.5.4.1.3;Renal bicarbonate excretion;93
11.5.4.2;Biochemical characteristics of non-respiratory alkalosis;94
11.5.4.3;Systemic effects of alkalosis;94
11.5.4.4;Management of non-respiratory alkalosis;94
11.5.4.5;Specific causes of non-respiratory alkalosis;94
11.5.4.5.1;Loss of gastric acid;94
11.5.4.5.2;Post-hypercapnic alkalosis;94
11.5.4.5.3;Mineralocorticoid excess;95
11.5.4.5.4;Miscellaneous;95
11.5.5;Respiratory alkalosis;95
11.5.5.1;Compensatory responses in respiratory alkalosis;95
11.5.5.1.1;Buffering;95
11.5.5.1.2;Hypoventilation;95
11.5.5.1.3;Renal hydrogen ion excretion;95
11.5.5.2;Biochemical features of respiratory alkalosis;95
11.5.5.3;Systemic effects of respiratory alkalosis;95
11.5.5.4;Management;95
11.5.6;The interpretation of acid–base data;96
11.5.7;Mixed disorders of hydrogen ion homoeostasis;97
11.6;Tissue oxygenation;98
11.6.1;Introduction;98
11.6.2;Pulmonary function;98
11.6.2.1;Alveolar ventilation;98
11.6.2.2;Oxygen uptake into blood;98
11.6.3;The role of haemoglobin in oxygen transport;99
11.6.4;The effects of pulmonary disease on oxygen uptake into blood;100
11.6.4.1;Shunting;100
11.6.4.2;Ventilation–perfusion imbalance;100
11.6.4.3;Differential effects of pulmonary disease on PaCO2 and PaO2 ;100
11.6.5;Oxygen transport to tissues;100
11.6.5.1;Oxygen delivery;100
11.6.5.2;Oxygen uptake;101
11.6.6;Hypoxia;101
11.6.6.1;Measurement of oxygen delivery to tissues;101
11.6.6.2;Detection of tissue hypoxia;102
11.6.6.3;Management of respiratory failure;102
11.7;Conclusion;103
11.8;Further reading;103
12;Chapter 6: Calcium, phosphate and magnesium;104
12.1;Calcium metabolism;104
12.1.1;Biological role of calcium;104
12.1.2;Distribution of calcium;104
12.1.3;Calcium fluxes;105
12.1.3.1;Gastrointestinal tract;105
12.1.3.2;Kidneys;105
12.1.3.3;Bone;106
12.1.4;Regulation of calcium metabolism;106
12.1.4.1;Parathyroid hormone;106
12.1.4.1.1;Measurement of circulating parathyroid hormone;107
12.1.4.1.2;Classification of hyperparathyroidism;107
12.1.4.2;Vitamin D;107
12.1.4.2.1;Synthesis and metabolism;107
12.1.4.2.2;Actions;108
12.1.4.2.3;Synthetic vitamin D analogues;109
12.1.4.2.4;Measurement of vitamin D metabolites;109
12.1.4.3;Calcitonin;109
12.1.4.3.1;Procalcitonin;110
12.1.4.4;Other hormones;110
12.1.5;Biochemical assessment of calcium metabolism;110
12.1.5.1;Plasma calcium;110
12.1.5.2;Intestinal calcium absorption;111
12.1.5.3;Urinary calcium;111
12.1.5.4;Indices of bone turnover;111
12.1.6;Hypercalcaemia;111
12.1.6.1;Causes of hypercalcaemia;112
12.1.6.1.1;Primary hyperparathyroidism;112
12.1.6.1.2;Familial hypocalciuric hypercalcaemia;113
12.1.6.1.3;Hypercalcaemia of malignancy;113
12.1.6.1.4;Granulomatous disease;114
12.1.6.1.5;Vitamin D toxicity;114
12.1.6.2;Investigation of hypercalcaemia;114
12.1.6.3;Treatment of hypercalcaemia;115
12.1.7;Hypocalcaemia;116
12.1.7.1;Clinical features;116
12.1.7.2;Causes of hypocalcaemia;117
12.1.7.2.1;Hypoparathyroidism;117
12.1.7.2.2;Pseudohypoparathyroidism;117
12.1.7.2.3;Vitamin D disorders;118
12.1.7.2.4;Other causes of hypocalcaemia;118
12.1.7.3;Investigation of hypocalcaemia;119
12.1.7.4;Treatment of hypocalcaemia;120
12.2;Phosphorus metabolism;120
12.2.1;Distribution of body phosphorus;120
12.2.1.1;Intracellular phosphorus;120
12.2.1.2;Phosphate homoeostasis;121
12.2.1.3;Dietary phosphate and intestinal absorption;122
12.2.1.4;The renal tubular reabsorption of phosphate;122
12.2.1.4.1;Factors regulating TMP/GFR;122
12.2.1.4.2;Disorders of renal phosphate metabolism;123
12.2.1.5;Plasma phosphate concentrations;124
12.2.2;Hyperphosphataemia;124
12.2.2.1;Consequences of hyperphosphataemia;125
12.2.2.2;Diagnostic approach to hyperphosphataemia;125
12.2.2.3;Therapeutic approach to hyperphosphataemia;125
12.2.3;Hypophosphataemia;126
12.2.3.1;Mechanisms;126
12.2.3.2;Consequences of hypophosphataemia;127
12.2.3.3;Diagnostic approach to hypophosphataemia;127
12.2.3.4;Therapeutic approach to hypophosphataemia;127
12.3;Magnesium metabolism;128
12.3.1;Plasma magnesium;128
12.3.2;Magnesium homoeostasis;128
12.3.3;Hypomagnesaemia;129
12.3.3.1;Causes;129
12.3.3.2;Consequences;130
12.3.3.2.1;Cardiac effects;130
12.3.3.3;Diagnostic approach to hypomagnesaemia;130
12.3.3.4;Therapeutic approach to hypomagnesaemia;132
12.3.4;Hypermagnesaemia;132
12.4;Conclusion;132
12.5;Further reading;132
12.6;Appendix 6.1:
Calcium absorption test;132
12.6.1;Interpretation;133
12.6.1.1;Reference;133
12.7;Appendix 6.2:
Analysis of tubular handling of calcium;133
12.7.1;Interpretation;133
12.8;Appendix 6.3:
Classification of pseudohypoparathyroidism;133
12.8.1;Analysis;133
12.8.2;Interpretation;133
12.8.2.1;Reference;133
12.9;Appendix 6.4: Estimation of TMP/GFR;134
12.10;Appendix 6.5:
Magnesium retention test;134
12.10.1;Reference;134
12.11;Appendix 6.6:
Renal tubular reabsorption of magnesium;134
13;Chapter 7: The kidneys, renal function and kidney disease;135
13.1;Anatomy;135
13.1.1;Gross anatomy;135
13.1.2;Microstructure;135
13.1.2.1;The glomerulus;136
13.1.2.2;The proximal convoluted tubule;136
13.1.2.3;The loop of Henle;136
13.1.2.4;The distal convoluted tubule and collecting duct;137
13.1.2.5;Other specialized cells;138
13.1.2.6;Blood vessels;138
13.2;Renal function;138
13.2.1;Renal blood flow and its control;138
13.2.2;Glomerular function;138
13.2.3;Tubular function;139
13.2.3.1;The proximal convoluted tubule;139
13.2.3.2;The loop of Henle;139
13.2.3.2.1;Tubuloglomerular feedback;139
13.2.3.2.2;The role of urea;140
13.2.3.3;The distal convoluted tubule;140
13.2.3.4;The collecting duct;140
13.2.3.4.1;Diuresis;140
13.3;Renal disease and its presentation;140
13.3.1;Introduction;140
13.3.2;Manifestations of renal disease;140
13.3.3;Diseases affecting the kidneys;141
13.4;The assessment of renal function;141
13.4.1;Introduction;141
13.4.2;Biochemical tests of renal function;141
13.4.2.1;Urinalysis;141
13.4.2.1.1;Appearance;141
13.4.2.1.2;Specific gravity and osmolality;142
13.4.2.1.3;pH;142
13.4.2.1.4;Glucose;142
13.4.2.1.5;Protein;142
13.4.2.1.6;Urinary sediment;142
13.4.2.1.7;Other substances;142
13.4.2.2;Measurement of glomerular filtration rate;142
13.4.2.2.1;Inulin clearance;143
13.4.2.2.2;Creatinine clearance;143
13.4.2.2.3;Plasma creatinine concentration;143
13.4.2.2.4;Calculated creatinine clearance and estimated glomerular filtration rate;145
13.4.2.2.5;Cockcroft and Gault;145
13.4.2.2.6;MDRD;145
13.4.2.2.7;CKD-EPI;145
13.4.2.2.8;Definition of CKD using eGFR;145
13.4.2.2.9;Cystatin C;146
13.4.2.2.10;Plasma urea concentration;146
13.4.2.2.11;Plasma ß2 -microglobulin;146
13.4.2.2.12;Isotopic techniques for measuring glomerular filtration rate;146
13.4.2.3;Other tests of renal function;147
13.5;Acute kidney injury (acute renal failure);147
13.5.1;Introduction;147
13.5.2;Classification and causes;147
13.5.3;Prerenal acute kidney injury;148
13.5.3.1;Diagnosis;148
13.5.3.2;Management;149
13.5.4;Intrinsic acute kidney injury;149
13.5.4.1;Diagnosis;149
13.5.4.2;Acute tubular necrosis;149
13.5.4.2.1;Pathogenesis;149
13.5.4.2.2;Natural history;150
13.5.5;Obstructive (postrenal) kidney injury;150
13.5.6;Acute kidney injury in the setting of chronic kidney disease;150
13.5.7;Hepatorenal syndrome;150
13.5.8;Metabolic consequences and management of acute kidney injury;151
13.5.8.1;General management;151
13.5.8.1.1;Fluid and electrolyte balance;151
13.5.8.1.2;Acid–base balance;151
13.5.8.1.3;Nutrition;151
13.5.8.1.4;Other measures;151
13.5.8.2;Renal replacement treatment;152
13.5.8.2.1;Haemodialysis;152
13.5.8.2.2;Continuous venovenous haemofiltration (CVVH);152
13.5.8.2.3;Continuous venovenous haemodiafiltration (CVVHDF);152
13.5.8.2.4;Peritoneal dialysis;152
13.6;Chronic kidney disease;152
13.6.1;Introduction;152
13.6.2;Aetiology and pathogenesis of chronic kidney disease;152
13.6.2.1;The progression of loss of renal function;153
13.6.3;The uraemic syndrome;153
13.6.3.1;Clinical features;154
13.6.3.2;Metabolic disturbances in CKD;154
13.6.3.2.1;Retention of nitrogenous waste products;154
13.6.3.2.2;Potassium metabolism;154
13.6.3.2.3;Acid–base metabolism;154
13.6.3.2.4;Calcium, phosphate and magnesium metabolism and renal bone disease;155
13.6.3.2.5;Protein metabolism;155
13.6.3.3;Endocrine disturbances in CKD;155
13.6.4;Growth retardation;155
13.6.5;Sexual dysfunction;156
13.6.6;Thyroid abnormalities;157
13.6.7;Anaemia;158
13.6.8;Endocrine control of salt and water balance;158
13.6.9;Carbohydrate metabolism and lipid metabolism;159
13.6.10;Management;159
13.6.10.1;General management;159
13.6.10.1.1;Slowing the progression of kidney disease;159
13.6.10.1.2;Prevention of complications;160
13.6.10.2;Renal replacement treatment;160
13.6.10.2.1;Haemodialysis;160
13.6.10.2.2;Haemofiltration;161
13.6.10.2.3;Peritoneal dialysis;161
13.6.10.2.4;Renal transplantation;161
13.7;Conclusion;162
13.7.1;Note about terminology;162
13.8;Acknowledgement;162
13.9;Further reading;162
14;Chapter 8: Proteinuria;163
14.1;Introduction;163
14.2;Protein conservation by the kidneys;163
14.2.1;The glomerular capillary wall;164
14.2.2;The theory of molecular sieving;164
14.2.3;Tubular reabsorption of proteins;165
14.2.4;Tubular secretion of proteins;165
14.3;Normal urinary protein content;166
14.3.1;Determinants of urine protein excretion;166
14.3.1.1;Age, sex and diurnal variation;166
14.3.1.2;Posture;166
14.3.1.3;Exercise and diet;166
14.3.1.4;Pregnancy;167
14.4;Proteinuria in kidney disease;167
14.4.1;Proteinuria in staging and prognosis of chronic kidney disease;167
14.4.2;Glomerular proteinuria and nephrotic syndrome;167
14.4.2.1;Mechanisms underlying glomerular proteinuria;168
14.4.2.1.1;Minimal change disease;168
14.4.2.1.2;Membranous nephropathy;169
14.4.2.1.3;Membranoproliferative glomerulonephritis;169
14.4.2.1.4;Focal segmental glomerulosclerosis;169
14.4.2.1.5;IgA nephropathy and Henoch–Schönlein purpura;169
14.4.2.2;Urine protein selectivity and classification of glomerulonephritis;169
14.4.2.3;Pathophysiological consequences of glomerular proteinuria;170
14.4.2.3.1;Hypoalbuminaemia;170
14.4.2.3.2;Oedema and salt and water retention;170
14.4.2.3.3;Abnormalities of other plasma proteins;170
14.4.2.3.4;Hyperlipidaemia;171
14.4.3;Tubular proteinuria;171
14.4.3.1;Renal disorders associated with tubular proteinuria;171
14.4.3.1.1;Drug and heavy metal induced tubular damage;172
14.4.3.2;Methods of assessing tubular damage;172
14.4.3.2.1;High molecular weight protein markers of renal tubular damage;172
14.4.3.2.2;Low molecular weight protein markers of renal tubular disease;173
14.4.4;Proteinuria of prerenal origin;173
14.4.4.1;Myoglobinuria and haemoglobinuria;173
14.4.4.2;Paraproteinaemias and Bence Jones proteinuria;174
14.5;Microalbuminuria as a marker of risk;175
14.5.1;Microalbuminuria and risk of diabetic complications;175
14.5.2;Cardiovascular risk;175
14.5.3;Microalbuminuria as a risk factor in other inflammatory processes;176
14.6;Clinical investigation of proteinuria;176
14.6.1;Urine dip-sticks;176
14.6.2;Collection of urine;176
14.6.3;Urine protein measurement;176
14.6.4;Stepwise investigation of proteinuria;177
14.7;Acknowledgement;178
14.8;Further reading;178
15;Chapter 9: Renal tubular disorders and renal stone disease;179
15.1;Introduction;179
15.2;Renal tubular disorders;179
15.2.1;Introduction;179
15.2.2;Physiology;179
15.2.3;Isolated abnormalities of tubular function;180
15.2.3.1;Glycosuria;180
15.2.3.1.1;Hereditary renal glycosuria;181
15.2.3.2;Amino acidurias;181
15.2.3.2.1;Cystinuria;181
15.2.3.2.2;Hartnup disorder;182
15.2.3.2.3;Familial renal iminoglycinuria;183
15.2.3.3;Dent disease;183
15.2.3.4;Phosphate transport defects;183
15.2.3.5;Renal tubular acidosis;183
15.2.3.5.1;Proximal (type 2) renal tubular acidosis;184
15.2.3.5.2;Distal (type 1) renal tubular acidosis;184
15.2.3.5.3;Distal renal tubular acidosis with hyperkalaemia (type 4);184
15.2.3.6;Hereditary renal hypouricaemia;184
15.2.4;Generalized tubular defects (Fanconi syndrome);185
15.3;Renal calculi;185
15.3.1;Introduction;185
15.3.2;Pathogenesis of renal stones;186
15.3.2.1;Calcium stones;186
15.3.2.1.1;Hypercalciuria;186
15.3.2.1.2;Hyperoxaluria;187
15.3.2.1.3;Other factors in calcium stone formation;188
15.3.2.2;Infection-related stones;188
15.3.2.3;Uric acid stones;188
15.3.2.4;Cystine stones;188
15.3.2.5;Miscellaneous rarities;188
15.3.3;Investigation of stone formers;189
15.3.4;Treatment;189
15.4;Conclusion;190
15.5;Acknowledgement;190
15.6;Further reading;190
15.7;Appendix 9.1. Diagnosis of renal tubular acidosis;190
15.7.1;Urinary acidification test;190
15.7.2;Fractional excretion of bicarbonate;190
16;Chapter 10: Clinical biochemistry of nutrition;191
16.1;Introduction;191
16.2;Nutritional requirements;191
16.2.1;The ‘correct’ intake;191
16.2.2;Energy;192
16.2.2.1;Carbohydrate;192
16.2.2.2;Fat;193
16.2.3;Protein;194
16.2.4;Micronutrients;195
16.2.5;Vitamins;195
16.2.5.1;Fat-soluble vitamins;195
16.2.5.1.1;Vitamin A;195
16.2.5.1.2;Vitamin E;196
16.2.5.1.3;Vitamin K;197
16.2.5.2;Water-soluble vitamins;198
16.2.5.2.1;Thiamin;198
16.2.5.2.2;Riboflavin;198
16.2.5.2.3;Nicotinamide;199
16.2.5.2.4;Vitamin B6 ;199
16.2.5.2.5;Pantothenic acid;200
16.2.5.2.6;Biotin;200
16.2.5.2.7;Vitamin C;200
16.2.5.2.8;Other organic substances;200
16.2.5.3;Trace elements;201
16.2.5.3.1;Zinc;201
16.2.5.3.2;Copper;201
16.2.5.3.3;Selenium;202
16.2.5.3.4;Molybdenum;202
16.2.5.3.5;Manganese;202
16.2.5.3.6;Chromium;202
16.2.6;Fibre;203
16.3;Assessment of nutritional status;203
16.3.1;General;203
16.3.1.1;Clinical assessment;204
16.3.1.2;Dietary assessment;204
16.3.1.3;Anthropometric measurements;204
16.3.1.3.1;Height and weight;204
16.3.1.3.2;Circumference measurements;205
16.3.1.3.3;Skinfold thickness;205
16.3.1.4;Functional assessment;205
16.3.1.4.1;Hepatic secretory proteins;205
16.3.1.4.2;The immune response;206
16.3.2;Laboratory-based assessment of individual nutrients;206
16.3.2.1;Energy;206
16.3.2.2;Protein;207
16.3.2.3;Vitamins;207
16.3.2.3.1;Vitamin A;208
16.3.2.3.2;Vitamin D;208
16.3.2.3.3;Vitamin E;208
16.3.2.3.4;Vitamin K;208
16.3.2.3.5;Thiamin;208
16.3.2.3.6;Riboflavin;208
16.3.2.3.7;Nicotinamide;209
16.3.2.3.8;Vitamin
B6 ;209
16.3.2.3.9;Pantothenic acid;209
16.3.2.3.10;Biotin;209
16.3.2.3.11;Vitamin C;209
16.3.2.4;Trace elements;209
16.3.2.4.1;Zinc;209
16.3.2.4.2;Copper;209
16.3.2.4.3;Selenium;210
16.3.2.4.4;Molybdenum;210
16.3.2.4.5;Manganese;210
16.3.2.4.6;Chromium;210
16.4;Conclusion;210
16.5;Acknowledgement;210
16.6;Further reading;210
17;Chapter 11: Nutritional disorders and their management;211
17.1;Introduction;211
17.2;Malnutrition;211
17.2.1;Protein–energy malnutrition in children;212
17.2.2;Chronic energy deficiency in Western adults;212
17.3;Obesity;212
17.3.1;Aetiology of obesity;213
17.3.2;Secondary causes of obesity;214
17.3.3;Appetite;214
17.3.3.1;Central appetite control;214
17.3.3.1.1;The hypothalamus;214
17.3.3.1.2;The brain stem;214
17.3.3.1.3;Hypothalamic messengers;214
17.3.3.1.3.1;Neuropeptide Y;214
17.3.3.1.3.2;Agouti-related protein;214
17.3.3.1.3.3;Melanocortins;214
17.3.3.1.3.4;Cocaine- and amfetamine-regulated transcript;215
17.3.3.1.3.5;5-Hydroxytryptamine;215
17.3.3.2;Peripheral signals of appetite;215
17.3.3.2.1;Gastric emptying and stretching;215
17.3.3.2.2;Hormones;215
17.3.3.2.2.1;Insulin;215
17.3.3.2.2.2;Cholecystokinin;215
17.3.3.2.2.3;Peptide YY;215
17.3.3.2.2.4;Pancreatic polypeptide (PP);215
17.3.3.2.2.5;Leptin;215
17.3.3.2.2.6;Ghrelin;216
17.3.3.2.2.7;Glucagon-like peptide-1;216
17.3.4;Management of obesity;216
17.3.4.1;Non-surgical options;216
17.3.4.2;Bariatric surgery;216
17.3.4.2.1;Restrictive procedures;217
17.3.4.2.2;Combined restrictive and malabsorptive procedures;217
17.4;Eating disorders;218
17.4.1;Anorexia nervosa;218
17.4.2;Bulimia nervosa;219
17.5;Diet in the aetiology of disease;219
17.5.1;Dental caries;219
17.5.2;Cancer;219
17.6;Therapeutic diets, dietary supplements and nutraceuticals;219
17.7;Provision of nutrition support;220
17.7.1;Indications for nutrition support;220
17.7.2;Enteral feeding;221
17.7.3;Parenteral nutrition;222
17.7.3.1;Composition of parenteral nutrition fluids;222
17.7.3.2;Complications of parenteral nutritional support;222
17.7.4;Short bowel syndrome;224
17.8;Conclusion;224
17.9;Acknowledgement;224
17.10;Further reading;224
18;Chapter 12: Clinical biochemistry of the gastrointestinal tract;225
18.1;Introduction;225
18.2;Mouth and oesophagus;226
18.3;Stomach;226
18.3.1;Helicobacter pylori;226
18.3.2;Diagnosis of H. pylori infection;227
18.3.3;Gastric acid secretion;227
18.3.4;Gastrin;227
18.3.5;Intrinsic factor;228
18.4;Pancreas;228
18.4.1;Pancreatic function tests;228
18.4.1.1;Direct or invasive function tests;228
18.4.1.2;Non-invasive pancreatic function testing;228
18.4.1.2.1;Serum enzymes;228
18.4.1.2.2;Faecal tests;229
18.5;Small bowel bacterial overgrowth;229
18.5.1;The normal intestinal microflora;229
18.5.2;Definition, causes and symptoms of small bowel bacterial overgrowth;230
18.5.3;Diagnosis of small bowel bacterial overgrowth;230
18.6;Maldigestion and malabsorption;230
18.6.1;Clinical features;230
18.6.2;Carbohydrate absorption;231
18.6.2.1;Dietary carbohydrates;231
18.6.2.2;Digestion of carbohydrates;232
18.6.2.2.1;Luminal events in carbohydrate digestion;232
18.6.2.2.2;Enterocyte events in carbohydrate digestion;232
18.6.2.3;Clinical aspects of carbohydrate absorption;233
18.6.2.3.1;Lactase deficiency;233
18.6.2.4;Investigation of carbohydrate absorption;233
18.6.2.4.1;Xylose absorption test;233
18.6.2.4.2;Lactose tolerance test;233
18.6.2.4.3;Differential tests of intestinal disaccharide hydrolysis;233
18.6.3;Protein absorption;233
18.6.3.1;Digestion of proteins;234
18.6.3.2;Clinical aspects of protein absorption;234
18.6.3.3;Investigation of protein absorption;235
18.6.4;Fat absorption;235
18.6.4.1;Digestion of triacylglycerols;235
18.6.4.1.1;Luminal digestion;235
18.6.4.1.2;Absorption of triacylglycerols;235
18.6.4.2;Digestion and absorption of other fats;235
18.6.4.3;Clinical aspects of fat malabsorption;235
18.6.4.4;Investigation of fat absorption;236
18.6.4.4.1;Faecal fat excretion;236
18.6.4.4.2;13/14 C-triolein breath test;236
18.7;Intestinal permeability;236
18.8;Faecal tests of intestinal inflammation;236
18.8.1;Calprotectin;236
18.8.2;Calprotectin in disease;236
18.8.2.1;Inflammatory bowel disease;236
18.8.2.2;Colorectal cancer;237
18.8.2.3;Irritable bowel syndrome;237
18.8.3;Neuroendocrine tumours of the gastrointestinal tract and pancreas (NETs);237
18.8.3.1;Intestinal carcinoid tumours and the carcinoid syndrome;237
18.8.3.1.1;The carcinoid syndrome;237
18.8.3.2;Pancreatic endocrine tumours;237
18.8.3.2.1;Insulinomas;238
18.8.3.2.2;Glucagonoma;238
18.8.3.2.3;VIPoma;238
18.8.3.2.4;Somatostatinoma;238
18.9;The acute abdomen;238
18.9.1;Introduction;238
18.9.2;Acute pancreatitis;239
18.9.2.1;Amylase;239
18.9.2.2;Lipase;240
18.9.2.3;Choice of test for pancreatitis;240
18.9.3;Ectopic pregnancy;240
18.9.4;Acute porphyria;241
18.9.5;Further reading;241
19;Chapter 13: Assessment of hepatic function and investigation of jaundice;242
19.1;Introduction;242
19.2;Anatomy of the liver;243
19.2.1;The hepatic circulation;243
19.2.2;Macroscopic structure;243
19.2.3;Microscopic structure;243
19.2.3.1;The acinus;243
19.2.4;Ultrastructure;244
19.2.5;Bile, bile ducts and biliary drainage;245
19.3;Hepatic regeneration;245
19.4;Physiological functions;245
19.4.1;Carbohydrate metabolism;245
19.4.2;Lipid metabolism;245
19.4.3;Protein metabolism;246
19.4.3.1;Synthesis;246
19.4.3.2;Metabolism of amino acids and disposal of urea;246
19.4.4;Biotransformation and excretion;246
19.4.5;Bile secretion;247
19.5;Liver function tests;247
19.5.1;Bilirubin and bile pigment metabolism;248
19.5.1.1;The significance of hyperbilirubinaemia;249
19.5.1.2;Tests for quantitation of bilirubin and its conjugated and unconjugated fractions;250
19.5.2;Plasma enzyme activities;250
19.5.2.1;Alkaline phosphatase;250
19.5.2.1.1;Overcoming the lack of tissue specificity;251
19.5.2.2;The aminotransferases;251
19.5.2.2.1;The mitochondrial isoenzyme of AST (mAST);252
19.5.2.3;Glutamyltransferase;252
19.5.2.4;Glutathione S-transferase (GST);252
19.5.3;Plasma proteins;252
19.5.3.1;Albumin;253
19.5.3.2;Prothrombin time and coagulation factors;253
19.5.3.3;Fetoprotein;253
19.5.3.4;1 -Antitrypsin;253
19.5.3.5;Transferrin;253
19.5.3.6;Caeruloplasmin;254
19.5.3.7;Acute phase reactants;254
19.5.3.8;Immunoglobulins;254
19.5.4;Bile acids;254
19.5.5;Quantitative evaluation of liver function;254
19.5.5.1;Pharmacological basis and practical requirements of clearance tests;254
19.5.6;Other tests of liver function;255
19.5.6.1;Serum tests for hepatic fibrosis;255
19.5.6.1.1;Collagen metabolites;255
19.5.6.1.2;Hyaluronate;255
19.5.6.1.3;Tissue inhibitor of metalloproteinase 1;255
19.5.6.1.4;European liver fibrosis score (EF) ;255
19.6;Uses of liver function tests;256
19.6.1;Differential diagnosis of jaundice;256
19.6.1.1;Pre-hepatic jaundice;256
19.6.1.1.1;Urinary bilirubin and urobilinogen;256
19.6.1.2;Hepatic (hepatocellular) jaundice;256
19.6.1.3;Post-hepatic (cholestatic) jaundice;256
19.6.1.3.1;Further investigation;256
19.6.2;The inherited hyperbilirubinaemias;256
19.6.2.1;Unconjugated types;257
19.6.2.1.1;Crigler–Najjar syndrome;257
19.6.2.1.2;Gilbert syndrome;257
19.6.2.2;Conjugated types;257
19.6.2.2.1;Dubin–Johnson syndrome;257
19.6.2.2.2;Rotor syndrome;257
19.6.3;Monitoring response to therapy;257
19.6.4;Neonatal jaundice;258
19.6.4.1;The neonatal hepatitis syndrome;258
19.6.4.1.1;Tests of bile duct patency;258
19.7;Abnormal liver function tests in asymptomatic patients;258
19.7.1;Bilirubin;258
19.7.2;Alkaline phosphatase;258
19.7.3;Aminotransferases;258
19.7.4;Glutamyltransferase;259
19.8;Normal liver function tests in the presence of overt liver disease;259
19.9;Role of liver function tests in assessing prognosis;259
19.9.1;Chronic liver disease;259
19.9.2;Acute liver failure;260
19.10;Conclusion;260
19.11;Further reading;260
20;Chapter 14: Acute and chronic liver disease;261
20.1;Classification of liver disease;261
20.2;Acute hepatitis and its sequelae;261
20.2.1;Differential diagnosis;262
20.2.2;Acute viral hepatitis;263
20.2.2.1;Outcome of acute viral hepatitis;263
20.2.2.1.1;Complete resolution;263
20.2.2.1.2;Progression to chronic liver disease;263
20.2.2.1.3;Progression to acute liver failure;263
20.3;Acute liver failure;264
20.3.1;Laboratory features;264
20.3.2;Laboratory criteria for liver transplantation;264
20.4;Chronic hepatitis;264
20.4.1;Differential diagnosis of chronic hepatitis;265
20.4.1.1;Viral hepatitis types B and C;265
20.4.1.2;Alcohol;266
20.4.1.3;Wilson disease;266
20.4.1.4;1 -Antitrypsin deficiency;266
20.4.1.5;Autoimmune hepatitis (AIH);266
20.4.1.5.1;Monitoring response to therapy;267
20.5;Primary biliary cirrhosis (PBC);267
20.6;Primary sclerosing cholangitis (PSC);267
20.7;Alcoholic liver disease;268
20.7.1;Ethanol metabolism;268
20.7.2;Liver pathology in alcoholic liver disease;268
20.7.2.1;Biochemical abnormalities;268
20.7.2.1.1;Alcoholic steatosis;268
20.7.2.1.2;Alcoholic hepatitis;268
20.7.2.1.3;Alcoholism and haemochromatosis;268
20.7.2.1.4;Porphyria cutanea tarda;269
20.7.3;Use of laboratory tests in clinical practice;269
20.7.3.1;Alcohol and metabolites;269
20.7.3.2;Effects of alcohol on protein metabolism;269
20.7.3.3;Plasma enzymes;269
20.7.4;Non-alcoholic fatty liver disease (NAFD) ;269
20.8;The concept of cirrhosis;270
20.8.1;Hepatic encephalopathy;270
20.8.2;Vascular disturbances in cirrhosis;270
20.8.3;Ascites;270
20.8.3.1;Monitoring treatment of ascites;271
20.8.4;Acute kidney injury;271
20.8.4.1;The hepatorenal syndrome (HRS);272
20.8.5;Sex hormones and their binding proteins;272
20.8.5.1;Physiology and biochemistry;273
20.8.5.2;Changes in men with cirrhosis;273
20.8.5.3;Changes in liver function during pregnancy;273
20.8.6;Glucose intolerance;274
20.9;Drugs and the liver;274
20.10;Neoplastic disease of the liver and biliary tract;275
20.10.1;Hepatocellular carcinoma and a -fetoprotein;275
20.11;Parenteral nutrition;275
20.12;Bacterial infections;275
20.13;Inherited metabolic disorders involving the liver;276
20.13.1;Iron overload and hereditary haemochromatosis;276
20.13.2;Wilson disease;277
20.13.2.1;Diagnosis;277
20.13.2.2;Long-term management of hepatic Wilson disease;278
20.13.2.3;Indian childhood cirrhosis;279
20.13.3;1-Antitrypsin deficiency;279
20.13.4;The hepatic porphyrias;279
20.13.5;Cystic fibrosis;279
20.13.6;Other inherited metabolic diseases;280
20.13.6.1;Tyrosinaemia;280
20.13.6.2;Galactosaemia;280
20.13.6.3;Fructose intolerance;281
20.13.6.4;The sphingolipidoses and Niemann–Pick disease type C;281
20.13.6.5;Glycogen storage diseases;281
20.14;Liver transplantation;281
20.14.1;Preoperative assessment;282
20.14.2;The immediate postoperative period;282
20.14.3;Intermediate follow-up;282
20.14.4;Long-term monitoring;282
20.15;Conclusion;283
20.16;Further reading;283
21;Chapter 15: Glucose metabolism and the pathophysiology of diabetes mellitus;284
21.1;Physiology and pathophysiology of glucose homoeostasis;284
21.1.1;Introduction: the maintenance of normoglycaemia;284
21.1.2;Normal glucose metabolism;285
21.1.2.1;Glucose transporters;286
21.1.2.2;The fate of intracellular glucose and its role in diabetes;288
21.1.3;Insulin;289
21.1.3.1;Biosynthesis;289
21.1.3.2;Secretion and pharmacokinetics;290
21.1.3.3;Abnormalities of the synthesis and secretion of insulin;290
21.1.3.4;Actions of insulin;290
21.1.3.5;The insulin receptor;292
21.1.3.6;Second messengers mediating the effects of insulin;292
21.1.4;Insulin-like growth factors and their receptors;292
21.2;Classification and diagnosis of diabetes mellitus;293
21.2.1;Introduction;293
21.2.2;Definitions;293
21.2.3;Type 1 diabetes mellitus;294
21.2.3.1;Introduction;294
21.2.3.2;Aetiology: genetic susceptibility and possible environmental cofactors;295
21.2.4;Type 2 diabetes mellitus;297
21.2.4.1;Introduction: the heterogeneity of type 2 diabetes;297
21.2.4.2;Genetic factors in type 2 diabetes mellitus;298
21.2.4.3;Glucoregulatory defects in type 2 diabetes mellitus;298
21.2.4.3.1;Pancreatic ß -Cell deficiency/dysfunction in type 2 diabetes mellitus;298
21.2.4.3.2;Amylin;299
21.2.4.3.3;Insulin resistance in type 2 diabetes mellitus;299
21.2.4.3.4;Abnormalities of non-insulin-mediated glucose disposal in type 2 diabetes mellitus;300
21.2.4.4;Associations of type 2 diabetes mellitus;300
21.2.4.4.1;The metabolic syndrome and obesity;300
21.2.4.4.2;Hypertension;300
21.2.4.4.3;Dyslipidaemia;301
21.2.4.5;Lipotoxicity and glucotoxicity;301
21.2.4.5.1;Lipotoxicity;301
21.2.4.5.2;Glucotoxicity;302
21.2.4.6;Prevention studies in type 2 diabetes;302
21.2.4.7;The role of bariatric surgery in managing type 2 diabetes;302
21.2.4.7.1;Tropical diabetes;304
21.2.4.7.2;Alcohol-related and pancreatic causes of diabetes;304
21.2.4.7.3;Haemochromatosis;304
21.2.4.7.4;Endocrine disorders;304
21.2.4.7.5;Iatrogenic diabetes;305
21.2.4.7.6;Rare conditions associated with glucose intolerance;305
21.2.4.7.7;Severe insulin resistance;305
21.2.4.7.8;Anti-insulin antibodies;306
21.2.4.7.9;Cirrhosis;306
21.2.5;Gestational diabetes mellitus;302
21.2.6;Maturity onset diabetes of the young (MODY);303
21.2.7;Secondary diabetes;304
21.3;Endocrine associations with diabetes;306
21.4;Diabetes, nutrition and growth;307
21.5;Mechanisms of diabetic tissue damage;307
21.5.1;Introduction;307
21.5.2;Pathogenesis;307
21.5.3;Other aspects of diabetic tissue damage;308
21.6;Conditions associated with inadequately controlled diabetes mellitus;309
21.7;Biochemical measurements in diabetes mellitus;310
21.7.1;Glucose measurements;310
21.7.2;Testing for ketones;310
21.7.3;Oral glucose tolerance test;311
21.7.4;Tests of recent glycaemic control;311
21.7.5;Screening for diabetes;312
21.7.6;Tests for insulin resistance;312
21.7.7;Research investigations;314
21.7.7.1;Hyperinsulinaemic clamps;314
21.7.7.2;Intravenous glucose tolerance testing;314
21.7.7.3;Measurement of ß-Cell function;314
21.7.7.4;Homoeostasis model assessment;314
21.8;Conclusion;314
21.9;Acknowledgement;314
21.10;Further reading;314
22;Chapter 16: The clinical management of diabetes mellitus;316
22.1;Introduction;316
22.2;General Aspects of Management;316
22.2.1;Nutrition;317
22.2.2;Exercise;317
22.2.3;Smoking cessation;318
22.2.4;Education about diabetes;318
22.2.5;Pharmacological management of cardiovascular risk;318
22.2.5.1;Aspirin;318
22.2.5.2;Lipid-lowering agents;319
22.2.5.3;Hypertension;319
22.2.5.4;Angiotensin-converting-enzyme inhibitors and angiotensin-II receptor antagonists;320
22.3;Glucose-owering Therapy in Diabetes ;320
22.3.1;Background;320
22.3.2;Insulin use in type 1 diabetes;321
22.3.2.1;Regular insulin;321
22.3.2.2;Insulin analogues;321
22.3.2.3;Intermediate-acting insulin;321
22.3.2.4;Premixed insulin analogues;321
22.3.2.5;Long-acting insulin analogues;322
22.3.2.6;Insulin regimens;322
22.3.2.7;Continuous subcutaneous insulin infusion;322
22.3.2.8;Insulin administration;322
22.3.2.9;Glycaemic management in type 2 diabetes;324
22.3.3;Metformin;324
22.3.3.1;Mechanism of action;324
22.3.3.2;Lactic acidosis;324
22.3.3.3;Other unwanted effects of metformin;325
22.3.4;Sulfonylureas (and related insulin secretagogues);325
22.3.4.1;Mechanism of action;325
22.3.4.2;Adverse effects of sulfonylureas;325
22.3.4.3;Other unwanted effects of sulfonylureas;326
22.3.4.4;Indications and clinical usage;326
22.3.5;Meglitinides;326
22.3.5.1;Adverse effects of meglitinides;326
22.3.6;Peroxisome proliferator activator . analogues;326
22.3.6.1;Mechanisms of action;326
22.3.6.2;Adverse effects;327
22.3.7;Glucagon-like peptide 1 analogues;327
22.3.7.1;Mechanisms of action;327
22.3.7.2;Adverse effects;328
22.3.8;Dipeptidyl peptidase IV inhibitors;328
22.3.8.1;Adverse effects of DPP-4 inhibitors;328
22.3.9;Alpha-glucosidase inhibitors;328
22.3.10;Sodium-glucose co-transporter 2 (SGT2) inhibitors ;328
22.3.11;Insulin use in type 2 diabetes;328
22.3.12;Bariatric surgery;328
22.3.13;Pancreatic transplantation;329
22.3.14;Islet cell transplantation;329
22.3.15;Immunotherapy for type 1 diabetes;329
22.4;Obstacles to Achieving Glycaemic Control;329
22.4.1;Intensive control;330
22.4.2;Hypoglycaemia;330
22.4.2.1;Hypoglycaemia-associated autonomic failure;331
22.4.2.2;The Somogyi effect and the dawn phenomenon;331
22.4.2.3;Exercise;332
22.4.2.4;Ethanol;332
22.4.3;Intercurrent illness, ‘sick day rules’ and stress;332
22.5;Chronic Complications of Diabetes;333
22.5.1;Nephropathy;333
22.5.1.1;Microalbuminuria;333
22.5.1.2;Management;334
22.5.1.3;End-stage disease;334
22.5.2;Neuropathy;334
22.5.2.1;Chronic sensorimotor neuropathy;334
22.5.2.2;Autonomic neuropathy;335
22.5.2.3;Mononeuropathies;335
22.5.3;The feet in diabetes;335
22.5.3.1;Foot ulcers;335
22.5.3.2;Charcot foot;335
22.5.4;Eye disease;336
22.5.5;Other complications;337
22.5.5.1;Brittle diabetes;337
22.5.5.2;Type 4 renal tubular acidosis;337
22.6;Emergencies in diabetes;337
22.6.1;Diabetic ketoacidosis;337
22.6.1.1;Biochemical features;338
22.6.1.2;Management;338
22.6.1.2.1;General measures;338
22.6.1.2.2;Fluids;339
22.6.1.2.3;Insulin;339
22.6.1.2.4;Potassium, magnesium and phosphate;339
22.6.1.2.5;Bicarbonate;339
22.6.1.2.6;Cerebral oedema;340
22.6.1.2.7;Resolution;340
22.6.2;Hyperosmolar hyperglycaemic state;340
22.6.2.1;Presentation and clinical features;340
22.6.2.2;Management;340
22.6.3;Other metabolic acidoses;341
22.6.4;Alcoholic ketoacidosis;341
22.7;Management of Diabetes in the Hospital Setting;341
22.7.1;Pregnancy;342
22.8;Conclusion;343
22.9;Acknowledgement;343
22.10;Further reading;343
23;Chapter 17: Hypoglycaemia;344
23.1;Glucose homoeostasis in the fed and the postabsorptive states;344
23.2;Hypoglycaemia;345
23.2.1;The neuroendocrine response to hypoglycaemia;345
23.2.2;Symptoms of hypoglycaemia;346
23.2.3;Acute neuroglycopenia (neurogenic);346
23.2.3.1;Subacute neuroglycopenia;346
23.2.3.2;Chronic neuroglycopenia;346
23.3;Classification of hypoglycaemic disorders;346
23.4;Practical approach to the investigation of hypoglycaemia;347
23.4.1;Evaluation of hypoglycaemia in persons without diabetes mellitus;347
23.4.2;Investigation of hypoglycaemia;347
23.4.2.1;Demonstration of hypoglycaemia;347
23.4.2.1.1;Measurement of blood glucose during spontaneous symptoms;347
23.4.2.1.2;Provocation tests;347
23.4.2.1.2.1;Prolonged fast test;347
23.4.2.1.2.2;Glucagon stimulation test;349
23.4.2.1.2.3;Mixed meal test;349
23.4.2.2;Identification of the cause of hypoglycaemia;349
23.4.2.2.1;Plasma insulin, C-peptide and proinsulin;349
23.4.2.2.2;Plasma ß-hydroxybutyrate ( ß-OHB);350
23.4.2.2.3;Insulin antibodies;350
23.4.2.2.4;Screening for oral hypoglycaemic agents;350
23.4.3;Evaluation of hypoglycaemia in patients with diabetes mellitus;350
23.4.3.1;Definition;350
23.4.3.2;Pathophysiology and risk factors;351
23.4.3.3;Incidence;351
23.4.3.4;Management;352
23.5;Emergency treatment of hypoglycaemia;352
23.6;Causes of hypoglycaemia;352
23.6.1;Surreptitious administration of hypoglycaemic agents (factitious or felonious hypoglycaemia);352
23.6.2;Islet cell tumours (insulinoma);352
23.6.2.1;Clinical features;353
23.6.2.2;Diagnosis;353
23.6.2.3;ocalization ;353
23.6.2.4;Treatment;353
23.6.3;Non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS);354
23.6.4;Non-islet cell tumour hypoglycaemia (NICTH);354
23.6.5;Autoimmune hypoglycaemia;355
23.6.6;Hypoglycaemia associated with renal impairment;355
23.6.7;Hypoglycaemia associated with liver disease;356
23.6.8;Hypoglycaemia due to endocrine deficiencies;356
23.6.9;Drug-induced hypoglycaemia;357
23.6.10;Alcohol-induced hypoglycaemia;357
23.6.11;Hypoglycaemia due to deficient energy intake;358
23.6.12;Septicaemia;358
23.6.13;Exercise-related hypoglycaemia;358
23.6.14;Postprandial (reactive) hypoglycaemia;358
23.6.15;The postprandial syndrome;358
23.6.16;Inherited metabolic disease;359
23.7;Conclusion;359
23.8;Further reading;359
24;Chapter 18: Hypothalamic, pituitary and adrenal disorders;360
24.1;Introduction;360
24.2;Clinical anatomy of the pituitary and hypothalamus;361
24.3;Physiology of hypothalamo– pituitary–end organ axes;361
24.4;Clinical anatomy and physiology of the adrenals;363
24.5;Assessment of normal pituitary function;363
24.5.1;Basal hormonal investigations;363
24.5.2;Dynamic tests of ACTH–adrenal function;365
24.5.2.1;Insulin stress test;365
24.5.2.2;Short tetracosactide (synacthen, tetracosactrin, ACTH) test;365
24.5.2.3;Other tests;365
24.5.3;Cortisol normal ranges, borderline responses, assay precision and dynamic test reproducibility;366
24.5.4;Assessment of growth hormone reserve;366
24.5.4.1;Insulin stress test;366
24.5.4.2;Other pharmacological tests;367
24.5.4.3;Exercise testing;367
24.5.4.4;Assessment of physiological growth hormone secretion;367
24.5.4.5;Re-evaluation of GH status in young adults;367
24.5.5;Releasing hormone tests;367
24.5.6;Other tests of gonadotrophin secretion;367
24.5.6.1;Clomifene test;367
24.5.6.2;Assessment of luteinizing hormone pulsatility;368
24.5.7;Dynamic tests of posterior pituitary function;368
24.5.7.1;Water deprivation test;368
24.5.7.2;Hypertonic saline infusion;368
24.5.8;Summary;368
24.5.8.1;Outline protocol for the investigation of a patient with pituitary disease;368
24.5.8.1.1;1. Does this patient have undiagnosed hypoadrenalism?;369
24.5.8.1.2;2. Is the proven hypoadrenalism primary or secondary?;369
24.5.8.1.3;3. Has this patient with known pituitary disease developed ACTH deficiency?;369
24.5.8.1.4;4. Does this patient on pharmacological steroid treatment still have adrenal suppression or could they now stop treatment?;369
24.5.9;A clinical approach to assessment of the whole ACTH–adrenal axis;369
24.5.10;Monitoring of pituitary function in disease states;370
24.5.10.1;Reassessment after pituitary surgery;370
24.5.10.2;Monitoring after pituitary irradiation;370
24.5.10.3;Monitoring in other pituitary disease states;371
24.6;Other diagnostic techniques in pituitary disease;371
24.6.1;Clinical assessment;371
24.6.2;Pituitary imaging techniques;371
24.7;Pituitary hypersecretion states;371
24.7.1;Pituitary adenomas;371
24.7.2;Prolactinoma;371
24.7.2.1;Differential diagnosis of hyperprolactinaemia;371
24.7.2.2;Role of dynamic tests of PR secretion ;372
24.7.2.3;Assessment of remaining pituitary function;372
24.7.2.4;Outline of presentation and management of prolactinoma;372
24.7.2.5;Monitoring the response to dopamine agonist therapy;373
24.7.2.6;Macroprolactinaemia;373
24.7.2.7;Hook effect;373
24.7.3;Acromegaly;373
24.7.3.1;Diagnosis of acromegaly;373
24.7.3.1.1;Basal GH and IGF-1 estimation;373
24.7.3.1.2;Glucose tolerance test;373
24.7.3.1.3;Other diagnostic tests;373
24.7.3.2;Outline of presentation and management of acromegaly;373
24.7.3.3;Monitoring the response to therapy;374
24.7.3.3.1;Low-dose dexamethasone suppression test;374
24.7.3.3.2;Overnight dexamethasone suppression test;375
24.7.3.3.3;Midnight salivary cortisol;375
24.7.3.3.4;Other tests;375
24.7.4;Diagnosis and differential diagnosis of Cushing syndrome;374
24.7.4.1;Clinical context of ACTH-dependent Cushing syndrome;375
24.7.4.2;Plasma cortisol and ACTH concentrations;376
24.7.4.3;High-dose dexamethasone suppression test;376
24.7.4.4;Corticotrophin releasing hormone test;376
24.7.4.5;Other tests;376
24.7.4.6;Petrosal sinus sampling for ACTH;376
24.7.5;Imaging;377
24.7.6;Outline of management;377
24.7.6.1;Reassessment after pituitary surgery;377
24.7.7;Thyroid stimulating hormone-secreting adenomas;377
24.7.8;Gonadotrophin-secreting adenomas;378
24.8;Hypothalamic and pituitary deficiency states;378
24.8.1;Diseases that may lead to generalized hypopituitarism;378
24.8.1.1;Non-functioning pituitary adenomas;378
24.8.1.2;Other pituitary and parasellar tumours;378
24.8.1.3;Inflammatory diseases and disorders of unknown aetiology;378
24.8.1.4;Other conditions;378
24.8.2;Growth hormone deficiency;378
24.8.3;Gonadotrophin deficiency;379
24.8.3.1;Interpretation of borderline testosterone concentrations;379
24.8.3.2;Delayed puberty;379
24.8.3.3;Hypothalamic amenorrhoea;380
24.8.4;Other isolated anterior pituitary deficiencies;380
24.8.5;Diabetes insipidus;380
24.9;Adrenal disease;380
24.9.1;Clinical features of Addison disease;380
24.9.2;Congenital adrenal hyperplasia;381
24.9.3;Assessment of adrenal incidentaloma;381
24.10;Monitoring pituitary and adrenal replacement therapy;381
24.11;Conclusion;382
24.12;Appendix 18.1 Test protocols;382
24.12.1;Assessment of basal pituitary function;382
24.12.2;Insulin stress test;382
24.12.3;Short tetracosactide (synacthen) test;383
24.12.4;Water deprivation test;383
24.12.5;Glucose tolerance test for the diagnosis of acromegaly;383
24.12.6;CRH test;383
25;Chapter 19: Thyroid dysfunction;384
25.1;Introduction;384
25.2;Normal thyroid physiology;385
25.2.1;The thyroid gland;385
25.2.2;Biological actions of thyroid hormones;385
25.2.3;Synthesis, storage and release of thyroid hormones;386
25.2.4;Iodine and thyroid hormone synthesis;387
25.2.5;Transport of thyroid hormones in blood;387
25.2.6;Free hormone hypothesis;387
25.2.7;Entry of thyroid hormone into tissues;388
25.2.8;Thyroid hormone deiodination and regulation of extrathyroidal T3 production;388
25.2.9;Catabolism of thyroid hormones;388
25.2.10;Nuclear action of thyroid hormones;388
25.2.11;Control of thyroid hormone synthesis and secretion;389
25.2.11.1;Classic feedback regulation;389
25.2.11.2;Other mechanisms;390
25.2.12;Extrathyroidal factors that may affect thyroid function;390
25.2.12.1;Age;390
25.2.12.1.1;Fetus;390
25.2.12.1.2;Neonate;390
25.2.12.1.3;Infancy and childhood;390
25.2.12.1.4;Elderly;390
25.2.12.2;Pregnancy;390
25.2.12.3;Non-thyroidal illness;391
25.2.12.4;Drugs;392
25.3;The evaluation of thyroid function;393
25.3.1;Clinical evaluation of thyroid status;393
25.3.2;In vitro tests of thyroid activity and pituitary–thyroid status;394
25.3.3;Measurement of thyroid stimulating hormone;394
25.3.4;Free T4 and free T3 measurements;394
25.3.4.1;Theoretical considerations;394
25.3.5;Methods for measuring free thyroid hormones;394
25.3.5.1;Equilibrium dialysis and ultrafiltration methods;394
25.3.6;Validity of commercial methods for free hormone analysis;394
25.3.7;Nomenclature of free thyroid hormone assays;395
25.3.8;Total T4 and total T3;395
25.3.9;Selective use of thyroid function tests;395
25.3.10;Interpreting results of thyroid function tests;396
25.3.10.1;Situations in which TSH usually provides the correct estimate of thyroid status;396
25.3.10.1.1;Overt primary hyperthyroidism;396
25.3.10.1.2;Overt primary hypothyroidism;396
25.3.10.1.3;Subclinical thyroid disease;396
25.3.11;Common situations in which TSH results may be misleading;396
25.3.11.1;Assay interference from endogenous heterophilic antibodies;396
25.3.11.2;Pregnancy;396
25.3.11.3;Secondary thyroid disorders;396
25.3.12;Reference ranges and significant changes;396
25.3.13;Miscellaneous tests;397
25.3.13.1;Thyrotrophin releasing hormone test;397
25.3.13.2;Thyroglobulin;397
25.3.13.3;Subunit;397
25.3.14;Autoantibodies to thyroidal antigens;397
25.3.14.1;Antibodies to thyroid peroxidase (TPOAb);397
25.3.14.2;Antibodies to thyroglobulin (TgAb);397
25.3.14.3;Antibodies to the thyroid stimulating hormone receptor;398
25.3.14.4;Antibodies and ophthalmopathy of Graves disease;398
25.3.15;Imaging the thyroid;398
25.3.15.1;Thyroid scintiscanning;398
25.3.15.2;Perchlorate discharge test;399
25.4;Hyperthyroidism;399
25.4.1;Clinical features;399
25.4.1.1;Cardiovascular system;399
25.4.1.2;Thyroid crisis;399
25.4.1.3;Gastrointestinal system;399
25.4.1.4;Central and peripheral nervous system;400
25.4.1.5;Locomotor system;400
25.4.1.6;Respiratory system;400
25.4.1.7;Skin and hair;400
25.4.1.8;The skeleton;400
25.4.1.9;The kidneys: mineral and water balance;400
25.4.1.10;Other endocrine systems;400
25.4.1.11;Hyperthyroidism in the elderly;400
25.4.2;Causes of hyperthyroidism;400
25.4.2.1;Graves disease;400
25.4.2.1.1;Thyroid involvement;401
25.4.2.1.2;Eyes;401
25.4.2.1.3;Skin;401
25.4.2.1.4;Diagnosis;401
25.4.2.1.5;Natural history;402
25.4.2.1.6;Treatment;402
25.4.2.1.7;Treatment of Graves ophthalmopathy;403
25.4.2.2;Toxic multinodular goitre;403
25.4.2.2.1;Clinical features;403
25.4.2.2.2;Diagnosis;403
25.4.2.2.3;Treatment;403
25.4.2.3;Toxic adenoma;403
25.4.2.3.1;Diagnosis;403
25.4.2.3.2;Treatment;403
25.4.2.4;Thyroid stimulating hormone-secreting pituitary tumour;403
25.4.2.4.1;Diagnosis;403
25.4.2.4.2;Treatment;404
25.4.2.5;Other causes of hyperthyroidism;404
25.4.2.5.1;Iodine;404
25.4.2.5.2;Amiodarone;404
25.4.2.5.3;Thyrotoxicosis factitia;404
25.4.2.5.4;Ectopic thyroid tissue;404
25.4.2.5.5;Other thyroid stimulators;405
25.4.2.5.6;Subclinical hyperthyroidism;405
25.4.3;Hyperthyroidism or non-thyroidal illness?;405
25.5;Hypothyroidism;405
25.5.1;Clinical features;405
25.5.1.1;Cardiovascular system;405
25.5.1.2;Gastrointestinal system;405
25.5.1.3;Central and peripheral nervous system;405
25.5.1.4;Locomotor system;406
25.5.1.5;Respiratory system;406
25.5.1.6;Skin and hair;406
25.5.1.7;The skeleton;406
25.5.1.8;The kidneys: mineral and water balance;406
25.5.1.9;Reproductive system;406
25.5.1.10;Other systems;406
25.5.2;Causes of hypothyroidism;407
25.5.2.1;Primary myxoedema;407
25.5.2.2;Post-surgery or post-radioiodine;407
25.5.2.3;Congenital hypothyroidism;407
25.5.2.4;Lithium treatment;408
25.5.2.5;Cytokine therapy;408
25.5.2.6;Iodine;408
25.5.2.7;Secondary hypothyroidism;408
25.5.3;Treatment of hypothyroidism;408
25.5.3.1;Myxoedema coma;408
25.5.3.2;Thyroid hormone replacement therapy;408
25.5.3.3;Subclinical hypothyroidism;409
25.6;Thyroiditis;409
25.6.1;Thyroiditis producing hyperthyroidism;409
25.6.1.1;Diagnosis and treatment;409
25.6.2;Hypothyroidism resulting from Hashimoto thyroiditis;410
25.6.2.1;Diagnosis;410
25.6.3;Other forms of thyroiditis;410
25.6.4;Hypothyroidism and the postpartum period;410
25.7;Neoplasia;410
25.7.1;Diagnosis;410
25.7.2;Treatment;411
25.7.3;Tumour markers;411
25.8;Syndromes of resistance to thyroid hormones;411
25.9;Screening;412
25.10;Acknowledgement;412
25.11;Further reading;412
26;Chapter 20: Metabolic response to stress;414
26.1;Introduction;414
26.2;The response to stress;414
26.2.1;Initiation of the stress response;414
26.2.2;Hypothalamo–pituitary–adrenal axis;415
26.2.2.1;Cortisol;416
26.2.2.2;Thyroid hormones;416
26.2.2.3;Sex hormones;416
26.2.2.4;Growth hormone;416
26.2.3;Adrenal medulla;416
26.3;Stress and the kidneys;417
26.4;Cytokines;417
26.5;Stress and inflammation;417
26.5.1;Catecholamines;418
26.5.2;Acute phase proteins;419
26.5.3;Coagulation factors;419
26.6;Shock;420
26.7;Care of the shocked patient;420
26.7.1;Definitions;420
26.7.2;Management;421
26.7.2.1;Immediate care;421
26.7.2.2;Organ support;421
26.7.2.3;Immunomodulation;422
26.8;Conclusion;422
26.9;Further reading;422
27;Chapter 21: Disorders of puberty and sex development;423
27.1;Introduction;423
27.2;Normal sex development;423
27.3;Normal pubertal development;425
27.3.1;Endocrinology of normal puberty;425
27.3.2;Physical signs of normal puberty;425
27.4;Disorders of sex development;427
27.4.1;Terminology of disorders of sex development;427
27.4.2;General principles of management;428
27.4.3;General examination of a newborn with suspected DSD;428
27.4.4;Evaluation of the external genitalia;428
27.4.5;Evaluation of the internal anatomy;429
27.4.6;Investigating the newborn with DSD;429
27.4.7;Investigating the adolescent with DSD;430
27.4.8;Steroid measurement and its interpretation;431
27.4.9;Anti-Müllerian hormone;431
27.4.10;Insulin-like factor 3;431
27.4.11;Inhibins;432
27.4.12;The human chorionic gonadotrophin (hCG) stimulation test;433
27.4.13;The role of the clinical geneticist;433
27.4.14;Classification of disorders of sex development;434
27.4.14.1;XX DSD;434
27.4.14.2;Disorders of androgen excess;434
27.4.14.3;XY DSD with low testosterone and low precursor concentrations;436
27.4.14.4;XY DSD with low testosterone and high steroid precursor concentrations;436
27.4.14.5;XY DSD with normal testosterone, normal precursor and low DHT concentrations;438
27.4.14.6;XY DSD with normal testosterone, normal precursor and normal DHT concentrations;438
27.5;Disorders of puberty;439
27.5.1;Precocious puberty;439
27.5.2;Gonadotrophin dependent puberty (central causes);439
27.5.2.1;Variants of early puberty;440
27.5.3;Delayed puberty;440
27.5.3.1;Delayed growth and puberty;441
27.5.4;Hypogonadotrophic hypogonadism;441
27.5.5;Primary hypogonadism;442
27.6;Further reading;442
27.7;Disorders of sex development;442
27.8;Puberty;442
28;Chapter 22: Reproductive function in the female;444
28.1;Introduction;444
28.2;Physiology;444
28.2.1;The ovaries;444
28.2.2;Plasma concentrations of reproductive hormones;446
28.2.3;Uterine changes;447
28.2.4;Conception;447
28.3;Hormones regulating reproductive function;447
28.3.1;Follicle stimulating hormone;447
28.3.2;Luteinizing hormone;447
28.3.3;Human chorionic gonadotrophin;447
28.3.4;Inhibin and activin;447
28.3.5;Prolactin;448
28.3.6;Anti-müllerian hormone;448
28.4;Reproductive steroid hormones;448
28.4.1;Structure;448
28.4.2;Biosynthetic enzymes;448
28.4.3;Steroid secretion through the menstrual cycle;449
28.4.4;Steroid hormone transport and metabolism;449
28.4.5;Actions of gonadal steroid hormones;450
28.4.5.1;Oestrogens;450
28.4.5.2;Progestogens;450
28.4.5.3;Androgens;450
28.5;Oligo- and amenorrhoea;450
28.6;Infertility;451
28.7;Hirsutism and virilism;452
28.8;Pregnancy;453
28.8.1;Introduction;453
28.8.2;Biochemical diagnosis of pregnancy;453
28.8.2.1;Human chorionic gonadotrophin;453
28.8.3;Diagnosis of ectopic pregnancy;453
28.8.4;Biochemical monitoring of pregnancy;454
28.8.4.1;Spontaneous abortion;454
28.8.4.1.1;Biochemical screening;454
28.8.4.1.2;Ultrasound;454
28.8.4.1.3;Current screening practice;454
28.8.5;Screening for fetal malformation;454
28.8.6;Fetal tissue sampling techniques;455
28.8.7;Chorionic villus sampling;455
28.8.7.1;Amniocentesis;455
28.8.7.2;Cordocentesis;456
28.8.8;Monitoring of maternal and fetal well-being;456
28.8.9;Intrapartum fetal monitoring;456
28.8.10;Biochemical changes during pregnancy;456
28.8.10.1;Plasma proteins;457
28.8.10.2;Plasma lipids and lipoproteins;457
28.8.10.3;Glucose tolerance;457
28.8.10.4;Other changes;457
28.8.11;Labour;457
28.9;Oral contraception and hormone replacement therapy;458
28.9.1;Introduction;458
28.9.2;Metabolic effects of oestrogens;459
28.9.3;Metabolic effects of progestogens;459
28.9.4;Metabolic effects of contraceptives;459
28.9.4.1;Effects of hormonal contraceptives on lipid metabolism and risk of vascular disease;459
28.9.4.2;Effects of oral contraceptives on glucose homoeostasis and diabetes;459
28.9.4.3;Other metabolic effects of oral contraceptives;460
28.9.4.4;Metabolic effects of injectable contraceptives;460
28.9.5;Hormone replacement therapy;460
28.9.5.1;Metabolic effects of the menopause;460
28.9.5.2;Metabolic effects of HRT;460
28.9.5.3;Adverse consequences of hormone replacement therapy;460
28.9.5.4;Hormone replacement therapy and heart disease;460
28.9.5.5;Hormone replacement therapy and osteoporosis;461
28.10;Acknowledgement;461
28.11;Further reading;461
28.12;Appendix 22.1 Acth stimulation test for the diagnosis of congenital adrenal hyperplasia;461
28.13;References;461
29;Chapter 23: Reproductive function in the male;462
29.1;Introduction;462
29.2;The testes;462
29.2.1;Production and actions of testosterone;462
29.2.2;Hypothalamo–pituitary control of testicular function;463
29.2.3;Testicular malignancy;464
29.2.4;Endocrine disrupting chemicals;464
29.3;Evaluation of testicular function;465
29.3.1;Semen analysis;465
29.3.2;Endocrine evaluation: hypothalamo–pituitary–gonadal axis;465
29.4;Male hypogonadism;466
29.4.1;Clinical features;466
29.4.2;Primary hypogonadism;466
29.4.2.1;Genetic causes;466
29.4.2.2;Cryptorchidism;466
29.4.3;Secondary hypogonadism;466
29.4.3.1;Congenital causes;466
29.4.3.2;Acquired causes;467
29.4.4;Defective hormone synthesis and hormone receptor defects;467
29.4.4.1;5a-Reductase deficiency;467
29.4.4.2;Androgen insensitivity syndromes;467
29.4.5;Treatment of hypogonadism;467
29.5;Gynaecomastia;468
29.5.1;Causes of gynaecomastia;468
29.5.2;Investigation;469
29.6;Impotence;469
29.6.1;Investigation;469
29.6.2;Treatment of erectile impotence;470
29.7;Appendix 23.1: Protocols for endocrine investigations;471
29.7.1;(i)
Gonadotrophin releasing hormone stimulation test;471
29.8;Reference;471
29.8.1;(ii)
Clomifene test;471
29.9;Reference;471
29.9.1;(iii)
Human chorionic gonadotrophin stimulation test;471
29.10;Reference;471
30;Chapter 24: Inherited metabolic disease;472
30.1;Introduction;472
30.2;Clinical presentation and pathophysiology;472
30.2.1;Neonatal presentation;473
30.2.1.1;Defects in synthesis and breakdown;473
30.2.1.2;Intoxications;473
30.2.1.3;Energy deficiency disorders;474
30.2.1.4;Seizure disorders;474
30.2.2;Presentation at weaning;475
30.2.3;Presentation in later infancy;475
30.2.4;Presentation at puberty;475
30.2.5;Presentation during adulthood;476
30.2.6;Presentation during pregnancy;476
30.2.7;Presentation postpartum;477
30.3;Newborn screening;477
30.4;Inheritance;477
30.4.1;Autosomal recessive inheritance;477
30.4.2;Autosomal dominant inheritance;478
30.4.3;X-linked inheritance;478
30.4.4;Mitochondrial inheritance;478
30.5;Diagnostic strategies;479
30.5.1;Essential laboratory investigations;480
30.5.1.1;Blood gas analysis;480
30.5.1.2;Blood glucose;480
30.5.1.3;Plasma ammonia;481
30.5.1.4;Liver function tests;481
30.5.1.5;Measurement of ketones;481
30.5.1.6;Urinary reducing substances;481
30.5.2;Second-line investigations;483
30.5.2.1;Plasma and urinary amino acids;483
30.5.2.2;Urinary organic acids;483
30.5.2.3;Urinary orotic acid;484
30.5.2.4;Blood acylcarnitines;484
30.5.2.5;Blood lactate and pyruvate;484
30.5.2.6;Urinary glycosaminoglycans;485
30.5.2.7;Plasma very long chain fatty acids;485
30.5.3;Functional and loading tests;485
30.5.3.1;Diagnostic fast;485
30.5.3.2;Allopurinol loading test;486
30.5.4;Confirmatory investigations;486
30.5.4.1;Enzyme analysis: general principles;486
30.5.4.1.1;Red cell galactose 1-phosphate uridyltransferase;486
30.5.4.1.2;Lysosomal enzyme screening;486
30.5.4.2;Complementation studies;486
30.5.4.3;Genetic mutation analysis;487
30.6;Prenatal diagnosis;487
30.7;Management;487
30.7.1;Strategies to replace a missing product;487
30.7.1.1;Supply of precursor;487
30.7.1.2;Replacement of product;488
30.7.1.3;Synthetic analogues;489
30.7.1.4;Alternate product;489
30.7.2;Inhibition of product breakdown;489
30.7.3;Enzyme replacement therapy;489
30.7.3.1;Cofactor supplementation;490
30.7.4;Organ transplantation;490
30.7.5;Gene therapy;492
30.7.6;Other molecular therapies;492
30.7.7;Strategies to reduce the formation of toxic metabolites;492
30.7.7.1;Reduction of metabolic load;492
30.7.7.2;Blockage of formation of toxic metabolites;492
30.7.8;Blockage of site of action of toxic metabolites;493
30.7.9;Strategies to remove toxic substances;493
30.7.9.1;Drugs;493
30.7.9.2;Dialysis and haemofiltration;494
30.7.10;Additional treatments;494
30.7.11;Substrate depletion;494
30.7.12;Substrate deprivation;494
30.8;Conclusion;494
31;Chapter 25: Paediatric clinical biochemistry;495
31.1;Introduction;495
31.2;Postnatal investigation of the small for gestational age newborn;495
31.2.1;Intrauterine infections;495
31.2.2;Maternal drug abuse;496
31.3;Respiratory disorders;496
31.3.1;Respiratory distress;496
31.3.1.1;Management of respiratory distress;497
31.3.2;Apnoea of prematurity;497
31.4;Renal function;497
31.4.1;Hyponatraemia;498
31.4.2;Hypernatraemia;498
31.4.3;Hydrogen ions;499
31.4.4;Interpretation of renal function tests;499
31.5;Carbohydrate metabolism;499
31.5.1;Neonatal hypoglycaemia;500
31.6;Calcium and phosphorus metabolism;501
31.6.1;Disorders of calcium and phosphorus metabolism;501
31.6.1.1;Hypercalcaemia;501
31.6.1.2;Hypocalcaemia;502
31.6.1.3;Osteopenia of prematurity;502
31.6.1.4;Rickets during childhood;503
31.6.1.5;Plasma alkaline phosphatase activity in infancy;503
31.7;Disorders of liver function;504
31.7.1;Bilirubin metabolism;504
31.7.2;Unconjugated hyperbilirubinaemia: physiological jaundice;504
31.7.3;Unconjugated hyperbilirubinaemia: pathological causes;505
31.7.3.1;Inherited disorders of bilirubin metabolism presenting in childhood;505
31.7.4;Conjugated hyperbilirubinaemia and hepatocellular disease;505
31.7.5;Liver disease in older children;506
31.7.5.1;Wilson disease;507
31.7.5.2;Reye syndrome or Reye-like illness;507
31.8;Internet resources [All Accessed October 2013];507
31.9;Further reading;507
32;Chapter 26: Introduction to haematology and transfusion science;508
32.1;Introduction;508
32.2;General Haematology;508
32.2.1;Analysis of the full blood count;508
32.2.1.1;Haemoglobin;509
32.2.1.2;Cell counting;509
32.2.1.3;Red cell indices;509
32.2.1.3.1;Mean cell volume;509
32.2.1.3.2;Mean cell haemoglobin;509
32.2.1.3.3;Mean cell haemoglobin concentration;509
32.2.1.4;White cell differential;509
32.2.1.5;Platelet count;510
32.2.1.5.1;Erythrocyte sedimentation rate (ESR);510
32.2.1.5.2;Plasma viscosity;510
32.2.2;Reticulocyte count;510
32.2.3;Erythrocyte sedimentation rate and plasma viscosity;510
32.2.4;Flow cytometry;510
32.2.5;Haematinic studies;511
32.2.6;Haemoglobinopathy screening;511
32.2.7;Tests for infectious mononucleosis;511
32.3;Morphology;512
32.3.1;Blood film examination;512
32.3.2;Normal red cell morphology;512
32.3.3;Morphology of the anaemias;512
32.3.3.1;Iron deficiency anaemia;512
32.3.3.2;Megaloblastic anaemia;512
32.3.3.3;Autoimmune haemolytic anaemia;512
32.3.3.4;Microangiopathic haemolytic anaemia;512
32.3.3.5;Malaria;514
32.3.4;Normal white cell morphology;514
32.3.5;Abnormal white cell morphology;515
32.3.6;Haematological malignancies;515
32.3.6.1;Acute leukaemia;515
32.3.6.2;Chronic leukaemia;516
32.3.6.2.1;Chronic myeloid leukaemia;516
32.3.6.2.2;Chronic lymphoid leukaemias;516
32.3.6.3;Myeloproliferative neoplasms;517
32.3.6.4;Myelodysplasia;517
32.3.6.5;Non-Hodgkin lymphoma;517
32.4;Haemostasis;518
32.4.1;Introduction;518
32.4.2;The coagulation cascade;518
32.4.3;Laboratory tests of coagulation;518
32.4.3.1;Prothrombin time;519
32.4.3.2;Activated partial thromboplastin time;519
32.4.3.3;Fibrinogen and thrombin time;519
32.4.3.4;D-dimer concentration;519
32.4.3.5;Specific factor assays;520
32.4.4;Interpretation of coagulation tests;520
32.4.4.1;Haemophilia;520
32.4.4.2;Disseminated intravascular coagulation;520
32.5;Blood Transfusion;521
32.5.1;Introduction;521
32.5.2;Blood group antigens;521
32.5.2.1;ABO blood group;521
32.5.2.2;Rh blood group;521
32.5.2.3;Other important blood groups and antibodies;521
32.5.3;Laboratory transfusion tests;522
32.5.3.1;Blood grouping and antibody screen;522
32.5.3.1.1;ABO and D grouping;522
32.5.3.1.2;Antibody screening;522
32.5.3.2;Antibody identification panels;522
32.5.3.3;Crossmatching (compatibility testing);522
32.5.3.3.1;Electronic crossmatch;522
32.5.3.3.2;Immediate spin crossmatch;523
32.5.3.3.3;Full crossmatch;523
32.5.4;Investigation of suspected transfusion reaction;523
32.5.5;Haemolytic disease of the newborn;523
32.5.6;Blood products;524
32.5.6.1;Red cells;524
32.5.6.2;Platelets;524
32.5.6.3;Fresh frozen plasma;524
32.5.6.4;Cryoprecipitate;524
32.5.6.5;Factor concentrates;524
32.5.7;Risks of transfusion;524
32.5.8;Regulations;525
32.6;Conclusion;525
32.7;Acknowledgements;525
32.8;Further reading;525
33;Chapter 27: Biochemical aspects of anaemia;526
33.1;Introduction;526
33.2;The formation, structure and function of the normal red cell;526
33.2.1;Formation;526
33.2.2;Structure of the red cell;527
33.2.3;Function of the red cell;528
33.3;Anaemia;528
33.4;Anaemias associated with a reduction in red cell production;528
33.4.1;Iron deficiency anaemia;528
33.4.1.1;Iron physiology;528
33.4.1.1.1;Iron requirements;530
33.4.1.1.2;Iron absorption;530
33.4.1.1.3;Iron transport and storage;530
33.4.1.2;Causes of iron deficiency anaemia;530
33.4.1.3;Clinical consequences of iron deficiency;531
33.4.1.4;Laboratory determination of iron status;531
33.4.1.4.1;Red cell parameters;531
33.4.1.4.2;Hypochromic red cells;531
33.4.1.4.3;Serum iron;531
33.4.1.4.4;Serum ferritin;531
33.4.1.4.5;Serum iron binding capacity, transferrin and transferrin saturation;531
33.4.1.4.6;Serum transferrin receptor;531
33.4.1.4.7;Hepcidin;531
33.4.1.4.8;Bone marrow aspiration;531
33.4.2;The megaloblastic anaemias resulting from vitamin B12 and folate deficiency;531
33.4.2.1;Folate metabolism;532
33.4.2.1.1;Folate requirements;532
33.4.2.1.2;Absorption of folate;532
33.4.2.2;Causes of folate deficiency;532
33.4.2.3;Features of folate deficiency;532
33.4.2.4;Laboratory determination of folate status;532
33.4.2.5;Vitamin B12
metabolism;532
33.4.2.5.1;Structure of vitamin B12;532
33.4.2.5.2;Source of vitamin B12;532
33.4.2.5.3;Vitamin B12 requirements;532
33.4.2.5.4;Absorption of vitamin B12;532
33.4.2.6;Causes of vitamin B12 deficiency;534
33.4.2.7;Features of vitamin B12 deficiency;534
33.4.2.8;Laboratory determination of vitamin B12 status;534
33.4.2.8.1;Serum vitamin B12 ;534
33.4.2.8.2;Serum methylmalonate and homocysteine;535
33.4.2.8.3;Deoxyuridine suppression test;535
33.4.2.8.4;Antibody tests;535
33.4.2.8.5;Schilling test;535
33.4.3;Anaemias due to reduction in red cell production: inherited causes;535
33.4.4;Anaemias associated with reduction in red cell production: acquired causes;535
33.4.4.1;Anaemia of chronic disease;535
33.4.4.2;Aplastic anaemia;535
33.4.4.3;Myelodysplasia;535
33.4.4.4;Malignant infiltration of the bone marrow;535
33.5;Anaemias associated with increased red cell loss;535
33.5.1;Bleeding;535
33.5.2;Haemolysis;535
33.5.2.1;Laboratory features of haemolysis;536
33.5.3;Causes of haemolytic anaemias;536
33.5.4;Inherited haemolytic anaemia;536
33.5.4.1;Membrane defects;536
33.5.4.2;Enzyme defects;537
33.5.4.2.1;Disorders of the pentose phosphate pathway and related enzymes of glutathione metabolism;537
33.5.4.2.2;Disorders of anaerobic glycolysis;539
33.5.4.2.3;Disorders of nucleotide metabolism;539
33.5.5;Acquired haemolytic anaemias;539
33.5.5.1;Immune haemolytic anaemias;539
33.5.5.2;Non-immune haemolytic anaemias;539
33.5.5.2.1;Infections;539
33.5.5.2.2;Traumatic and microangiopathic disorders;539
33.5.5.2.3;Acquired disorders of the red cell membrane;540
33.6;Diagnosis of haemolysis;540
33.6.1;Clinical evidence;540
33.6.2;Laboratory investigations;540
33.6.2.1;Laboratory investigations for the presence of haemolysis;540
33.6.2.1.1;Red cell morphology;540
33.6.2.1.2;Total and unconjugated bilirubin;540
33.6.2.1.3;Haptoglobin;540
33.6.2.1.4;Haemopexin;541
33.6.2.1.5;Methaemalbumin;541
33.6.2.1.6;Free haemoglobin;541
33.6.2.1.7;Haemosiderinuria;541
33.6.2.1.8;Red cell survival;541
33.6.2.2;Laboratory investigations for the cause of haemolysis;541
33.6.2.2.1;Coombs test (direct antiglobulin test);541
33.6.2.2.2;Tests for abnormal haemoglobin;541
33.6.2.2.3;Osmotic fragility tests;541
33.6.2.2.4;The autohaemolysis test;541
33.6.2.2.5;Flow cytometry;542
33.6.2.3;Tests for enzyme deficiencies;542
33.6.2.3.1;Glucose 6-phosphate dehydrogenase;542
33.6.2.3.2;Pyrimidine 5'-nucleotidase;542
33.6.2.3.3;Red cell metabolites;542
33.6.2.3.4;Glycolytic intermediates;542
33.7;Conclusion;543
33.8;Acknowledgements;543
33.9;Further reading;543
34;Chapter 28: The porphyrias: inherited disorders of haem synthesis;544
34.1;Introduction and overview;544
34.1.1;Biochemistry of haem synthesis;544
34.1.2;Overview of the porphyrias;545
34.1.3;Molecular genetics of the porphyrias;545
34.2;Porphyrias presenting with acute attacks;549
34.2.1;The autosomal dominant acute porphyrias;549
34.2.1.1;Pathophysiology of acute attacks;549
34.2.1.2;Clinical presentation of acute attacks;549
34.2.1.3;Chronic complications;550
34.2.1.4;Diagnosis of acute porphyria;550
34.2.1.5;Management of an acute attack;550
34.2.1.5.1;Supportive treatment;550
34.2.1.5.2;Specific treatment;551
34.2.1.6;Preventing acute attacks;551
34.2.1.7;Severely affected patients;551
34.2.1.8;Managing asymptomatic relatives of patients;552
34.2.1.8.1;Family studies;552
34.2.1.9;Safe prescribing;552
34.2.1.10;Specific situations;553
34.2.1.10.1;Pregnancy;553
34.2.1.10.2;Anaesthesia;553
34.2.2;Rare forms of acute porphyria;553
34.2.2.1;AA dehydratase deficiency porphyria ;553
34.2.2.2;Homozygous acute porphyrias;553
34.3;The cutaneous porphyrias;553
34.3.1;Bullous porphyrias;553
34.3.1.1;Pathophysiology of skin lesions;554
34.3.1.2;Skin symptoms and signs;554
34.3.1.3;Biochemical features and diagnostic approach;554
34.3.1.4;Individual disorders;555
34.3.1.4.1;Porphyria cutanea tarda;555
34.3.1.4.2;Hepatoerythropoietic porphyria;556
34.3.1.4.3;Congenital erythropoietic porphyria;556
34.3.2;Erythropoietic protoporphyria and X-linked dominant protoporphyria;557
34.3.2.1;Skin symptoms and signs;557
34.3.2.2;Treatment;558
34.3.2.3;Chronic complications and their management;558
34.4;Secondary disorders of porphyrin metabolism;558
34.5;Conclusion;559
34.6;Further reading;559
34.7;Internet resources;560
35;Chapter 29: The haemoglobinopathies;561
35.1;Introduction;561
35.1.1;The structure and function of haemoglobin;561
35.1.2;The genetic control of haemoglobin synthesis;562
35.2;The thalassaemias;563
35.2.1;a Thalassaemia;563
35.2.2;ß Thalassaemia;564
35.3;Structural haemoglobin variants;565
35.3.1;Sickle cell anaemia;566
35.3.2;Other structural haemoglobin variants;567
35.4;Laboratory diagnosis of haemoglobinopathies;568
35.5;Conclusion;570
35.6;Further reading;570
36;Chapter 30: Immunology for clinical biochemists;571
36.1;The immune system;571
36.1.1;Introduction;571
36.1.2;Immune responses;571
36.1.2.1;Antigens;572
36.1.2.2;Clonality;572
36.1.3;The innate immune system;572
36.1.4;The adaptive immune system;573
36.1.4.1;Lymphoid tissue;573
36.1.4.2;Cells;573
36.1.4.2.1;Neutrophils;575
36.1.4.2.2;Basophils and eosinophils;576
36.1.4.2.3;Monocytes;577
36.1.4.2.4;Lymphocytes;577
36.1.4.3;Antigen recognition;577
36.1.4.3.1;Immunoglobulins;577
36.1.4.3.2;T cell receptors;580
36.1.4.3.3;Human leukocyte antigens (HA) ;580
36.1.4.4;Antigen presentation;581
36.1.4.5;Cellular immune activation;581
36.1.5;Complement;581
36.1.5.1;The complement system;581
36.1.5.2;Activation via the alternative pathway;581
36.1.5.3;Activation via the classical pathway;581
36.1.5.4;Activation via the lectin pathway;581
36.1.5.5;Regulation of the complement pathways;581
36.1.6;Acute phase proteins;582
36.1.7;Cytokines;583
36.1.7.1;Inflammatory cytokines;585
36.1.7.2;Mechanisms of immunological damage;585
36.1.7.3;Type I hypersensitivity;585
36.1.7.4;Type II hypersensitivity;586
36.1.7.5;Type III hypersensitivity;586
36.1.7.6;Type IV hypersensitivity;586
36.1.8;Conclusion;586
36.2;Diseases of the immune system;586
36.2.1;Introduction;586
36.2.2;Immune deficiency;586
36.2.2.1;Development of immunity in humans;586
36.2.2.2;Infection and immune deficiency;587
36.2.2.3;Investigation of patients with suspected immune deficiency;587
36.2.2.4;Primary immunodeficiencies;588
36.2.2.4.1;B ymphocyte (humoral) system ;588
36.2.2.4.1.1;IgA deficiency;588
36.2.2.4.1.2;Common variable immunodeficiency (CVID);588
36.2.2.4.1.3;X-linked agammaglobulinaemia;589
36.2.2.4.2;T ymphocyte (cell-mediated immunity) system ;589
36.2.2.4.2.1;Severe combined immunodeficiencies (SCID);589
36.2.2.4.2.2;DiGeorge syndrome;589
36.2.2.4.2.3;X-linked hyper-IgM syndrome/CD40 ligand deficiency;589
36.2.2.4.3;Phagocytic (polymorphonuclear and mononuclear) system;590
36.2.2.4.3.1;Chronic granulomatous disease;590
36.2.2.4.4;Leukocyte adhesion defect types I and II;590
36.2.2.4.5;Complement system;590
36.2.2.4.5.1;C1 Esterase inhibitor deficiency;590
36.2.2.4.6;Transient hypogammaglobulinaemia of infancy;590
36.2.2.5;Secondary immune deficiency;590
36.2.2.5.1;Protein loss;590
36.2.2.5.2;Splenectomy;591
36.2.3;Allergies;591
36.2.3.1;Investigation of patients with allergies;591
36.2.3.2;Anaphylaxis;592
36.2.3.2.1;The investigation of anaphylaxis;593
36.2.4;Autoimmune diseases;593
36.2.4.1;Autoimmune endocrine diseases;594
36.2.4.1.1;Thyroid;594
36.2.4.1.2;Pancreas;594
36.2.4.1.3;Adrenals;594
36.2.4.1.4;Autoimmune polyendocrine syndromes (APS);594
36.2.4.1.4.1;Autoimmune diseases of the gut;594
36.2.4.1.4.2;Autoimmune liver diseases;595
36.2.4.1.4.3;Autoimmune skin diseases;596
36.2.4.1.4.4;Autoimmune kidney diseases;596
36.2.4.1.4.5;Autoimmune articular diseases;596
36.2.4.1.5;Rheumatoid arthritis (RA);596
36.2.4.1.6;Other connective tissue diseases;598
36.2.4.1.6.1;Antinuclear antibodies;598
36.2.4.1.6.2;Antibodies to double-stranded DNA;598
36.2.4.1.6.3;Antibodies to extractable nuclear antigens;598
36.2.4.1.6.4;Antinuclear antibodies in pregnancy;598
36.2.4.1.6.5;Antiphospholipid antibodies;598
36.3;Lymphoid malignancies;599
36.3.1;B lymphocytes and monoclonal proteins;599
36.3.1.1;Clinical significance of monoclonal proteins;599
36.3.1.2;Prevalence of monoclonal proteins;600
36.3.1.3;Laboratory investigation of paraproteins;600
36.3.1.4;Identification of paraproteins;600
36.3.1.5;Typing of monoclonal immunoglobulins in serum and urine;602
36.3.1.5.1;Immunofixation;602
36.3.1.6;Quantitation of monoclonal components;603
36.3.1.7;Cryoproteins;604
36.3.2;2 -Microglobulin;605
36.3.3;B cell malignancies;605
36.3.3.1;Myeloma;605
36.3.3.2;Solitary plasmacytoma;606
36.3.3.3;Waldenström macroglobulinaemia;606
36.3.3.4;Lymphomas, chronic lymphocytic leukaemia and heavy chain diseases;606
36.3.3.5;Monoclonal gammopathy of unknown significance (MGUS);607
36.3.3.6;Transient paraproteinaemia;607
36.3.3.7;Serum free light chains (SFC) ;607
36.3.3.8;Amyloidosis;607
36.4;Infection and sepsis;608
36.4.1;Diagnosis and monitoring of infections;609
36.4.1.1;C-reactive protein and markers of the acute phase response;609
36.5;Transplantation;610
36.5.1;Organ transplantation;610
36.5.2;Stem cell transplantation;611
36.6;Conclusion;611
36.7;Further reading;612
36.8;Appendix 30.1: Immunological investigations;613
36.8.1;Quantification of total immunoglobulin concentrations;613
36.8.2;IgG subclasses;613
36.8.3;Quantification of specific antibody responses;613
36.8.4;Quantification of IgE;613
36.8.5;Complement;613
36.8.6;Enumeration of cell numbers;613
36.8.7;Functional assays;613
36.8.8;Neutrophil function tests;614
36.8.9;Autoantibodies;614
37;Chapter 31: Metabolic bone disease;615
37.1;Bone biology;615
37.1.1;Anatomy of bone;615
37.1.1.1;Macroscopic;615
37.1.1.2;Microscopic;615
37.1.2;Bone matrix proteins;616
37.1.2.1;Collagen;616
37.1.2.2;Non-collagenous proteins;617
37.1.2.2.1;Osteocalcin;617
37.1.2.3;Other bone proteins;617
37.1.3;Cellular elements of bone;618
37.1.3.1;Osteoblasts;618
37.1.3.2;Osteocytes;618
37.1.3.3;Osteoclasts;619
37.1.3.4;Bone remodelling and its regulation;619
37.1.4;Biochemical markers of bone turnover;620
37.1.4.1;Markers of bone formation;620
37.1.4.1.1;Alkaline phosphatase;620
37.1.4.1.2;Osteocalcin;621
37.1.4.1.3;Procollagen 1 extension peptides;622
37.1.4.2;Markers of bone resorption;622
37.1.4.2.1;Hydroxyproline;622
37.1.4.2.2;Glycosylated hydroxylysine;622
37.1.4.2.3;Collagen cross-links;622
37.1.4.2.4;Collagen telopeptides;623
37.1.4.2.5;Tartrate-resistant acid phosphatase;624
37.1.4.2.6;New markers;624
37.1.4.2.7;Variation in bone turnover markers;624
37.2;Osteoporosis;624
37.2.1;Causes of osteoporosis;625
37.2.2;Investigation and diagnosis;626
37.2.2.1;Clinical risk factors for fracture;626
37.2.2.2;Bone densitometry;626
37.2.2.3;Biochemical investigation;627
37.2.2.4;Other investigations;628
37.2.3;Treatment;628
37.2.3.1;Lifestyle modifications;628
37.2.3.2;Calcium and vitamin D;628
37.2.3.3;Pharmacological management;628
37.2.3.3.1;Bisphosphonates;628
37.2.3.3.2;Hormone replacement therapy;629
37.2.3.3.3;Selective oestrogen receptor modulators;629
37.2.3.3.4;Parathyroid hormone;629
37.2.3.3.5;Other pharmacological treatments;629
37.2.3.4;Biochemical responses to treatments;630
37.3;Osteomalacia;631
37.3.1;Calciopenic osteomalacia;631
37.3.1.1;Vitamin D deficiency;631
37.3.1.2;Defects in 1,25-dihydroxyvitamin D synthesis or action;632
37.3.1.3;Laboratory investigation;632
37.3.1.4;Responses to therapy;633
37.3.2;Phosphopenic osteomalacia;633
37.3.2.1;Laboratory investigation;634
37.3.2.2;Treatment;634
37.3.2.2.1;Hypophosphatasia;634
37.3.3;Osteomalacia and acidosis;634
37.3.4;Defective osteoblast function and osteomalacia;634
37.4;Chronic kidney disease – mineral and bone disorder;635
37.4.1;Aetiology;635
37.4.1.1;Parathyroid hormone–calcitriol–FGF23 axis;635
37.4.1.2;Aluminium retention;636
37.4.1.2.1;Calcium;636
37.4.1.2.2;Phosphate;637
37.4.1.2.3;Parathyroid hormone;637
37.4.1.2.4;FGF23;637
37.4.1.2.5;Alkaline phosphatase;637
37.4.1.2.6;Other markers of bone turnover;637
37.4.1.2.7;Aluminium;637
37.4.1.2.8;Radiology, scintigraphy and densitometry;638
37.4.1.2.9;Bone histology;638
37.4.2;Clinical features;636
37.4.3;Investigations;636
37.4.4;Treatment;638
37.4.4.1;Hyperparathyroidism;638
37.4.4.1.1;Vitamin D derivatives;638
37.4.4.1.2;Phosphate metabolism;638
37.4.4.1.3;Parathyroidectomy;638
37.4.4.1.4;Calcimimetic agents;639
37.4.4.2;Aluminium toxicity;639
37.4.5;Bone disease after renal transplantation;639
37.5;Bone disease in primary hyperparathyroidism;639
37.5.1;Clinical, biochemical and histological features;639
37.5.2;Treatment;640
37.6;Paget disease of bone;640
37.6.1;Epidemiology;640
37.6.2;Aetiology;640
37.6.3;Natural history;640
37.6.4;Pathology;641
37.6.5;Clinical features;641
37.6.6;Investigations;641
37.6.6.1;Radiology;641
37.6.6.2;Biochemical tests;641
37.6.6.2.1;Bone turnover markers;641
37.6.6.2.2;Plasma and urinary calcium;642
37.6.7;Responses to treatment;642
37.7;Bone turnover and bone disease in children;643
37.8;Genetic bone diseases;643
37.8.1;Osteogenesis imperfecta;643
37.8.2;High bone mass;645
37.8.2.1;Osteopetrosis;645
37.8.2.2;Progressive diaphyseal dysplasia;645
37.8.3;Familial or idiopathic hyperphosphatasia (juvenile Paget disease);645
37.8.4;Other disorders;645
37.8.4.1;Familial expansile osteolysis and related disorders;645
37.8.4.2;Fibrogenesis imperfecta ossium;645
37.8.4.3;Polyostotic fibrous dysplasia;645
37.9;Conclusion;645
37.10;Further reading;646
37.11;Appendix 31.1:
Indications for diagnostic transiliac bone biopsy;646
37.12;Appendix 31.2:
Protocol for desferrioxamine test in dialysis patients;646
38;Chapter 32: Biochemistry of articular disorders;647
38.1;Introduction;647
38.2;The articular system;647
38.3;Disorders of the articular system;648
38.3.1;Osteoarthritis (OA);648
38.3.2;Inflammatory arthritis;648
38.3.3;The connective tissue diseases;649
38.3.4;Aches and pains;649
38.3.5;Crystal arthritis;650
38.3.5.1;Hyperuricaemia and gout;650
38.3.5.1.1;Asymptomatic hyperuricaemia;651
38.3.5.1.2;Acute gout;651
38.3.5.1.3;Chronic tophaceous gout;652
38.3.5.1.4;Diagnosis;652
38.3.5.1.5;Treatment;652
38.3.5.2;Calcium pyrophosphate deposition (CPPD);653
38.3.5.3;Basic calcium phosphate deposition disease;653
38.3.5.4;Other crystals found in synovial fluid;654
38.4;Articular involvement in Endocrine and Metabolic diseases;654
38.4.1;Diabetes mellitus;654
38.4.2;Other endocrine disorders;654
38.4.3;Haemochromatosis;654
38.4.4;Alkaptonuria;654
38.5;Laboratory testing in articular disease;654
38.5.1;Anaemia in rheumatoid arthritis;654
38.5.2;The acute phase response;655
38.5.3;Examination of synovial fluid;655
38.5.4;Rheumatoid factor;655
38.5.5;Other autoantibody tests;655
38.6;Conclusion;656
38.7;Further reading;656
39;Chapter 33: Muscle disease;657
39.1;Introduction;657
39.2;Functional anatomy and physiology of muscle;657
39.3;Diseases of muscle and their investigation;661
39.4;Biochemical investigation of muscle disease;662
39.4.1;Routine’ biochemical studies;662
39.4.2;Plasma creatine kinase activity;662
39.4.2.1;Statin induced elevation of creatine kinase;664
39.4.3;Other enzymes measurable in plasma;664
39.4.4;Myoglobinuria;664
39.5;Investigation of muscle disease;664
39.5.1;Non-metabolic, genetically determined myopathies;664
39.5.2;Metabolic, genetically determined myopathies;665
39.5.2.1;Disorders of carbohydrate metabolism;665
39.5.2.1.1;Dynamic/functional tests;665
39.5.2.1.2;Histocytochemistry;665
39.5.2.1.3;Biochemical investigations;665
39.5.2.2;Defects of the respiratory chain;666
39.5.2.2.1;Dynamic/functional tests in blood;666
39.5.2.2.2;Histocytochemistry;666
39.5.2.2.3;Biochemical investigations;666
39.5.2.2.3.1;Measurement of mitochondrial oxidations;666
39.5.2.2.3.2;Measurement of activity of individual respiratory chain complexes;667
39.5.2.2.4;Molecular biology techniques;667
39.5.2.3;Defects of fatty acid oxidation;667
39.5.2.3.1;Dynamic/functional tests ;668
39.5.2.3.1.1;Intermediary metabolites and metabolic fuels in blood.;668
39.5.2.3.1.2;Measurement of plasma, tissue and urine carnitine concentrations;668
39.5.2.3.1.3;Measurement of dicarboxylic acids and acylglycines in urine;668
39.5.2.3.2;Specific biochemical investigation ;668
39.5.2.3.2.1;Measurement of flux through ß -oxidation;668
39.5.2.3.2.2;Measurement of carnitine transport and enzyme activity;668
39.6;Conclusion;670
39.7;Acknowledgements;670
39.8;Further reading;670
39.9;Appendix 33.1:
The forearm exercise test;670
40;Chapter 34: Investigation of cerebrospinal fluid;671
40.1;Introduction;671
40.2;Cerebrospinal fluid physiology;672
40.2.1;Formation;672
40.2.2;Composition;672
40.2.3;Analysis of cisternal or ventricular fluid;672
40.3;Investigations relevant to physiology and pathophysiology;672
40.3.1;Sampling and pressure;672
40.3.2;Appearance;672
40.3.3;Cells;672
40.3.4;Glucose;673
40.3.5;Lactate;673
40.3.6;Proteins;673
40.3.6.1;Assessment of blood–brain barrier permeability and reduced fluid flow;675
40.3.6.2;Intrathecal immunoglobulin synthesis;675
40.3.6.2.1;Cerebrospinal fluid protein index;675
40.3.6.3;Oligoclonal bands;675
40.3.7;Brain-specific proteins;676
40.3.8;Cerebrospinal fluid oto- and rhinorrhoea;677
40.3.9;Haem pigments and ferritin;677
40.3.9.1;Examination of CSF for haem and bilirubin;678
40.3.9.1.1;Neopterin;678
40.3.9.1.2;ß2-Microglobulin ( ß2M);678
40.3.9.1.3;C-reactive protein (CRP);678
40.3.10;Enzymes in CSF;678
40.3.11;Markers of inflammation;678
40.3.12;Non-biochemical investigations;679
40.4;Biochemical investigations in CNS disorders;680
40.4.1;Acute infections;680
40.4.2;Chronic infections;680
40.4.3;Haemorrhage and obstruction;681
40.4.4;Inherited metabolic diseases;681
40.4.5;Malignancy;681
40.4.6;Dementia;681
40.4.7;Cerebrospinal fluid analysis in demyelinating diseases;682
40.5;Conclusion;682
40.6;Acknowledgement;683
40.7;Further reading;683
41;Chapter 35: Biochemical aspects of psychiatric disorders;684
41.1;Introduction: psychiatry as a clinical discipline;684
41.1.1;Investigations in psychiatry;685
41.2;The classification of psychiatric disorders;685
41.3;The aetiology of psychiatric disorders;686
41.4;Biochemical investigations in psychiatric disorders;686
41.5;Psychiatric manifestations of organic disease;687
41.5.1;Acute confusional state (delirium);687
41.5.2;Anxiety;687
41.5.3;Dementia;688
41.5.4;Depression;689
41.5.4.1;Introduction;689
41.5.4.2;Depression and thyroid function;689
41.5.4.3;Depression and adrenal function;689
41.5.4.4;Depression in the metabolic syndrome and diabetes;690
41.5.5;Post-traumatic stress disorder;690
41.5.6;Schizophrenia;690
41.6;Endocrine and metabolic manifestations of psychiatric disease;691
41.6.1;Abnormalities of the hypothalamo–pituitary–adrenal axis;691
41.6.2;Abnormalities of the hypothalamo– pituitary–thyroid axis;691
41.6.3;Abnormalities of the hypothalamo–pituitary–gonadal axis;691
41.6.4;Abnormalities of growth hormone secretion;692
41.6.5;Abnormalities of prolactin secretion;692
41.6.6;Other metabolic abnormalities;692
41.7;Metabolic complications of psychotropic drugs;692
41.7.1;Lithium;692
41.7.2;Drugs causing hyperprolactinaemia;692
41.7.3;Drugs causing hyponatraemia;692
41.7.4;Drugs causing hyperglycaemia and hyperlipidaemia;693
41.7.5;Drugs interfering with hepatic function;693
41.8;Future developments;693
41.9;Conclusion;693
41.10;Further reading;693
42;Chapter 36: Biochemical aspects of neurological disease;694
42.1;Introduction;694
42.2;Encephalopathy;694
42.2.1;Toxic and metabolic encephalopathy;696
42.2.1.1;Carbon monoxide;696
42.2.1.2;Alcohol;696
42.2.1.3;Opioids;696
42.2.1.4;Thiamin (vitamin B1) deficiency;697
42.2.1.5;Vitamin B12 deficiency;697
42.2.1.6;Liver failure;697
42.2.1.7;Chronic kidney disease and established renal failure;697
42.2.1.8;Respiratory failure;697
42.2.1.9;Cardiorespiratory failure;698
42.2.1.10;Disorders of glucose metabolism;698
42.2.1.11;Hyponatremia;698
42.2.1.12;Hypernatraemia;698
42.2.1.13;Hypercalaemia;698
42.2.2;Septic encephalopathy;698
42.2.3;Autoimmune encephalopathy;699
42.2.4;Dementia;699
42.3;Spinal cord disorders;699
42.3.1;Vitamin B12 deficiency (subacute combined degeneration of the spinal cord);699
42.3.2;Folate deficiency;700
42.3.3;Copper deficiency;700
42.3.4;Vitamin E deficiency;700
42.3.5;Hepatic myelopathy;700
42.3.6;Hexosaminidase A deficiency;700
42.3.7;Adrenomyeloneuropathy;700
42.4;Peripheral neuropathy;700
42.4.1;Small fibre painful axonal neuropathy;702
42.4.2;Diabetic neuropathies;702
42.4.2.1;Symmetrical polyneuropathies;702
42.4.2.2;Focal and multifocal neuropathies;702
42.4.2.3;Pathophysiology of diabetic neuropathy;702
42.4.2.3.1;Polyol pathway;702
42.4.2.3.2;Non-enzymatic glycation;703
42.4.2.3.3;Oxidative stress;703
42.4.3;Immune mediated neuropathies;703
42.4.4;Acute inflammatory neuropathies and variants;703
42.4.5;Chronic inflammatory demyelinating polyneuropathies and variants including paraproteinaemic neuropathies;703
42.4.5.1;Monoclonal gammopathy of unknown significance;703
42.4.5.2;Multiple myeloma;703
42.4.5.3;Waldenström macroglobulinaemia;704
42.4.5.4;POEMS syndrome;704
42.4.6;Chronic kidney disease and established renal failure;704
42.4.7;Liver disease;704
42.4.8;Endocrine disturbances;704
42.4.8.1;Hypothyroidism;704
42.4.8.2;Hyperthyroidism;704
42.4.8.3;Acromegaly;704
42.4.9;Nutritional peripheral neuropathies;704
42.4.9.1;Vitamin
B12 deficiency;704
42.4.9.2;Thiamin (vitamin B1) deficiency;705
42.4.9.3;Vitamin B6 (pyridoxine) deficiency;705
42.4.9.4;Vitamin E deficiency;705
42.4.9.5;Niacin (vitamin B3), pantothenic acid (vitamin B5) and folic acid deficiencies;705
42.4.9.6;Chronic hypophosphataemia;705
42.4.9.7;Copper deficiency;705
42.4.10;Neuropathy associated with bariatric surgery;705
42.4.11;Strachan syndrome;705
42.4.12;Metabolic neuropathies;705
42.4.12.1;Refsum disease (heredopathica atactica polyneuritiformis);705
42.4.12.2;Porphyric neuropathy;706
42.4.12.3;Fabry disease (angiokeratoma corporis diffusum; a -galactosidase deficiency);706
42.4.12.4;Cerebrotendinous xanthomatosis (cholestanolosis);706
42.4.12.5;Tangier disease;707
42.4.12.6;Amyloidosis;707
42.4.13;Mitochondrial disorders;707
42.4.14;Paraneoplastic neuropathies;707
42.5;Movement disorders;708
42.5.1;Parkinsonism;708
42.5.2;Tremor;709
42.5.3;Dystonia;709
42.5.3.1;DYT1 dystonia (Oppenheim dystonia);709
42.5.3.2;Dopa-responsive dystonia (DRD);709
42.5.4;Wilson disease;709
42.5.5;Chorea;710
42.5.6;Myoclonus;710
42.5.7;Tics;710
42.6;Ataxia;710
42.6.1;Friedreich ataxia;710
42.6.2;Ataxia with isolated vitamin E deficiency;710
42.6.3;Abetalipoproteinemia;711
42.6.4;Ataxia telangiectasia;711
42.6.5;Early onset ataxia with oculomotor apraxia and hypoalbuminemia;711
42.6.6;Fragile X-associated tremor/ataxia syndrome;711
42.6.7;Hexosaminidase deficiency (GM2 gangliosidoses);711
42.6.8;Cerebrotendinous xanthomatosis (cholestanolosis);711
42.6.9;Neuronal ceroid lipofuscinosis;712
42.6.10;Coeliac disease;712
42.7;Inflammatory disorders of the central nervous system;712
42.8;Conclusion;712
42.9;Acknowledgement;712
42.10;Further reading;712
42.11;Internet resources;712
43;Chapter 37: Ipids and disorders of lipoprotein metabolism;713
43.1;Introduction;714
43.2;Lipids;714
43.2.1;Sterols;714
43.2.1.1;Cholesterol;714
43.2.1.1.1;Cholesterol and membranes;714
43.2.1.2;Phytosterols;715
43.2.2;Fatty acids;715
43.2.3;Triglycerides;715
43.2.4;Phospholipids;715
43.2.5;Eicosanoids;716
43.2.6;Sphingolipids;716
43.2.7;Nuclear lipids;717
43.3;Lipoproteins;717
43.3.1;Chylomicrons;718
43.3.2;Very low density lipoproteins;719
43.3.3;Intermediate density lipoproteins;719
43.3.4;Low density lipoproteins;719
43.3.5;High density lipoproteins;719
43.3.6;Lipoprotein(a);719
43.3.7;Lipoprotein X;719
43.4;Apolipoproteins;719
43.4.1;Apolipoprotein A;720
43.4.1.1;Apolipoprotein A-I;720
43.4.1.2;Apolipoprotein A-II;720
43.4.1.3;Apolipoprotein A-IV;720
43.4.1.4;Apolipoprotein A-V;720
43.4.2;Apolipoprotein B;720
43.4.2.1;Apolipoprotein B-100;720
43.4.2.2;Apolipoprotein B-48;720
43.4.3;Apolipoprotein C;720
43.4.3.1;Apolipoprotein C-I;721
43.4.3.2;Apolipoprotein C-II;721
43.4.3.3;Apolipoprotein C-III;721
43.4.4;Apolipoprotein D;721
43.4.5;Apolipoprotein E;721
43.4.6;Apolipoprotein M;721
43.4.7;Apolipoprotein(a);721
43.5;Cholesterol absorption;721
43.5.1;Sitosterolaemia;722
43.6;Triglyceride digestion;722
43.7;Bile acid metabolism;722
43.8;Lipoprotein metabolism;722
43.8.1;Assembly of apolipoprotein B-containing lipoproteins;722
43.8.2;Exogenous pathway;724
43.8.2.1;Lipolysis in adipose tissue;724
43.8.3;Endogenous pathway;724
43.8.3.1;Hepatic cholesterol trafficking;725
43.8.4;High density lipoprotein metabolism;725
43.8.4.1;Assembly of lipoproteins;725
43.8.4.2;Cholesterol efflux;726
43.8.4.3;Reverse cholesterol transport;726
43.9;Enzymes involved in lipoprotein metabolism;727
43.9.1;Lecithin cholesterol acyltransferase;727
43.9.2;Lipases;727
43.9.2.1;Lipoprotein lipase;727
43.9.2.2;Hepatic lipase;727
43.9.2.3;Endothelial lipase;727
43.9.2.4;Lipase maturation factor 1;728
43.9.2.5;Pancreatic triglyceride lipase;728
43.9.2.6;Hormone sensitive lipase;728
43.9.2.7;Carboxyl ester lipase;728
43.9.2.8;Lysosomal acid lipase;728
43.9.2.8.1;Wolman disease;728
43.9.2.8.2;Cholesteryl ester storage disease;728
43.9.2.9;Phospholipase A2;728
43.9.3;Acyl-CoA:cholesterol acyltransferase;729
43.10;Transfer proteins involved in lipoprotein metabolism;729
43.10.1;Cholesteryl ester transfer protein (CETP);729
43.10.2;Phospholipid transfer protein (PTP);729
43.10.3;Fatty acid transport proteins;729
43.11;Receptors involved in lipoprotein metabolism;729
43.11.1;The D receptor ;729
43.11.2;D receptor-related protein ;730
43.11.3;Scavenger receptor class B type 1;730
43.11.4;Other scavenger receptors;730
43.11.5;Peroxisome proliferator-activated receptor family;731
43.11.6;Other nuclear receptors;731
43.12;Other proteins involved in lipoprotein synthesis, transport and metabolism;731
43.12.1;Microsomal triglyceride transfer protein;731
43.12.2;ATP binding cassette transporter family;731
43.12.3;Proprotein convertase subtilisin kexin 9;731
43.12.4;Sterol regulatory element binding proteins;732
43.12.5;Sortilins;732
43.12.6;Glycosylphosphatidylinositol-anchored HD-binding protein 1 ;732
43.12.7;Angiopoietin-like protein 3;732
43.13;Classification of lipoprotein disorders;732
43.14;The primary dyslipoproteinaemias;734
43.14.1;Hypobetalipoproteinaemia;734
43.14.1.1;Abetalipoproteinaemia;735
43.14.1.2;Chylomicron retention disease;735
43.14.1.3;Familial hypobetalipoproteinaemia;735
43.14.2;Familial combined hyperlipidaemia;735
43.14.3;Familial hypertriglyceridaemia;735
43.14.3.1;Chylomicronaemia syndrome;736
43.14.3.1.1;Lipoprotein lipase deficiency;736
43.14.3.1.2;Apo C-II deficiency;736
43.14.3.1.3;Familial lipoprotein lipase inhibitor;736
43.14.3.1.4;Classic familial hypercholesterolaemia (FH);737
43.14.3.1.5;Familial defective apolipoprotein B-100 (FDB);738
43.14.3.1.6;Gain of function mutation in PCSK9;738
43.14.3.1.7;Autosomal recessive hypercholesterolaemia;738
43.14.4;Remnant hyperlipoproteinaemia;736
43.14.5;Familial hypercholesterolaemia;737
43.14.6;Polygenic hypercholesterolaemia;739
43.14.7;Dysalphalipoproteinaemias;739
43.14.7.1;Abnormal apolipoprotein A structure;739
43.14.7.2;Apo A-I deficiency;739
43.14.8;Disorders of HD metabolism ;739
43.14.8.1;Tangier disease;739
43.14.8.2;Familial lecithin–cholesterol acyltransferase deficiency;740
43.14.8.3;Fish eye disease;740
43.14.8.4;Hepatic triglyceride lipase deficiency;740
43.14.8.5;Cholesterol ester transfer protein deficiency;740
43.15;Acquired hyperlipidaemias;740
43.15.1;Diabetes mellitus;740
43.15.2;Hypothyroidism;741
43.15.3;Nephrotic syndrome;741
43.15.4;Chronic kidney disease;741
43.15.5;Renal transplantation;742
43.15.6;Liver disease;742
43.15.7;Alcohol;742
43.15.8;Drug-related hyperlipidaemia;742
43.16;Acquired hypolipidaemia;743
43.17;Investigation of lipid disorders;743
43.17.1;Total cholesterol;743
43.17.2;Triglycerides;743
43.17.3;High density lipoprotein cholesterol;743
43.17.4;Low density lipoprotein cholesterol;743
43.17.4.1;Non-HD-cholesterol ;744
43.17.5;Apolipoproteins;744
43.17.5.1;Apolipoprotein A-I;744
43.17.5.2;Apolipoprotein B;744
43.17.5.3;Apolipoprotein E;744
43.17.5.4;Lipoprotein(a);744
43.17.6;Post-heparin lipolytic activity;744
43.17.7;Lipoprotein separation techniques;744
43.17.7.1;Ultracentrifugation;744
43.17.7.2;Lipoprotein electrophoresis;745
43.17.8;Genotyping;745
43.18;Treatment of hyperlipidaemia;745
43.19;Conclusion;747
43.20;Acknowledgement;747
43.21;Further reading;747
44;Chapter 38: Clinical biochemistry of the cardiovascular system;748
44.1;Introduction;748
44.1.1;Cardiovascular disease;748
44.1.2;Role of the laboratory;750
44.2;Cardiac muscle structure and biochemistry;751
44.3;Arterial structure and function;752
44.4;Atherosclerosis;752
44.4.1;Theories of early atherogenesis;752
44.4.2;The response-to-injury hypothesis;752
44.4.3;The lipid oxidation hypothesis;752
44.4.4;The fibrofatty lesion;754
44.4.5;The complicated plaque/plaque rupture;754
44.5;Acute myocardial damage;755
44.5.1;Biomarkers of acute myocardial damage;755
44.5.1.1;Troponins;756
44.5.1.2;High-sensitivity troponins;757
44.5.1.3;Other causes of elevated cTn;757
44.5.1.4;Creatine kinase-MB (CK-MB);758
44.5.1.5;Myoglobin;759
44.5.1.6;Heart-type fatty acid binding protein (H-FABP);759
44.5.1.7;Other;759
44.5.1.8;Tests for other causes of chest pain;759
44.5.2;Heart failure;760
44.5.3;Natriuretic peptides;760
44.5.3.1;Critical values;760
44.5.3.2;Non-HF factors influencing NPs;760
44.5.3.3;Clinical utility;760
44.6;Cardiovascular risk factors;761
44.6.1;Cardiovascular risk assessment;761
44.6.2;Unmodifiable risk factors;762
44.6.2.1;Age;762
44.6.2.2;Gender;762
44.6.2.3;Race;763
44.6.2.4;Family history;763
44.6.2.5;Genetic factors;763
44.6.2.6;Low birth weight;763
44.6.3;Potentially modifiable risk factors;763
44.6.3.1;Smoking;763
44.6.3.2;Lipids and lipoproteins;763
44.6.3.3;Thrombogenesis, rheology and clotting factors;764
44.6.3.4;Hypertension;764
44.6.3.5;Obesity;764
44.6.3.6;Impaired glucose tolerance and diabetes;765
44.6.3.7;Metabolic syndrome;765
44.6.3.8;Physical activity;765
44.6.3.9;Psychological factors;765
44.6.3.10;Inflammation and infection;766
44.6.3.11;Relative importance of coronary risk factors;766
44.6.4;Dietary factors;767
44.6.4.1;Salt;767
44.6.4.2;Simple sugars;767
44.6.4.3;Ethanol;767
44.6.4.4;Fish and fish oils;767
44.6.4.5;Soy protein;767
44.6.4.6;Fatty acids;767
44.6.4.7;Plant sterols;768
44.6.4.8;Fibre;768
44.6.4.9;Fruit and vegetables, tea and coffee;768
44.6.4.10;Dietary pattern;768
44.7;Hypertension;768
44.7.1;Definition;768
44.7.2;Cause;769
44.7.2.1;Primary hypertension;769
44.7.2.2;Secondary hypertension;770
44.7.2.2.1;Kidney disease;770
44.7.2.2.2;Endocrine disease;770
44.7.3;Laboratory assessment of hypertension;770
44.7.3.1;Investigation for secondary causes;770
44.7.4;Renovascular hypertension;770
44.7.5;Primary aldosteronism (hyperaldosteronism);771
44.7.5.1;Forms of PA;772
44.7.5.2;Biochemical investigation;773
44.7.5.2.1;Confounding factors;773
44.7.5.2.1.1;Posture;773
44.7.5.2.1.2;Time of day;773
44.7.5.2.1.3;Drugs;773
44.7.5.2.1.4;Dietary sodium;773
44.7.5.2.1.5;Plasma potassium;773
44.7.5.2.1.6;Phase of menstrual cycle;773
44.7.5.2.1.7;Renal impairment/elderly patients;773
44.7.5.2.1.8;Other conditions;773
44.7.5.3;Localization;773
44.7.6;Phaeochromocytoma;774
44.7.6.1;Biochemical investigation;774
44.7.6.2;Localization;775
44.7.6.3;Management;775
44.7.7;Malignant hypertension;775
44.7.8;Hypertension in pregnancy;775
44.7.9;Management of hypertension;775
44.8;Conclusion;776
44.9;Further reading;776
44.10;Atherogenesis;776
44.11;Myocardial injury;776
44.12;Heart failure;776
44.13;Cardiovascular risk factors and prevention;776
44.14;Hypertension;776
44.15;Appendix 1: Protocol for investigation of aldosteronism: screening and confirmatory tests;776
44.15.1;Patient preparation;776
44.15.2;Screening procedure;777
44.15.2.1;Interpretation of results of screening test;777
44.16;Confirmatory tests;777
44.16.1;Saline suppression test;777
44.16.1.1;Procedure;777
44.16.1.2;Interpretation;777
44.16.2;Fludrocortisone suppression test;777
44.16.2.1;Procedure;777
44.16.2.2;Interpretation;777
45;Chapter 39: Therapeutic drug monitoring;778
45.1;Introduction;778
45.1.1;Pharmacokinetics and pharmacodynamics;778
45.1.1.1;Adherence;778
45.1.1.2;Absorption;779
45.1.1.3;Distribution;779
45.1.1.4;Elimination (metabolism and excretion);779
45.1.1.5;Protein binding;780
45.1.1.6;Pharmacodynamic factors;780
45.1.2;Which drugs should be measured?;780
45.2;Use of therapeutic drug monitoring;782
45.2.1;Appropriate clinical question;782
45.2.2;Accurate patient information;783
45.2.3;Appropriate sample;783
45.2.4;Accurate analysis;785
45.2.5;Relevant clinical interpretation;785
45.2.6;Effective action taken;785
45.3;Provision of a therapeutic drug monitoring service;786
45.3.1;Staff;786
45.3.2;Turnaround time;786
45.3.3;Point-of-care testing;786
45.3.4;Reporting;786
45.3.5;Units;786
45.3.6;Quality assurance;787
45.3.7;Continuing education;787
45.4;Pharmacodynamic monitoring, biomarkers and pharmacogenetics;787
45.4.1;Integrating information;788
45.5;Individual drugs;788
45.5.1;Analgesic/anti-inflammatory drugs;788
45.5.1.1;Aspirin (acetylsalicylic acid);788
45.5.1.1.1;Value of monitoring:;788
45.5.2;Antiarrhythmics and cardiac glycosides;788
45.5.2.1;Amiodarone;788
45.5.2.1.1;Value of monitoring:;788
45.5.2.2;Digoxin and digitoxin;788
45.5.2.2.1;Value of monitoring:;789
45.5.2.3;Disopyramide;789
45.5.2.3.1;Value of monitoring:;789
45.5.2.4;Flecainide;789
45.5.2.4.1;Value of monitoring:;789
45.5.2.5;Procainamide;789
45.5.2.5.1;Value of monitoring:;789
45.5.3;Anticonvulsants (antiepileptics);789
45.5.3.1;Carbamazepine/oxcarbazepine;789
45.5.3.1.1;Value of monitoring:;789
45.5.3.2;Ethosuximide;789
45.5.3.2.1;Value of monitoring:;789
45.5.3.3;Phenobarbital/primidone;790
45.5.3.3.1;Value of monitoring:;790
45.5.3.4;Phenytoin;790
45.5.3.4.1;Value of monitoring;790
45.5.3.5;Valproate;790
45.5.3.5.1;Value of monitoring;790
45.5.3.6;Newer anticonvulsant drugs;790
45.5.3.6.1;Value of monitoring;791
45.5.4;Antidepressants and antipsychotic drugs;791
45.5.4.1;Tricyclic antidepressants (amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, trimip ...;791
45.5.4.1.1;Value of monitoring;791
45.5.4.2;Selective serotonin release inhibitors (SSRIs) (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertralin ...;791
45.5.4.2.1;Value of monitoring;791
45.5.4.3;Lithium;791
45.5.4.3.1;Value of monitoring;791
45.5.4.4;Other antidepressants;791
45.5.4.4.1;Value of monitoring;791
45.5.4.5;Antipsychotic drugs;791
45.5.4.5.1;Value of monitoring;791
45.5.5;Antimicrobial drugs;792
45.5.5.1;Aminoglycosides (amikacin, gentamicin, tobramycin);792
45.5.5.1.1;Value of monitoring;792
45.5.5.2;Glycopeptides (vancomycin and teicoplanin);792
45.5.5.2.1;Value of monitoring;792
45.5.5.3;Chloramphenicol;792
45.5.5.3.1;Value of monitoring;792
45.5.5.4;Antifungal drugs;792
45.5.5.4.1;Value of monitoring;793
45.5.5.5;Antitubercular drugs;793
45.5.5.5.1;Value of monitoring;793
45.5.5.6;Antiretroviral drugs;793
45.5.5.6.1;Value of monitoring;793
45.5.5.6.2;Value of monitoring;794
45.5.6;Antineoplastic drugs;793
45.5.6.1;Methotrexate;794
45.5.6.1.1;Value of monitoring;794
45.5.7;Bronchodilator drugs;794
45.5.7.1;Theophylline/caffeine;794
45.5.7.1.1;Value of monitoring;794
45.5.8;Immunosuppressants;794
45.5.8.1;Ciclosporin;795
45.5.8.1.1;Value of monitoring;795
45.5.8.2;Sirolimus;795
45.5.8.2.1;Value of monitoring;795
45.5.8.3;Tacrolimus;795
45.5.8.3.1;Value of monitoring;795
45.5.8.4;Mycophenolic acid;795
45.5.8.4.1;Value of monitoring;796
45.5.9;Opiate and opioid drugs;796
45.5.9.1;Methadone/buprenorphine;796
45.5.9.1.1;Value of monitoring;796
45.5.9.2;Morphine;796
45.5.9.2.1;Value of monitoring;796
45.6;Acknowledgement;796
45.7;Further reading;796
45.7.1;General pharmacokinetics;796
45.7.2;Analytical methods;796
45.7.3;Antiarrhythmics/cardiac glycosides;796
45.7.4;Anticonvulsants;796
45.7.5;Antidepressants/antipsychotics;796
45.7.6;Antimicrobial drugs;796
45.7.7;Antifungal drugs;796
45.7.8;Antitubercular drugs;797
45.7.9;Antiretrovirals;797
45.7.10;Antineoplastic drugs;797
45.7.11;Immunosuppressants;797
45.7.12;Methadone/buprenorphine;797
45.8;Appendix 39.1:
Calculations for the determination of dose requirements to achieve steady-state concentrations;797
46;Chapter 40: Poisoning;798
46.1;Introduction;798
46.2;Aetiology of poisoning;799
46.2.1;Intrauterine;799
46.2.2;Neonates;799
46.2.3;Infants;799
46.2.4;Childhood;799
46.2.5;Adult life;799
46.3;Types of lesion in poisoning;799
46.4;Diagnosis and management of poisoning: general principles;800
46.4.1;Diagnosis;800
46.4.2;Management;802
46.4.2.1;Respiratory support;802
46.4.2.2;Cardiovascular support;802
46.4.2.3;Central nervous system complications;802
46.4.2.4;Body temperature;804
46.4.2.5;Renal complications;804
46.4.2.6;General supportive care;805
46.4.2.7;Intestinal decontamination;805
46.4.2.8;Antidotes;805
46.4.2.9;Elimination techniques;806
46.5;Specific poisons;806
46.5.1;Paracetamol (acetaminophen);806
46.5.1.1;Mechanisms;806
46.5.1.2;Toxic dose;806
46.5.1.3;Clinical features;806
46.5.1.4;Management;806
46.5.2;Salicylate;807
46.5.2.1;Mechanisms;807
46.5.2.2;Clinical features;807
46.5.2.3;Laboratory measurements;807
46.5.2.4;Management;808
46.5.3;Chloroquine;809
46.5.4;Digoxin;809
46.5.4.1;Clinical features;809
46.5.4.2;Management;809
46.5.5;Iron;809
46.5.5.1;Toxicity;809
46.5.5.2;Clinical features;809
46.5.5.3;Analysis;809
46.5.5.4;Treatment;809
46.5.5.4.1;Chelation therapy;809
46.5.6;Other metals;809
46.5.7;Organophosphates;810
46.5.7.1;Toxicity;810
46.5.7.2;Clinical features and management;810
46.5.8;Alcohols and glycols;810
46.5.8.1;Ethanol (ethyl alcohol);810
46.5.8.2;Methanol (methyl alcohol);811
46.5.8.3;Ethylene glycol;811
46.5.9;Drug and substance abuse;811
46.5.9.1;Amfetamines;812
46.5.9.2;3,4-Methylenedioxymetamfetamine (MDMA);812
46.5.9.3;Heroin (diamorphine);813
46.5.9.4;Lysergic acid diethylamide (SD);813
46.5.9.5;Cocaine;813
46.5.9.6;Cannabis;813
46.5.9.7;Solvents;814
46.5.10;Benzodiazepines;814
46.5.11;Theophylline;814
46.5.11.1;Clinical features;814
46.5.11.2;Management;814
46.5.12;Antidepressants;814
46.5.12.1;Tricyclic antidepressants;814
46.5.12.1.1;Clinical features;814
46.5.12.1.2;Management;814
46.5.12.2;Monoamine oxidase inhibitors;815
46.5.12.2.1;Toxicity;815
46.5.12.2.2;Management;815
46.5.12.3;Other antidepressants;815
46.5.12.3.1;Lofepramine;815
46.5.12.3.2;Trazodone;815
46.5.12.3.3;Venlafaxine;815
46.5.12.3.4;Fluvoxamine, fluoxetine, sertraline, paroxetine;815
46.5.12.3.5;Citalopram;815
46.5.13;Lithium;815
46.5.13.1;Toxicity;815
46.5.13.2;Clinical features;815
46.5.13.3;Management;815
46.5.14;Cyanide;816
46.5.15;Carbon monoxide;816
46.5.15.1;Toxicity;816
46.5.15.2;Clinical features;816
46.5.16;Methaemoglobinaemia;816
46.5.16.1;Causes;816
46.5.16.2;Symptoms;817
46.5.16.3;Management;817
46.5.17;Plant and fungal toxins;817
46.6;Conclusion;818
46.7;Acknowledgement;818
46.8;Further reading;818
46.9;Appendix 40.1:
Poisons centres;818
47;Chapter 41: Metabolic effects of tumours;819
47.1;Introduction;819
47.2;Neuroendocrine Tumours;819
47.2.1;Carcinoid tumours;819
47.2.1.1;Clinical presentation;819
47.2.1.2;Metabolism of serotonin;820
47.2.1.3;Laboratory investigation;820
47.2.1.4;Diagnostic imaging;821
47.2.1.5;Treatment;821
47.3;Multiple endocrine neoplasia;821
47.3.1;Multiple endocrine neoplasia type 1;821
47.3.1.1;Parathyroid disease;821
47.3.1.2;Gastroenteropancreatic neuroendocrine tumours;822
47.3.1.3;Pituitary tumours;822
47.3.1.4;Foregut carcinoid tumours;822
47.3.1.5;Adrenal tumours;822
47.3.1.6;Tumourigenesis in MEN1;822
47.3.1.7;Diagnosis of MEN1;822
47.3.1.7.1;Genetic screening;823
47.3.1.7.2;Biochemical screening;823
47.3.1.8;Surveillance of MEN1 patients and carriers;823
47.3.1.8.1;Diagnosis;823
47.3.1.8.2;Imaging;824
47.3.1.8.3;Treatment;824
47.3.1.8.4;Surveillance;824
47.3.2;Multiple endocrine neoplasia type 2;823
47.3.3;Other familial syndromes associated with multiple endocrine neoplasia;824
47.4;Metabolic Changes in Malignancy;824
47.4.1;Introduction;824
47.4.2;Paraneoplastic syndromes;825
47.4.2.1;Neurological paraneoplastic syndromes;825
47.4.2.2;Humoral paraneoplastic syndromes;825
47.4.2.3;Adrenocorticotropin;825
47.4.2.4;Vasopressin;825
47.4.2.5;PTH-related peptide;825
47.4.2.6;Tumour-induced osteomalacia;827
47.4.2.7;Other paraneoplastic syndromes and features of malignant disease;827
47.4.2.7.1;Haematological sequelae;827
47.4.2.7.2;Hyperuricaemia;827
47.4.3;Cancer cachexia;827
47.4.3.1;Changes in metabolism;828
47.4.3.2;Treatment;829
47.5;Endocrine Sequelae of Tumours and their Treatment;829
47.5.1;Effects on somatic growth;829
47.5.2;Reproductive consequences of therapy;830
47.6;Conclusion;831
47.7;Further reading;831
48;Chapter 42: Tumour markers;832
48.1;Introduction;832
48.1.1;Evaluation of the clinical utility of tumour markers;832
48.1.2;Tumour marker requests and the responsibilities of the clinical laboratory;836
48.1.2.1;Reasons for requesting tumour markers;836
48.1.2.2;Choice of tumour marker test;836
48.1.2.3;Pre-analytical requirements;836
48.1.2.4;Analytical requirements;837
48.1.2.5;Reporting of tumour marker results;838
48.2;Tumour Markers in the Management of Specific Cancers;838
48.2.1;Bladder cancer;838
48.2.2;Breast cancer;838
48.2.2.1;Screening and diagnosis;839
48.2.2.2;Prognosis;839
48.2.2.3;Monitoring;839
48.2.3;Cervical cancer;840
48.2.3.1;Screening and diagnosis;840
48.2.3.2;Prognosis;840
48.2.3.3;Monitoring;840
48.2.4;Choriocarcinoma;840
48.2.5;Colorectal cancer;840
48.2.5.1;Screening;840
48.2.5.2;Diagnosis;841
48.2.5.3;Prognosis and staging;841
48.2.5.4;Monitoring;841
48.2.5.5;Monitoring of advanced disease;842
48.2.5.6;Cautions and caveats;842
48.2.5.7;Genetic pre-screening for hereditary non-polyposis colon cancer;842
48.2.5.8;K-RAS mutation detection;842
48.2.6;Gastric cancer;842
48.2.7;Gastrointestinal stromal tumours (GIST);842
48.2.8;Germ cell tumours;843
48.2.8.1;Screening;843
48.2.8.2;Diagnosis;843
48.2.8.3;Prognosis;844
48.2.8.4;Monitoring;844
48.2.8.5;Long-term surveillance;845
48.2.9;Gestational trophoblastic neoplasia;845
48.2.9.1;Hydatidiform moles;846
48.2.9.2;Invasive moles;846
48.2.9.3;Choriocarcinoma;846
48.2.9.4;Placental site trophoblastic tumours;846
48.2.9.5;Screening;846
48.2.9.6;Diagnosis;846
48.2.9.7;Prognosis;846
48.2.9.8;Monitoring;846
48.2.10;Hepatocellular carcinoma (primary liver cancer);846
48.2.10.1;Screening of high-risk groups;847
48.2.10.2;Diagnosis;847
48.2.10.3;Prognosis;847
48.2.10.4;Monitoring;847
48.2.11;Lung cancer;847
48.2.11.1;Screening;848
48.2.11.2;Differential diagnosis;848
48.2.11.3;Prognosis;848
48.2.11.4;Monitoring;848
48.2.11.5;Epidermal growth factor receptor and K-RAS mutation analysis;848
48.2.12;Melanoma;848
48.2.12.1;BRAF mutation analysis;848
48.2.13;Neonatal and paediatric tumours;848
48.2.13.1;Germ cell tumours in childhood;849
48.2.13.2;Hepatoblastoma;849
48.2.13.3;Neuroblastoma;849
48.2.14;Ovarian cancer;849
48.2.14.1;Screening;849
48.2.14.2;Diagnosis;850
48.2.14.3;Prognosis;850
48.2.14.4;Detection of residual disease;850
48.2.14.5;Monitoring;850
48.2.14.6;Long-term surveillance;851
48.2.15;Pancreatic cancer;851
48.2.16;Prostate cancer;851
48.2.16.1;Screening and diagnosis;851
48.2.16.2;Management;852
48.2.16.3;Analytical and reporting requirements;852
48.2.17;Testicular cancer;852
48.2.18;Thyroid cancer;853
48.2.18.1;Screening, diagnosis and prognosis;853
48.2.18.2;Monitoring;853
48.2.18.3;Analytical and reporting requirements;853
48.2.19;Cancers of unknown primary;853
48.3;Summary;853
49;Chapter 43: Molecular clinical biochemistry;855
49.1;Introduction;855
49.2;Genes and gene expression;855
49.2.1;What is a gene?;855
49.2.1.1;The Human Genome Project;856
49.2.1.2;The ‘Encode’ project;856
49.2.2;Gene expression;857
49.2.3;Mutation, the source of diversity and disease;857
49.2.4;Genesis of an individual: the formation of gametes;860
49.2.5;Genes in families and populations;861
49.2.6;The variable expression of genetic disease;862
49.3;The techniques of genetic analysis;863
49.3.1;Detection of specific sequences in DNA;863
49.3.1.1;Use of proteins that recognize DNA sequences: restriction endonucleases;863
49.3.1.2;Hybridization: probes and the polymerase chain reaction (PCR);863
49.3.2;Detection of mutations;866
49.3.2.1;Detecting known mutations;866
49.3.2.2;Scanning or screening methods;868
49.3.2.3;Tracking of mutant genes;869
49.3.2.4;Next generation sequencing;870
49.4;The applications of DNA analysis;871
49.4.1;Diagnosis of index cases;871
49.4.2;Prenatal diagnosis;871
49.4.3;Screening;872
49.4.3.1;Screening of individuals;872
49.4.3.2;Population screening;872
49.4.4;Pharmacogenetics;872
49.4.5;Inherited diseases – some examples;873
49.4.5.1;Single gene disorders;873
49.4.5.2;1 -Antitrypsin deficiency;873
49.4.5.3;Cystic fibrosis;874
49.4.5.4;Muscular dystrophy;875
49.4.5.5;Huntington disease;876
49.4.6;Multifactorial and polygenic disease;877
49.4.6.1;Atherosclerosis;877
49.4.6.2;Familial hypercholesterolaemia;877
49.4.6.3;Apolipoprotein E genotypes;878
49.4.7;Cancer genetics;878
49.4.7.1;Oncogenes and suppressor genes;878
49.4.7.2;Multiple endocrine neoplasia (MEN);880
49.5;Gene therapy;880
49.5.1;Stem cells in gene therapy;881
49.5.2;Gene therapy in cancer;882
49.6;Conclusion;882
49.7;Acknowledgements;882
49.8;Glossary;882
49.9;Further reading;884
49.9.1;Background;884
49.9.2;Internet resources;884
49.9.3;Journals;884
50;Chapter 44: Forensic biochemistry;885
50.1;Introduction;885
50.2;Samples and sampling;886
50.3;Poisoning with endogenous agents;887
50.3.1;Hydroxybutyrate;887
50.3.2;Insulin;888
50.3.3;Magnesium;888
50.3.4;Sodium;889
50.4;Post-mortem biochemistry;889
50.4.1;Vitreous humour;890
50.5;Specific diagnostic problems;891
50.5.1;Anaphylaxis/anaphylactoid reactions;891
50.5.2;Diabetes;891
50.5.3;Drowning;891
50.5.4;Hypothermia/hyperthermia;891
50.5.5;Inflammation;893
50.5.6;Sudden death;893
50.5.7;Further reading;893
50.5.7.1;Up-to-date reviews on post-mortem biochemistry;893
50.5.7.2;Practical guidance on post-mortem samples and sampling;893
50.5.7.3;Clinical and post-mortem diagnosis of disorders of glucose metabolism;893
50.5.7.4;Reviews on post-mortem diagnosis of anaphylaxis, hyperthermia/hypothermia and sepsis;893
51;Index;894

Leseproben

Contributors

S. Faisal Ahmed, MB ChB MD FRCPCH,     Professor of Child Health, Honorary Consultant in Paediatric Endocrinology, University of Glasgow, Royal Hospital for Sick Children, Glasgow, UK

David Ah-Moye, HND(MLS) FIBMS DMLM,     Biomedical Scientist (Deputy Laboratory Manager), Haematology Department, Gloucestershire Royal Hospital, Great Western Road, Gloucester, UK

Roopen Arya, BM BCh MA PhD FRCP FRCPath,     Consultant Haematologist, Department of Haematological Medicine, King’s College Hospital, London, UK

Ruth M. Ayling, BSc MB BS MSc PhD FRCP FRCPath,     Consultant Chemical Pathologist, Derriford Hospital, Plymouth, UK

Michael N. Badminton, MBChB PhD FRCPath,     Senior Lecturer and Honorary Consultant, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, UK

Graham R. Bayly, BA BM FRCP FRCPath,     Consultant Biochemist, Bristol Royal Infirmary, Bristol, UK

Sarah Belsey, BSc MSc,     Clinical Scientist, Toxicology Unit, Department of Clinical Biochemistry, King's College Hospital, London, UK

Robin Berry, PhD FRCA DICM,     Consultant in Anaesthetics and Intensive Care, Derriford Hospital, Plymouth, UK

Laurence A. Bindoff, MSc MRCP MD,     Professor of Neurology, Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway

Ingvar T. Bjarnason, MD MSc FRCPath FRCP(Glasg) DSc,     Professor of Digestive Diseases, Department of Gastroenterology, King’s College Hospital, London, UK

Adrian Bomford, MD FRCP,     Reader in Medicine/Honorary Consultant Physician, Institute of Liver Studies, King’s College Hospital, London, UK

Helen Bruce, MChem MSc FRCPath,     Principal Clinical Scientist, Department of Clinical Biochemistry, Royal Surrey County Hospital, Surrey, UK

Fiona Carragher, MSc FRCPath,     Consultant Clinical Scientist, Department of Chemical Pathology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Carrie Chadwick, BSc (Hons) MSc FRCPath,     Consultant Clinical Scientist, Aintree University Hospital Foundation Trust; Laboratory Director, The Walton Centre Foundation Trust, Liverpool, UK

Mike Champion, MSc FRCP FRCPCH,     Consultant in Paediatric Metabolic Medicine, Department of Paediatric Metabolic Medicine, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Timothy Cundy, MA MD FRCP FRACP,     Professor of Medicine, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand

Ceinwen Davies, BSc MSc,     Coagulation Supervisor, Haematology Department, Gloucestershire Royal Hospital, Gloucester, UK

Teifion Davies, BSc MB BS PhD DPMSA MSB CBiol FRCPsych,     Director of Undergraduate Psychiatry Teaching, King’s College London, Institute of Psychiatry, London, UK

Zoe Davies, MA BM BCh MRCP,     Specialist Trainee in Diabetes and Endocrinology, London Deanery, London, UK

Anne Dawnay, PhD FRCPath,     Consultant Biochemist and Honorary Senior Lecturer, University College Hospitals, London, UK

Colin M. Dayan, MA MB BS FRCP PhD,     Professor of Clinical Diabetes and Metabolism, Director, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, Wales, UK

James W. Dear, PhD FRCPEdin,     Consultant in Clinical Pharmacology, National Poisons Information Service, Royal Infirmary of Edinburgh; Senior Clinical Lecturer, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK

James E. East, BSc MB ChB MRCP MD,     Consultant Gastroenterologist, John Radcliffe Hospital, Oxford, UK

George H. Elder, MD FRCP FRCPath FMedSci,     Emeritus Professor, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, UK

Robert J. Flanagan, PhD ERT MFSSoc CChem FRSC FRCPath HFCMHP,     Consultant Clinical Scientist, Toxicology Unit, Clinical Biochemistry, King's College Hospital, London, UK

Rebecca Frewin, BSc MB ChB MRCP FRCPath,     Consultant Haematologist, Haematology Department, Edward Jenner Unit, Gloucester Royal Hospital, Gloucester, UK

Clare M. Galtrey, MA MB BChir PhD MRCP,     Specialist Trainee in Neurology, St George's Hospital, London, UK

Philip Gillen, FRCA FFICM,     Consultant in Anaesthetics and Intensive Care, Derriford Hospital, Plymouth, UK

Roberta Goodall, BSc MSc FIMLS FRCPath,     Formerly Consultant Scientist, Department of Clinical Biochemistry, North Bristol NHS Trust, Southmead Hospital, Bristol, UK

Joanne Goody, BSc MSc,     Assistant Laboratory Manager, Blood Transfusion Department, Gloucestershire Hospital NHS Foundation Trust, Cheltenham General Hospital, Cheltenham, UK

Andrew Grey, MD FRACP,     Associate Professor of Medicine, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand

Mike Hallworth, MA MSc FRCPath EurClinChem,     Consultant Clinical Scientist, Royal Shrewsbury Hospital, Shrewsbury, UK

Paul Hart, MB BS BSc FRCP PhD,     Consultant Neurologist, Epsom and St. Helier NHS Trust, London; Atkinson Morley Neuroscience Unit, St Georges Hospital; Royal Marsden Hospital, London, UK

Peter Hayward, BSc MSc,     Blood Transfusion Section Supervisor, Gloucestershire Hospital NHS Foundation Trust, Cheltenham General Hospital, Cheltenham, UK

Trevor A. Howlett, MD FRCP,     Consultant Physician and Endocrinologist, Department of Diabetes and Endocrinology, Leicester Royal Infirmary, Leicester, UK

Min Htut, MB BS MMedSci MD MRCP DGM DTM&H,     Consultant Neurologist and Honorary Consultant Neurophysiologist, Epsom and St Helier University Hospitals NHS Trust, London, and St. George's Hospital, London, UK

Jeremy G. Jones, MD FRACP FAFRM,     Consultant Rheumatologist, North West Wales NHS Trust, Ysbyty Gwynedd; Senior Clinical Lecturer, School of Sport, Health and Exercise Sciences, University of Wales, Bangor, UK

Geoffrey Keir, PhD MSc FRCPath FIBMS,     Clinical Scientist and Honorary Senior Lecturer, Neuroimmunology and CSF Laboratory, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK

Mourad H. Labib, MB ChB FRCPath,     Consultant Chemical Pathologist, Clinical Biochemistry Department, Dudley Group of Hospitals, Russells Hall Hospital, West Midlands, UK

Marta Lapsley, MB BCh BAO MD FRCPath,     Consultant Chemical Pathologist, Epsom and St Helier University Hospitals NHS Trust, London, UK; Honorary Senior Lecturer in Clinical Endocrinology and Nutrition, University of Surrey, Surrey, UK

Terhi...