- 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.
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. - Expanded sections on haematology and immunology for clinical biochemists provide a thorough understanding of both laboratory and clinical aspects- New chapters are included on important evolving areas such as the metabolic response to stress, forensic aspects of clinical biochemistry and data quality management- An extended editorial team - including three expert new additions ensures accuracy of information and relevance to current curricula and clinical practice- A superb new accompanying electronic version provides an enhanced learning experience and rapid reference anytime, anywhere! Elsevier ExpertConsult.comEnhanced eBooks for medical professionalsCompatible with PC, Mac , most mobile devices and eReaders, browse, search, and interact with this title online and offline. Redeem your PIN at expertconsult.com today!- Straightforward navigation and search across all Elsevier titles- Seamless, real-time integration between devices- Adjustable text size and brightness- Notes and highlights sharing with other users through social media- Interactive content
Front Cover 1
Clinical Biochemistry: Metabolic and clinical aspects 4
Copyright 5
Contents 6
Preface 8
Contributors 9
Chapter 1: Uses of biochemical data in clinical medicine 12
Introduction 12
Specific uses of biochemical tests 13
Diagnosis 13
Management 14
Assessment of disease severity 14
Prognosis 14
Monitoring the progression of disease 14
Screening 15
Population screening 15
Selective screening 15
Individual screening 15
Other uses of biochemical investigations 16
Conclusion 16
Further reading 16
Chapter 2: Acquisition and interpretation of biochemical data 17
Introduction 17
The Test Request 17
Factors Affecting Test Results 18
Preanalytical factors 18
Technical factors 18
Biological factors 18
Endogenous factors 19
Age 19
Sex 19
Ethnic origin 19
Body mass 19
Exogenous factors 19
Time-dependent changes 19
Stress 20
Posture 20
Food intake 20
Drugs 20
Other factors 20
Intrinsic biological variation 20
Analytical range 21
Accuracy and bias 21
Precision 22
Specificity and interference 22
Practicalities: what is desirable performance? 22
Analytical goals 23
Analytical factors 21
Postanalytical factors 23
Interpretation of Results 24
Normal and abnormal 24
The meaning of normal 24
Reference values 25
Problems with reference intervals 25
Comparison of observed results with reference limits 26
Comparison of results with previous values 26
The Predictive Value of Tests 27
Introduction 27
Definitions 27
Example 28
Prevalence and predictive value 29
Practical applications of the predictive value model 30
Receiver operating characteristic curves 30
Likelihood ratios 30
Conclusion 31
Acknowledgement 31
Further reading 31
Chapter 3: Quality aspects of laboratory medicine 32
Introduction 32
What is quality? 32
Quality standards 32
Quality assurance 32
Regulation of laboratories 33
Quality management systems 33
Personnel 33
Premises and environment 33
Information systems 34
Evaluation and audit 34
Clinical quality indicators 35
Clinical effectiveness 35
Key performance indicators 35
Demand management 36
Evidence-based clinical biochemistry 36
Point-of-care testing 36
Conclusion 37
Further Reading 37
Chapter 4: Sodium, water and potassium 38
Physiology 38
Introduction 38
Extracellular fluid and sodium 39
Renal control of sodium output 39
Intrinsic renal control of tubular reabsorption of sodium 39
Renin–angiotensin–aldosterone axis 39
Natriuretic peptides 40
Sodium appetite 41
Intracellular fluid and water 41
Control of renal water output 41
Osmoregulation 41
Non-osmotic control of arginine vasopressin 42
Renal responsiveness to arginine vasopressin 42
Control of water intake 42
Osmoregulation 42
Non-osmotic control of thirst 43
Extracellular fluid, intracellular fluid and potassium 43
Extracellular and intracellular fluid distribution of potassium 43
Renal control of potassium output 44
Intrinsic tubular control 44
Aldosterone 44
Disorders of sodium metabolism 44
Sodium deficiency 44
Clinical presentation 44
Causes of sodium deficiency 44
Extrarenal sodium loss 45
Primary renal sodium loss 45
Secondary renal sodium loss 46
Laboratory investigation of sodium deficiency 46
Management of sodium deficiency 47
Sodium excess 47
Clinical presentation 47
Causes of sodium excess 48
Sodium excess with oedema 48
Pregnancy 48
Menstrual cycle 49
Idiopathic oedema 49
Sodium excess without oedema 49
Laboratory investigation of sodium excess 50
Management of sodium excess 50
Disorders of water metabolism 50
Polyuria 50
Primary polyuria with secondary polydipsia 50
Pregnancy and polyuria 52
Polyuria secondary to primary polydipsia 52
Laboratory investigation and treatment of polyuria 52
Water deprivation test 53
Hypertonic saline infusion 53
Management of polyuria 53
Nocturnal polyuria 54
Laboratory investigation and treatment of nocturnal polyuria 54
Hypernatraemia 55
Water deficiency with thirst 55
Water deficiency without thirst 55
Management of hypernatraemia 56
Management of hypodipsic hypernatraemia syndromes 56
Hyponatraemia 57
Acute dilutional hyponatraemia 57
Chronic dilutional hyponatraemia 58
The syndrome of inappropriate antidiuretic hormone secretion 59
Sick cell syndrome 60
Low osmotic load hyponatraemia 60
Cerebral salt wasting 61
Laboratory investigation of hyponatraemia 61
Management of hyponatraemia 62
Recommended management of symptomatic acute dilutional hyponatraemia 62
Recommended management of chronic dilutional hyponatraemia 62
Disorders of potassium metabolism 63
Hypokalaemia 63
Causes of hypokalaemia 63
Redistribution hypokalaemia in vitro 63
Redistribution hypokalaemia in vivo 63
Hypokalaemic periodic paralysis 63
Extrarenal causes of potassium depletion 64
Renal causes of potassium depletion 65
Renal hypokalaemic acidosis 65
Renal hypokalaemic alkalosis 66
Renal hypokalaemia without specific acid–base disorder 67
Laboratory investigation of hypokalaemia 67
Management of hypokalaemia 68
Hyperkalaemia 68
Causes of hyperkalaemia 69
Redistribution hyperkalaemia in vitro 69
Redistribution hyperkalaemia in vivo 69
Hyperkalaemic periodic paralysis 70
Potassium retention 70
Syndromes of hypoaldosteronism 70
Laboratory investigation of hyperkalaemia 71
Management of hyperkalaemia 72
Conclusion 72
Further reading 72
Appendix 4.1. Formulae 73
(a)
73
(b)
73
(c)
73
(d)
73
Reference 73
(e)
73
Reference 73
(f)
73
(g)
73
(h)
73
Reference 74
Appendix 4.2. Dynamic function tests 74
(a)
74
Notes 74
Vasopressin test 74
Interpretation 74
Reference 74
(b)
74
Pre-infusion preparation 74
Infusion protocol 74
Notes 74
Reference 75
(c)
75
Interpretation 75
Reference 75
Chapter 5: Hydrogen ion homoeostasis and tissue oxygenation and their disorders 76
Introduction 76
The physiological role of hydrogen ions 76
Definitions 76
Hydrogen ion homoeostasis 77
Buffering 77
Bicarbonate 77
Phosphate 78
Haemoglobin 78
Other proteins 78
Ammonia 78
Hydrogen ion turnover 79
Hydrogen ion production 79
Carbon dioxide 79
Incomplete metabolism of glucose: glycolysis and lactate metabolism 79
Incomplete metabolism of triglycerides: ketogenesis 80
Complete oxidation of glucose and triglycerides 80
Amino acid metabolism 80
Hydrogen ion excretion 81
Carbon dioxide 81
Hydrogen ions 81
Bicarbonate reabsorption 81
Acidification of the urine 81
The role of urinary ammonium excretion 82
The role of the liver in hydrogen ion homoeostasis 83
Summary 84
The assessment of acid–base status 84
Clinical assessment 84
Laboratory assessment 84
Hydrogen ion concentration and PCO2 84
Derived variables 84
Anion gap 85
Other investigations 85
Disorders of hydrogen ion homoeostasis 85
Introduction 85
Non-respiratory acidosis 85
Compensatory responses in non-respiratory acidosis 85
Buffering 85
Hyperventilation 85
Renal hydrogen ion excretion 86
Biochemical characteristics of non-respiratory acidosis 86
Systemic effects of acidosis 86
The cardiovascular system 86
Oxygen delivery to tissues 87
The nervous system 87
Potassium homoeostasis 87
Bone 87
Other effects 87
Management of non-respiratory acidosis 87
Specific causes of non-respiratory acidosis 87
Ketoacidosis 87
Other acid–base disturbances associated with alcohol 88
Lactic acidosis 88
Dilutional (expansion) acidosis 89
Acidosis in renal disease 89
Respiratory acidosis 91
Compensatory responses in respiratory acidosis 91
Buffering 91
Hyperventilation 92
Renal hydrogen ion excretion 92
Biochemical characteristics of respiratory acidosis 92
Systemic effects of respiratory acidosis 92
Management 92
Non-respiratory alkalosis 93
Compensation for non-respiratory alkalosis 93
Buffering 93
Hypoventilation 93
Renal bicarbonate excretion 93
Biochemical characteristics of non-respiratory alkalosis 94
Systemic effects of alkalosis 94
Management of non-respiratory alkalosis 94
Specific causes of non-respiratory alkalosis 94
Loss of gastric acid 94
Post-hypercapnic alkalosis 94
Mineralocorticoid excess 95
Miscellaneous 95
Respiratory alkalosis 95
Compensatory responses in respiratory alkalosis 95
Buffering 95
Hypoventilation 95
Renal hydrogen ion excretion 95
Biochemical features of respiratory alkalosis 95
Systemic effects of respiratory alkalosis 95
Management 95
The interpretation of acid–base data 96
Mixed disorders of hydrogen ion homoeostasis 97
Tissue oxygenation 98
Introduction 98
Pulmonary function 98
Alveolar ventilation 98
Oxygen uptake into blood 98
The role of haemoglobin in oxygen transport 99
The effects of pulmonary disease on oxygen uptake into blood 100
Shunting 100
Ventilation–perfusion imbalance 100
Differential effects of pulmonary disease on PaCO2 and PaO2 100
Oxygen transport to tissues 100
Oxygen delivery 100
Oxygen uptake 101
Hypoxia 101
Measurement of oxygen delivery to tissues 101
Detection of tissue hypoxia 102
Management of respiratory failure 102
Conclusion 103
Further reading 103
Chapter 6: Calcium, phosphate and magnesium 104
Calcium metabolism 104
Biological role of calcium 104
Distribution of calcium 104
Calcium fluxes 105
Gastrointestinal tract 105
Kidneys 105
Bone 106
Regulation of calcium metabolism 106
Parathyroid hormone 106
Measurement of circulating parathyroid hormone 107
Classification of hyperparathyroidism 107
Vitamin D 107
Synthesis and metabolism 107
Actions 108
Synthetic vitamin D analogues 109
Measurement of vitamin D metabolites 109
Calcitonin 109
Procalcitonin 110
Other hormones 110
Biochemical assessment of calcium metabolism 110
Plasma calcium 110
Intestinal calcium absorption 111
Urinary calcium 111
Indices of bone turnover 111
Hypercalcaemia 111
Causes of hypercalcaemia 112
Primary hyperparathyroidism 112
Familial hypocalciuric hypercalcaemia 113
Hypercalcaemia of malignancy 113
Granulomatous disease 114
Vitamin D toxicity 114
Investigation of hypercalcaemia 114
Treatment of hypercalcaemia 115
Hypocalcaemia 116
Clinical features 116
Causes of hypocalcaemia 117
Hypoparathyroidism 117
Pseudohypoparathyroidism 117
Vitamin D disorders 118
Other causes of hypocalcaemia 118
Investigation of hypocalcaemia 119
Treatment of hypocalcaemia 120
Phosphorus metabolism 120
Distribution of body phosphorus 120
Intracellular phosphorus 120
Phosphate homoeostasis 121
Dietary phosphate and intestinal absorption 122
The renal tubular reabsorption of phosphate 122
Factors regulating TMP/GFR 122
Disorders of renal phosphate metabolism 123
Plasma phosphate concentrations 124
Hyperphosphataemia 124
Consequences of hyperphosphataemia 125
Diagnostic approach to hyperphosphataemia 125
Therapeutic approach to hyperphosphataemia 125
Hypophosphataemia 126
Mechanisms 126
Consequences of hypophosphataemia 127
Diagnostic approach to hypophosphataemia 127
Therapeutic approach to hypophosphataemia 127
Magnesium metabolism 128
Plasma magnesium 128
Magnesium homoeostasis 128
Hypomagnesaemia 129
Causes 129
Consequences 130
Cardiac effects 130
Diagnostic approach to hypomagnesaemia 130
Therapeutic approach to hypomagnesaemia 132
Hypermagnesaemia 132
Conclusion 132
Further reading 132
Appendix 6.1:
132
Interpretation 133
Reference 133
Appendix 6.2:
133
Interpretation 133
Appendix 6.3:
133
Analysis 133
Interpretation 133
Reference 133
Appendix 6.4: Estimation of TMP/GFR 134
Appendix 6.5:
134
Reference 134
Appendix 6.6:
134
Chapter 7: The kidneys, renal function and kidney disease 135
Anatomy 135
Gross anatomy 135
Microstructure 135
The glomerulus 136
The proximal convoluted tubule 136
The loop of Henle 136
The distal convoluted tubule and collecting duct 137
Other specialized cells 138
Blood vessels 138
Renal function 138
Renal blood flow and its control 138
Glomerular function 138
Tubular function 139
The proximal convoluted tubule 139
The loop of Henle 139
Tubuloglomerular feedback 139
The role of urea 140
The distal convoluted tubule 140
The collecting duct 140
Diuresis 140
Renal disease and its presentation 140
Introduction 140
Manifestations of renal disease 140
Diseases affecting the kidneys 141
The assessment of renal function 141
Introduction 141
Biochemical tests of renal function 141
Urinalysis 141
Appearance 141
Specific gravity and osmolality 142
pH 142
Glucose 142
Protein 142
Urinary sediment 142
Other substances 142
Measurement of glomerular filtration rate 142
Inulin clearance 143
Creatinine clearance 143
Plasma creatinine concentration 143
Calculated creatinine clearance and estimated glomerular filtration rate 145
Cockcroft and Gault 145
MDRD 145
CKD-EPI 145
Definition of CKD using eGFR 145
Cystatin C 146
Plasma urea concentration 146
Plasma ß2 -microglobulin 146
Isotopic techniques for measuring glomerular filtration rate 146
Other tests of renal function 147
Acute kidney injury (acute renal failure) 147
Introduction 147
Classification and causes 147
Prerenal acute kidney injury 148
Diagnosis 148
Management 149
Intrinsic acute kidney injury 149
Diagnosis 149
Acute tubular necrosis 149
Pathogenesis 149
Natural history 150
Obstructive (postrenal) kidney injury 150
Acute kidney injury in the setting of chronic kidney disease 150
Hepatorenal syndrome 150
Metabolic consequences and management of acute kidney injury 151
General management 151
Fluid and electrolyte balance 151
Acid–base balance 151
Nutrition 151
Other measures 151
Renal replacement treatment 152
Haemodialysis 152
Continuous venovenous haemofiltration (CVVH) 152
Continuous venovenous haemodiafiltration (CVVHDF) 152
Peritoneal dialysis 152
Chronic kidney disease 152
Introduction 152
Aetiology and pathogenesis of chronic kidney disease 152
The progression of loss of renal function 153
The uraemic syndrome 153
Clinical features 154
Metabolic disturbances in CKD 154
Retention of nitrogenous waste products 154
Potassium metabolism 154
Acid–base metabolism 154
Calcium, phosphate and magnesium metabolism and renal bone disease 155
Protein metabolism 155
Endocrine disturbances in CKD 155
Growth retardation 155
Sexual dysfunction 156
Thyroid abnormalities 157
Anaemia 158
Endocrine control of salt and water balance 158
Carbohydrate metabolism and lipid metabolism 159
Management 159
General management 159
Slowing the progression of kidney disease 159
Prevention of complications 160
Renal replacement treatment 160
Haemodialysis 160
Haemofiltration 161
Peritoneal dialysis 161
Renal transplantation 161
Conclusion 162
Note about terminology 162
Acknowledgement 162
Further reading 162
Chapter 8: Proteinuria 163
Introduction 163
Protein conservation by the kidneys 163
The glomerular capillary wall 164
The theory of molecular sieving 164
Tubular reabsorption of proteins 165
Tubular secretion of proteins 165
Normal urinary protein content 166
Determinants of urine protein excretion 166
Age, sex and diurnal variation 166
Posture 166
Exercise and diet 166
Pregnancy 167
Proteinuria in kidney disease 167
Proteinuria in staging and prognosis of chronic kidney disease 167
Glomerular proteinuria and nephrotic syndrome 167
Mechanisms underlying glomerular proteinuria 168
Minimal change disease 168
Membranous nephropathy 169
Membranoproliferative glomerulonephritis 169
Focal segmental glomerulosclerosis 169
IgA nephropathy and Henoch–Schönlein purpura 169
Urine protein selectivity and classification of glomerulonephritis 169
Pathophysiological consequences of glomerular proteinuria 170
Hypoalbuminaemia 170
Oedema and salt and water retention 170
Abnormalities of other plasma proteins 170
Hyperlipidaemia 171
Tubular proteinuria 171
Renal disorders associated with tubular proteinuria 171
Drug and heavy metal induced tubular damage 172
Methods of assessing tubular damage 172
High molecular weight protein markers of renal tubular damage 172
Low molecular weight protein markers of renal tubular disease 173
Proteinuria of prerenal origin 173
Myoglobinuria and haemoglobinuria 173
Paraproteinaemias and Bence Jones proteinuria 174
Microalbuminuria as a marker of risk 175
Microalbuminuria and risk of diabetic complications 175
Cardiovascular risk 175
Microalbuminuria as a risk factor in other inflammatory processes 176
Clinical investigation of proteinuria 176
Urine dip-sticks 176
Collection of urine 176
Urine protein measurement 176
Stepwise investigation of proteinuria 177
Acknowledgement 178
Further reading 178
Chapter 9: Renal tubular disorders and renal stone disease 179
Introduction 179
Renal tubular disorders 179
Introduction 179
Physiology 179
Isolated abnormalities of tubular function 180
Glycosuria 180
Hereditary renal glycosuria 181
Amino acidurias 181
Cystinuria 181
Hartnup disorder 182
Familial renal iminoglycinuria 183
Dent disease 183
Phosphate transport defects 183
Renal tubular acidosis 183
Proximal (type 2) renal tubular acidosis 184
Distal (type 1) renal tubular acidosis 184
Distal renal tubular acidosis with hyperkalaemia (type 4) 184
Hereditary renal hypouricaemia 184
Generalized tubular defects (Fanconi syndrome) 185
Renal calculi 185
Introduction 185
Pathogenesis of renal stones 186
Calcium stones 186
Hypercalciuria 186
Hyperoxaluria 187
Other factors in calcium stone formation 188
Infection-related stones 188
Uric acid stones 188
Cystine stones 188
Miscellaneous rarities 188
Investigation of stone formers 189
Treatment 189
Conclusion 190
Acknowledgement 190
Further reading 190
Appendix 9.1. Diagnosis of renal tubular acidosis 190
Urinary acidification test 190
Fractional excretion of bicarbonate 190
Chapter 10: Clinical biochemistry of nutrition 191
Introduction 191
Nutritional requirements 191
The ‘correct’ intake 191
Energy 192
Carbohydrate 192
Fat 193
Protein 194
Micronutrients 195
Vitamins 195
Fat-soluble vitamins 195
Vitamin A 195
Vitamin E 196
Vitamin K 197
Water-soluble vitamins 198
Thiamin 198
Riboflavin 198
Nicotinamide 199
Vitamin B6 199
Pantothenic acid 200
Biotin 200
Vitamin C 200
Other organic substances 200
Trace elements 201
Zinc 201
Copper 201
Selenium 202
Molybdenum 202
Manganese 202
Chromium 202
Fibre 203
Assessment of nutritional status 203
General 203
Clinical assessment 204
Dietary assessment 204
Anthropometric measurements 204
Height and weight 204
Circumference measurements 205
Skinfold thickness 205
Functional assessment 205
Hepatic secretory proteins 205
The immune response 206
Laboratory-based assessment of individual nutrients 206
Energy 206
Protein 207
Vitamins 207
Vitamin A 208
Vitamin D 208
Vitamin E 208
Vitamin K 208
Thiamin 208
Riboflavin 208
Nicotinamide 209
Vitamin
209
Pantothenic acid 209
Biotin 209
Vitamin C 209
Trace elements 209
Zinc 209
Copper 209
Selenium 210
Molybdenum 210
Manganese 210
Chromium 210
Conclusion 210
Acknowledgement 210
Further reading 210
Chapter 11: Nutritional disorders and their management 211
Introduction 211
Malnutrition 211
Protein–energy malnutrition in children 212
Chronic energy deficiency in Western adults 212
Obesity 212
Aetiology of obesity 213
Secondary causes of obesity 214
Appetite 214
Central appetite control 214
The hypothalamus 214
The brain stem 214
Hypothalamic messengers 214
Neuropeptide Y 214
Agouti-related protein 214
Melanocortins 214
Cocaine- and amfetamine-regulated transcript 215
5-Hydroxytryptamine 215
Peripheral signals of appetite 215
Gastric emptying and stretching 215
Hormones 215
Insulin 215
Cholecystokinin 215
Peptide YY 215
Pancreatic polypeptide (PP) 215
Leptin 215
Ghrelin 216
Glucagon-like peptide-1 216
Management of obesity 216
Non-surgical options 216
Bariatric surgery 216
Restrictive procedures 217
Combined restrictive and malabsorptive procedures 217
Eating disorders 218
Anorexia nervosa 218
Bulimia nervosa 219
Diet in the aetiology of disease 219
Dental caries 219
Cancer 219
Therapeutic diets, dietary supplements and nutraceuticals 219
Provision of nutrition support 220
Indications for nutrition support 220
Enteral feeding 221
Parenteral nutrition 222
Composition of parenteral nutrition fluids 222
Complications of parenteral nutritional support 222
Short bowel syndrome 224
Conclusion 224
Acknowledgement 224
Further reading 224
Chapter 12: Clinical biochemistry of the gastrointestinal tract 225
Introduction 225
Mouth and oesophagus 226
Stomach 226
Helicobacter pylori 226
Diagnosis of H. pylori infection 227
Gastric acid secretion 227
Gastrin 227
Intrinsic factor 228
Pancreas 228
Pancreatic function tests 228
Direct or invasive function tests 228
Non-invasive pancreatic function testing 228
Serum enzymes 228
Faecal tests 229
Small bowel bacterial overgrowth 229
The normal intestinal microflora 229
Definition, causes and symptoms of small bowel bacterial overgrowth 230
Diagnosis of small bowel bacterial overgrowth 230
Maldigestion and malabsorption 230
Clinical features 230
Carbohydrate absorption 231
Dietary carbohydrates 231
Digestion of carbohydrates 232
Luminal events in carbohydrate digestion 232
Enterocyte events in carbohydrate digestion 232
Clinical aspects of carbohydrate absorption 233
Lactase deficiency 233
Investigation of carbohydrate absorption 233
Xylose absorption test 233
Lactose tolerance test 233
Differential tests of intestinal disaccharide hydrolysis 233
Protein absorption 233
Digestion of proteins 234
Clinical aspects of protein absorption 234
Investigation of protein absorption 235
Fat absorption 235
Digestion of triacylglycerols 235
Luminal digestion 235
Absorption of triacylglycerols 235
Digestion and absorption of other fats 235
Clinical aspects of fat malabsorption 235
Investigation of fat absorption 236
Faecal fat excretion 236
13/14 C-triolein breath test 236
Intestinal permeability 236
Faecal tests of intestinal inflammation 236
Calprotectin 236
Calprotectin in disease 236
Inflammatory bowel disease 236
Colorectal cancer 237
Irritable bowel syndrome 237
Neuroendocrine tumours of the gastrointestinal tract and pancreas (NETs) 237
Intestinal carcinoid tumours and the carcinoid syndrome 237
The carcinoid syndrome 237
Pancreatic endocrine tumours 237
Insulinomas 238
Glucagonoma 238
VIPoma 238
Somatostatinoma 238
The acute abdomen 238
Introduction 238
Acute pancreatitis 239
Amylase 239
Lipase 240
Choice of test for pancreatitis 240
Ectopic pregnancy 240
Acute porphyria 241
Further reading 241
Chapter 13: Assessment of hepatic function and investigation of jaundice 242
Introduction 242
Anatomy of the liver 243
The hepatic circulation 243
Macroscopic structure 243
Microscopic structure 243
The acinus 243
Ultrastructure 244
Bile, bile ducts and biliary drainage 245
Hepatic regeneration 245
Physiological functions 245
Carbohydrate metabolism 245
Lipid metabolism 245
Protein metabolism 246
Synthesis 246
Metabolism of amino acids and disposal of urea 246
Biotransformation and excretion 246
Bile secretion 247
Liver function tests 247
Bilirubin and bile pigment metabolism 248
The significance of hyperbilirubinaemia 249
Tests for quantitation of bilirubin and its conjugated and unconjugated fractions 250
Plasma enzyme activities 250
Alkaline phosphatase 250
Overcoming the lack of tissue specificity 251
The aminotransferases 251
The mitochondrial isoenzyme of AST (mAST) 252
Glutamyltransferase 252
Glutathione S-transferase (GST) 252
Plasma proteins 252
Albumin 253
Prothrombin time and coagulation factors 253
Fetoprotein 253
1 -Antitrypsin 253
Transferrin 253
Caeruloplasmin 254
Acute phase reactants 254
Immunoglobulins 254
Bile acids 254
Quantitative evaluation of liver function 254
Pharmacological basis and practical requirements of clearance tests 254
Other tests of liver function 255
Serum tests for hepatic fibrosis 255
Collagen metabolites 255
Hyaluronate 255
Tissue inhibitor of metalloproteinase 1 255
European liver fibrosis score (EF) 255
Uses of liver function tests 256
Differential diagnosis of jaundice 256
Pre-hepatic jaundice 256
Urinary bilirubin and urobilinogen 256
Hepatic (hepatocellular) jaundice 256
Post-hepatic (cholestatic) jaundice 256
Further investigation 256
The inherited hyperbilirubinaemias 256
Unconjugated types 257
Crigler–Najjar syndrome 257
Gilbert syndrome 257
Conjugated types 257
Dubin–Johnson syndrome 257
Rotor syndrome 257
Monitoring response to therapy 257
Neonatal jaundice 258
The neonatal hepatitis syndrome 258
Tests of bile duct patency 258
Abnormal liver function tests in asymptomatic patients 258
Bilirubin 258
Alkaline phosphatase 258
Aminotransferases 258
Glutamyltransferase 259
Normal liver function tests in the presence of overt liver disease 259
Role of liver function tests in assessing prognosis 259
Chronic liver disease 259
Acute liver failure 260
Conclusion 260
Further reading 260
Chapter 14: Acute and chronic liver disease 261
Classification of liver disease 261
Acute hepatitis and its sequelae 261
Differential diagnosis 262
Acute viral hepatitis 263
Outcome of acute viral hepatitis 263
Complete resolution 263
Progression to chronic liver disease 263
Progression to acute liver failure 263
Acute liver failure 264
Laboratory features 264
Laboratory criteria for liver transplantation 264
Chronic hepatitis 264
Differential diagnosis of chronic hepatitis 265
Viral hepatitis types B and C 265
Alcohol 266
Wilson disease 266
1 -Antitrypsin deficiency 266
Autoimmune hepatitis (AIH) 266
Monitoring response to therapy 267
Primary biliary cirrhosis (PBC) 267
Primary sclerosing cholangitis (PSC) 267
Alcoholic liver disease 268
Ethanol metabolism 268
Liver pathology in alcoholic liver disease 268
Biochemical abnormalities 268
Alcoholic steatosis 268
Alcoholic hepatitis 268
Alcoholism and haemochromatosis 268
Porphyria cutanea tarda 269
Use of laboratory tests in clinical practice 269
Alcohol and metabolites 269
Effects of alcohol on protein metabolism 269
Plasma enzymes 269
Non-alcoholic fatty liver disease (NAFD) 269
The concept of cirrhosis 270
Hepatic encephalopathy 270
Vascular disturbances in cirrhosis 270
Ascites 270
Monitoring treatment of ascites 271
Acute kidney injury 271
The hepatorenal syndrome (HRS) 272
Sex hormones and their binding proteins 272
Physiology and biochemistry 273
Changes in men with cirrhosis 273
Changes in liver function during pregnancy 273
Glucose intolerance 274
Drugs and the liver 274
Neoplastic disease of the liver and biliary tract 275
Hepatocellular carcinoma and a -fetoprotein 275
Parenteral nutrition 275
Bacterial infections 275
Inherited metabolic disorders involving the liver 276
Iron overload and hereditary haemochromatosis 276
Wilson disease 277
Diagnosis 277
Long-term management of hepatic Wilson disease 278
Indian childhood cirrhosis 279
1-Antitrypsin deficiency 279
The hepatic porphyrias 279
Cystic fibrosis 279
Other inherited metabolic diseases 280
Tyrosinaemia 280
Galactosaemia 280
Fructose intolerance 281
The sphingolipidoses and Niemann–Pick disease type C 281
Glycogen storage diseases 281
Liver transplantation 281
Preoperative assessment 282
The immediate postoperative period 282
Intermediate follow-up 282
Long-term monitoring 282
Conclusion 283
Further reading 283
Chapter 15: Glucose metabolism and the pathophysiology of diabetes mellitus 284
Physiology and pathophysiology of glucose homoeostasis 284
Introduction: the maintenance of normoglycaemia 284
Normal glucose metabolism 285
Glucose transporters 286
The fate of intracellular glucose and its role in diabetes 288
Insulin 289
Biosynthesis 289
Secretion and pharmacokinetics 290
Abnormalities of the synthesis and secretion of insulin 290
Actions of insulin 290
The insulin receptor 292
Second messengers mediating the effects of insulin 292
Insulin-like growth factors and their receptors 292
Classification and diagnosis of diabetes mellitus 293
Introduction 293
Definitions 293
Type 1 diabetes mellitus 294
Introduction 294
Aetiology: genetic susceptibility and possible environmental cofactors 295
Type 2 diabetes mellitus 297
Introduction: the heterogeneity of type 2 diabetes 297
Genetic factors in type 2 diabetes mellitus 298
Glucoregulatory defects in type 2 diabetes mellitus 298
Pancreatic ß -Cell deficiency/dysfunction in type 2 diabetes mellitus 298
Amylin 299
Insulin resistance in type 2 diabetes mellitus 299
Abnormalities of non-insulin-mediated glucose disposal in type 2 diabetes mellitus 300
Associations of type 2 diabetes mellitus 300
The metabolic syndrome and obesity 300
Hypertension 300
Dyslipidaemia 301
Lipotoxicity and glucotoxicity 301
Lipotoxicity 301
Glucotoxicity 302
Prevention studies in type 2 diabetes 302
The role of bariatric surgery in managing type 2 diabetes 302
Tropical diabetes 304
Alcohol-related and pancreatic causes of diabetes 304
Haemochromatosis 304
Endocrine disorders 304
Iatrogenic diabetes 305
Rare conditions associated with glucose intolerance 305
Severe insulin resistance 305
Anti-insulin antibodies 306
Cirrhosis 306
Gestational diabetes mellitus 302
Maturity onset diabetes of the young (MODY) 303
Secondary diabetes 304
Endocrine associations with diabetes 306
Diabetes, nutrition and growth 307
Mechanisms of diabetic tissue damage 307
Introduction 307
Pathogenesis 307
Other aspects of diabetic tissue damage 308
Conditions associated with inadequately controlled diabetes mellitus 309
Biochemical measurements in diabetes mellitus 310
Glucose measurements 310
Testing for ketones 310
Oral glucose tolerance test 311
Tests of recent glycaemic control 311
Screening for diabetes 312
Tests for insulin resistance 312
Research investigations 314
Hyperinsulinaemic clamps 314
Intravenous glucose tolerance testing 314
Measurement of ß-Cell function 314
Homoeostasis model assessment 314
Conclusion 314
Acknowledgement 314
Further reading 314
Chapter 16: The clinical management of diabetes mellitus 316
Introduction 316
General Aspects of Management 316
Nutrition 317
Exercise 317
Smoking cessation 318
Education about diabetes 318
Pharmacological management of cardiovascular risk 318
Aspirin 318
Lipid-lowering agents 319
Hypertension 319
Angiotensin-converting-enzyme inhibitors and angiotensin-II receptor antagonists 320
Glucose-owering Therapy in Diabetes 320
Background 320
Insulin use in type 1 diabetes 321
Regular insulin 321
Insulin analogues 321
Intermediate-acting insulin 321
Premixed insulin analogues 321
Long-acting insulin analogues 322
Insulin regimens 322
Continuous subcutaneous insulin infusion 322
Insulin administration 322
Glycaemic management in type 2 diabetes 324
Metformin 324
Mechanism of action 324
Lactic acidosis 324
Other unwanted effects of metformin 325
Sulfonylureas (and related insulin secretagogues) 325
Mechanism of action 325
Adverse effects of sulfonylureas 325
Other unwanted effects of sulfonylureas 326
Indications and clinical usage 326
Meglitinides 326
Adverse effects of meglitinides 326
Peroxisome proliferator activator . analogues 326
Mechanisms of action 326
Adverse effects 327
Glucagon-like peptide 1 analogues 327
Mechanisms of action 327
Adverse effects 328
Dipeptidyl peptidase IV inhibitors 328
Adverse effects of DPP-4 inhibitors 328
Alpha-glucosidase inhibitors 328
Sodium-glucose co-transporter 2 (SGT2) inhibitors 328
Insulin use in type 2 diabetes 328
Bariatric surgery 328
Pancreatic transplantation 329
Islet cell transplantation 329
Immunotherapy for type 1 diabetes 329
Obstacles to Achieving Glycaemic Control 329
Intensive control 330
Hypoglycaemia 330
Hypoglycaemia-associated autonomic failure 331
The Somogyi effect and the dawn phenomenon 331
Exercise 332
Ethanol 332
Intercurrent illness, ‘sick day rules’ and stress 332
Chronic Complications of Diabetes 333
Nephropathy 333
Microalbuminuria 333
Management 334
End-stage disease 334
Neuropathy 334
Chronic sensorimotor neuropathy 334
Autonomic neuropathy 335
Mononeuropathies 335
The feet in diabetes 335
Foot ulcers 335
Charcot foot 335
Eye disease 336
Other complications 337
Brittle diabetes 337
Type 4 renal tubular acidosis 337
Emergencies in diabetes 337
Diabetic ketoacidosis 337
Biochemical features 338
Management 338
General measures 338
Fluids 339
Insulin 339
Potassium, magnesium and phosphate 339
Bicarbonate 339
Cerebral oedema 340
Resolution 340
Hyperosmolar hyperglycaemic state 340
Presentation and clinical features 340
Management 340
Other metabolic acidoses 341
Alcoholic ketoacidosis 341
Management of Diabetes in the Hospital Setting 341
Pregnancy 342
Conclusion 343
Acknowledgement 343
Further reading 343
Chapter 17: Hypoglycaemia 344
Glucose homoeostasis in the fed and the postabsorptive states 344
Hypoglycaemia 345
The neuroendocrine response to hypoglycaemia 345
Symptoms of hypoglycaemia 346
Acute neuroglycopenia (neurogenic) 346
Subacute neuroglycopenia 346
Chronic neuroglycopenia 346
Classification of hypoglycaemic disorders 346
Practical approach to the investigation of hypoglycaemia 347
Evaluation of hypoglycaemia in persons without diabetes mellitus 347
Investigation of hypoglycaemia 347
Demonstration of hypoglycaemia 347
Measurement of blood glucose during spontaneous symptoms 347
Provocation tests 347
Prolonged fast test 347
Glucagon stimulation test 349
Mixed meal test 349
Identification of the cause of hypoglycaemia 349
Plasma insulin, C-peptide and proinsulin 349
Plasma ß-hydroxybutyrate ( ß-OHB) 350
Insulin antibodies 350
Screening for oral hypoglycaemic agents 350
Evaluation of hypoglycaemia in patients with diabetes mellitus 350
Definition 350
Pathophysiology and risk factors 351
Incidence 351
Management 352
Emergency treatment of hypoglycaemia 352
Causes of hypoglycaemia 352
Surreptitious administration of hypoglycaemic agents (factitious or felonious hypoglycaemia) 352
Islet cell tumours (insulinoma) 352
Clinical features 353
Diagnosis 353
ocalization 353
Treatment 353
Non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) 354
Non-islet cell tumour hypoglycaemia (NICTH) 354
Autoimmune hypoglycaemia 355
Hypoglycaemia associated with renal impairment 355
Hypoglycaemia associated with liver disease 356
Hypoglycaemia due to endocrine deficiencies 356
Drug-induced hypoglycaemia 357
Alcohol-induced hypoglycaemia 357
Hypoglycaemia due to deficient energy intake 358
Septicaemia 358
Exercise-related hypoglycaemia 358
Postprandial (reactive) hypoglycaemia 358
The postprandial syndrome 358
Inherited metabolic disease 359
Conclusion 359
Further reading 359
Chapter 18: Hypothalamic, pituitary and adrenal disorders 360
Introduction 360
Clinical anatomy of the pituitary and hypothalamus 361
Physiology of hypothalamo– pituitary–end organ axes 361
Clinical anatomy and physiology of the adrenals 363
Assessment of normal pituitary function 363
Basal hormonal investigations 363
Dynamic tests of ACTH–adrenal function 365
Insulin stress test 365
Short tetracosactide (synacthen, tetracosactrin, ACTH) test 365
Other tests 365
Cortisol normal ranges, borderline responses, assay precision and dynamic test reproducibility 366
Assessment of growth hormone reserve 366
Insulin stress test 366
Other pharmacological tests 367
Exercise testing 367
Assessment of physiological growth hormone secretion 367
Re-evaluation of GH status in young adults 367
Releasing hormone tests 367
Other tests of gonadotrophin secretion 367
Clomifene test 367
Assessment of luteinizing hormone pulsatility 368
Dynamic tests of posterior pituitary function 368
Water deprivation test 368
Hypertonic saline infusion 368
Summary 368
Outline protocol for the investigation of a patient with pituitary disease 368
1. Does this patient have undiagnosed hypoadrenalism? 369
2. Is the proven hypoadrenalism primary or secondary? 369
3. Has this patient with known pituitary disease developed ACTH deficiency? 369
4. Does this patient on pharmacological steroid treatment still have adrenal suppression or could they now stop treatment? 369
A clinical approach to assessment of the whole ACTH–adrenal axis 369
Monitoring of pituitary function in disease states 370
Reassessment after pituitary surgery 370
Monitoring after pituitary irradiation 370
Monitoring in other pituitary disease states 371
Other diagnostic techniques in pituitary disease 371
Clinical assessment 371
Pituitary imaging techniques 371
Pituitary hypersecretion states 371
Pituitary adenomas 371
Prolactinoma 371
Differential diagnosis of hyperprolactinaemia 371
Role of dynamic tests of PR secretion 372
Assessment of remaining pituitary function 372
Outline of presentation and management of prolactinoma 372
Monitoring the response to dopamine agonist therapy 373
Macroprolactinaemia 373
Hook effect 373
Acromegaly 373
Diagnosis of acromegaly 373
Basal GH and IGF-1 estimation 373
Glucose tolerance test 373
Other diagnostic tests 373
Outline of presentation and management of acromegaly 373
Monitoring the response to therapy 374
Low-dose dexamethasone suppression test 374
Overnight dexamethasone suppression test 375
Midnight salivary cortisol 375
Other tests 375
Diagnosis and differential diagnosis of Cushing syndrome 374
Clinical context of ACTH-dependent Cushing syndrome 375
Plasma cortisol and ACTH concentrations 376
High-dose dexamethasone suppression test 376
Corticotrophin releasing hormone test 376
Other tests 376
Petrosal sinus sampling for ACTH 376
Imaging 377
Outline of management 377
Reassessment after pituitary surgery 377
Thyroid stimulating hormone-secreting adenomas 377
Gonadotrophin-secreting adenomas 378
Hypothalamic and pituitary deficiency states 378
Diseases that may lead to generalized hypopituitarism 378
Non-functioning pituitary adenomas 378
Other pituitary and parasellar tumours 378
Inflammatory diseases and disorders of unknown aetiology 378
Other conditions 378
Growth hormone deficiency 378
Gonadotrophin deficiency 379
Interpretation of borderline testosterone concentrations 379
Delayed puberty 379
Hypothalamic amenorrhoea 380
Other isolated anterior pituitary deficiencies 380
Diabetes insipidus 380
Adrenal disease 380
Clinical features of Addison disease 380
Congenital adrenal hyperplasia 381
Assessment of adrenal incidentaloma 381
Monitoring pituitary and adrenal replacement therapy 381
Conclusion 382
Appendix 18.1 Test protocols 382
Assessment of basal pituitary function 382
Insulin stress test 382
Short tetracosactide (synacthen) test 383
Water deprivation test 383
Glucose tolerance test for the diagnosis of acromegaly 383
CRH test 383
Chapter 19: Thyroid dysfunction 384
Introduction 384
Normal thyroid physiology 385
The thyroid gland 385
Biological actions of thyroid hormones 385
Synthesis, storage and release of thyroid hormones 386
Iodine and thyroid hormone synthesis 387
Transport of thyroid hormones in blood 387
Free hormone hypothesis 387
Entry of thyroid hormone into tissues 388
Thyroid hormone deiodination and regulation of extrathyroidal T3 production 388
Catabolism of thyroid hormones 388
Nuclear action of thyroid hormones 388
Control of thyroid hormone synthesis and secretion 389
Classic feedback regulation 389
Other mechanisms 390
Extrathyroidal factors that may affect thyroid function 390
Age 390
Fetus 390
Neonate 390
Infancy and childhood 390
Elderly 390
Pregnancy 390
Non-thyroidal illness 391
Drugs 392
The evaluation of thyroid function 393
Clinical evaluation of thyroid status 393
In vitro tests of thyroid activity and pituitary–thyroid status 394
Measurement of thyroid stimulating hormone 394
Free T4 and free T3 measurements 394
Theoretical considerations 394
Methods for measuring free thyroid hormones 394
Equilibrium dialysis and ultrafiltration methods 394
Validity of commercial methods for free hormone analysis 394
Nomenclature of free thyroid hormone assays 395
Total T4 and total T3 395
Selective use of thyroid function tests 395
Interpreting results of thyroid function tests 396
Situations in which TSH usually provides the correct estimate of thyroid status 396
Overt primary hyperthyroidism 396
Overt primary hypothyroidism 396
Subclinical thyroid disease 396
Common situations in which TSH results may be misleading 396
Assay interference from endogenous heterophilic antibodies 396
Pregnancy 396
Secondary thyroid disorders 396
Reference ranges and significant changes 396
Miscellaneous tests 397
Thyrotrophin releasing hormone test 397
Thyroglobulin 397
Subunit 397
Autoantibodies to thyroidal antigens 397
Antibodies to thyroid peroxidase (TPOAb) 397
Antibodies to thyroglobulin (TgAb) 397
Antibodies to the thyroid stimulating hormone receptor 398
Antibodies and ophthalmopathy of Graves disease 398
Imaging the thyroid 398
Thyroid scintiscanning 398
Perchlorate discharge test 399
Hyperthyroidism 399
Clinical features 399
Cardiovascular system 399
Thyroid crisis 399
Gastrointestinal system 399
Central and peripheral nervous system 400
Locomotor system 400
Respiratory system 400
Skin and hair 400
The skeleton 400
The kidneys: mineral and water balance 400
Other endocrine systems 400
Hyperthyroidism in the elderly 400
Causes of hyperthyroidism 400
Graves disease 400
Thyroid involvement 401
Eyes 401
Skin 401
Diagnosis 401
Natural history 402
Treatment 402
Treatment of Graves ophthalmopathy 403
Toxic multinodular goitre 403
Clinical features 403
Diagnosis 403
Treatment 403
Toxic adenoma 403
Diagnosis 403
Treatment 403
Thyroid stimulating hormone-secreting pituitary tumour 403
Diagnosis 403
Treatment 404
Other causes of hyperthyroidism 404
Iodine 404
Amiodarone 404
Thyrotoxicosis factitia 404
Ectopic thyroid tissue 404
Other thyroid stimulators 405
Subclinical hyperthyroidism 405
Hyperthyroidism or non-thyroidal illness? 405
Hypothyroidism 405
Clinical features 405
Cardiovascular system 405
Gastrointestinal system 405
Central and peripheral nervous system 405
Locomotor system 406
Respiratory system 406
Skin and hair 406
The skeleton 406
The kidneys: mineral and water balance 406
Reproductive system 406
Other systems 406
Causes of hypothyroidism 407
Primary myxoedema 407
Post-surgery or post-radioiodine 407
Congenital hypothyroidism 407
Lithium treatment 408
Cytokine therapy 408
Iodine 408
Secondary hypothyroidism 408
Treatment of hypothyroidism 408
Myxoedema coma 408
Thyroid hormone replacement therapy 408
Subclinical hypothyroidism 409
Thyroiditis 409
Thyroiditis producing hyperthyroidism 409
Diagnosis and treatment 409
Hypothyroidism resulting from Hashimoto thyroiditis 410
Diagnosis 410
Other forms of thyroiditis 410
Hypothyroidism and the postpartum period 410
Neoplasia 410
Diagnosis 410
Treatment 411
Tumour markers 411
Syndromes of resistance to thyroid hormones 411
Screening 412
Acknowledgement 412
Further reading 412
Chapter 20: Metabolic response to stress 414
Introduction 414
The response to stress 414
Initiation of the stress response 414
Hypothalamo–pituitary–adrenal axis 415
Cortisol 416
Thyroid hormones 416
Sex hormones 416
Growth hormone 416
Adrenal medulla 416
Stress and the kidneys 417
Cytokines 417
Stress and inflammation 417
Catecholamines 418
Acute phase proteins 419
Coagulation factors 419
Shock 420
Care of the shocked patient 420
Definitions 420
Management 421
Immediate care 421
Organ support 421
Immunomodulation 422
Conclusion 422
Further reading 422
Chapter 21: Disorders of puberty and sex development 423
Introduction 423
Normal sex development 423
Normal pubertal development 425
Endocrinology of normal puberty 425
Physical signs of normal puberty 425
Disorders of sex development 427
Terminology of disorders of sex development 427
General principles of management 428
General examination of a newborn with suspected DSD 428
Evaluation of the external genitalia 428
Evaluation of the internal anatomy 429
Investigating the newborn with DSD 429
Investigating the adolescent with DSD 430
Steroid measurement and its interpretation 431
Anti-Müllerian hormone 431
Insulin-like factor 3 431
Inhibins 432
The human chorionic gonadotrophin (hCG) stimulation test 433
The role of the clinical geneticist 433
Classification of disorders of sex development 434
XX DSD 434
Disorders of androgen excess 434
XY DSD with low testosterone and low precursor concentrations 436
XY DSD with low testosterone and high steroid precursor concentrations 436
XY DSD with normal testosterone, normal precursor and low DHT concentrations 438
XY DSD with normal testosterone, normal precursor and normal DHT concentrations 438
Disorders of puberty 439
Precocious puberty 439
Gonadotrophin dependent puberty (central causes) 439
Variants of early puberty 440
Delayed puberty 440
Delayed growth and puberty 441
Hypogonadotrophic hypogonadism 441
Primary hypogonadism 442
Further reading 442
Disorders of sex development 442
Puberty 442
Chapter 22: Reproductive function in the female 444
Introduction 444
Physiology 444
The ovaries 444
Plasma concentrations of reproductive hormones 446
Uterine changes 447
Conception 447
Hormones regulating reproductive function 447
Follicle stimulating hormone 447
Luteinizing hormone 447
Human chorionic gonadotrophin 447
Inhibin and activin 447
Prolactin 448
Anti-müllerian hormone 448
Reproductive steroid hormones 448
Structure 448
Biosynthetic enzymes 448
Steroid secretion through the menstrual cycle 449
Steroid hormone transport and metabolism 449
Actions of gonadal steroid hormones 450
Oestrogens 450
Progestogens 450
Androgens 450
Oligo- and amenorrhoea 450
Infertility 451
Hirsutism and virilism 452
Pregnancy 453
Introduction 453
Biochemical diagnosis of pregnancy 453
Human chorionic gonadotrophin 453
Diagnosis of ectopic pregnancy 453
Biochemical monitoring of pregnancy 454
Spontaneous abortion 454
Biochemical screening 454
Ultrasound 454
Current screening practice 454
Screening for fetal malformation 454
Fetal tissue sampling techniques 455
Chorionic villus sampling 455
Amniocentesis 455
Cordocentesis 456
Monitoring of maternal and fetal well-being 456
Intrapartum fetal monitoring 456
Biochemical changes during pregnancy 456
Plasma proteins 457
Plasma lipids and lipoproteins 457
Glucose tolerance 457
Other changes 457
Labour 457
Oral contraception and hormone replacement therapy 458
Introduction 458
Metabolic effects of oestrogens 459
Metabolic effects of progestogens 459
Metabolic effects of contraceptives 459
Effects of hormonal contraceptives on lipid metabolism and risk of vascular disease 459
Effects of oral contraceptives on glucose homoeostasis and diabetes 459
Other metabolic effects of oral contraceptives 460
Metabolic effects of injectable contraceptives 460
Hormone replacement therapy 460
Metabolic effects of the menopause 460
Metabolic effects of HRT 460
Adverse consequences of hormone replacement therapy 460
Hormone replacement therapy and heart disease 460
Hormone replacement therapy and osteoporosis 461
Acknowledgement 461
Further reading 461
Appendix 22.1 Acth stimulation test for the diagnosis of congenital adrenal hyperplasia 461
References 461
Chapter 23: Reproductive function in the male 462
Introduction 462
The testes 462
Production and actions of testosterone 462
Hypothalamo–pituitary control of testicular function 463
Testicular malignancy 464
Endocrine disrupting chemicals 464
Evaluation of testicular function 465
Semen analysis 465
Endocrine evaluation: hypothalamo–pituitary–gonadal axis 465
Male hypogonadism 466
Clinical features 466
Primary hypogonadism 466
Genetic causes 466
Cryptorchidism 466
Secondary hypogonadism 466
Congenital causes 466
Acquired causes 467
Defective hormone synthesis and hormone receptor defects 467
5a-Reductase deficiency 467
Androgen insensitivity syndromes 467
Treatment of hypogonadism 467
Gynaecomastia 468
Causes of gynaecomastia 468
Investigation 469
Impotence 469
Investigation 469
Treatment of erectile impotence 470
Appendix 23.1: Protocols for endocrine investigations 471
(i)
471
Reference 471
(ii)
471
Reference 471
(iii)
471
Reference 471
Chapter 24: Inherited metabolic disease 472
Introduction 472
Clinical presentation and pathophysiology 472
Neonatal presentation 473
Defects in synthesis and breakdown 473
Intoxications 473
Energy deficiency disorders 474
Seizure disorders 474
Presentation at weaning 475
Presentation in later infancy 475
Presentation at puberty 475
Presentation during adulthood 476
Presentation during pregnancy 476
Presentation postpartum 477
Newborn screening 477
Inheritance 477
Autosomal recessive inheritance 477
Autosomal dominant inheritance 478
X-linked inheritance 478
Mitochondrial inheritance 478
Diagnostic strategies 479
Essential laboratory investigations 480
Blood gas analysis 480
Blood glucose 480
Plasma ammonia 481
Liver function tests 481
Measurement of ketones 481
Urinary reducing substances 481
Second-line investigations 483
Plasma and urinary amino acids 483
Urinary organic acids 483
Urinary orotic acid 484
Blood acylcarnitines 484
Blood lactate and pyruvate 484
Urinary glycosaminoglycans 485
Plasma very long chain fatty acids 485
Functional and loading tests 485
Diagnostic fast 485
Allopurinol loading test 486
Confirmatory investigations 486
Enzyme analysis: general principles 486
Red cell galactose 1-phosphate uridyltransferase 486
Lysosomal enzyme screening 486
Complementation studies 486
Genetic mutation analysis 487
Prenatal diagnosis 487
Management 487
Strategies to replace a missing product 487
Supply of precursor 487
Replacement of product 488
Synthetic analogues 489
Alternate product 489
Inhibition of product breakdown 489
Enzyme replacement therapy 489
Cofactor supplementation 490
Organ transplantation 490
Gene therapy 492
Other molecular therapies 492
Strategies to reduce the formation of toxic metabolites 492
Reduction of metabolic load 492
Blockage of formation of toxic metabolites 492
Blockage of site of action of toxic metabolites 493
Strategies to remove toxic substances 493
Drugs 493
Dialysis and haemofiltration 494
Additional treatments 494
Substrate depletion 494
Substrate deprivation 494
Conclusion 494
Chapter 25: Paediatric clinical biochemistry 495
Introduction 495
Postnatal investigation of the small for gestational age newborn 495
Intrauterine infections 495
Maternal drug abuse 496
Respiratory disorders 496
Respiratory distress 496
Management of respiratory distress 497
Apnoea of prematurity 497
Renal function 497
Hyponatraemia 498
Hypernatraemia 498
Hydrogen ions 499
Interpretation of renal function tests 499
Carbohydrate metabolism 499
Neonatal hypoglycaemia 500
Calcium and phosphorus metabolism 501
Disorders of calcium and phosphorus metabolism 501
Hypercalcaemia 501
Hypocalcaemia 502
Osteopenia of prematurity 502
Rickets during childhood 503
Plasma alkaline phosphatase activity in infancy 503
Disorders of liver function 504
Bilirubin metabolism 504
Unconjugated hyperbilirubinaemia: physiological jaundice 504
Unconjugated hyperbilirubinaemia: pathological causes 505
Inherited disorders of bilirubin metabolism presenting in childhood 505
Conjugated hyperbilirubinaemia and hepatocellular disease 505
Liver disease in older children 506
Wilson disease 507
Reye syndrome or Reye-like illness 507
Internet resources [All Accessed October 2013] 507
Further reading 507
Chapter 26: Introduction to haematology and transfusion science 508
Introduction 508
General Haematology 508
Analysis of the full blood count 508
Haemoglobin 509
Cell counting 509
Red cell indices 509
Mean cell volume 509
Mean cell haemoglobin 509
Mean cell haemoglobin concentration 509
White cell differential 509
Platelet count 510
Erythrocyte sedimentation rate (ESR) 510
Plasma viscosity 510
Reticulocyte count 510
Erythrocyte sedimentation rate and plasma viscosity 510
Flow cytometry 510
Haematinic studies 511
Haemoglobinopathy screening 511
Tests for infectious mononucleosis 511
Morphology 512
Blood film examination 512
Normal red cell morphology 512
Morphology of the anaemias 512
Iron deficiency anaemia 512
Megaloblastic anaemia 512
Autoimmune haemolytic anaemia 512
Microangiopathic haemolytic anaemia 512
Malaria 514
Normal white cell morphology 514
Abnormal white cell morphology 515
Haematological malignancies 515
Acute leukaemia 515
Chronic leukaemia 516
Chronic myeloid leukaemia 516
Chronic lymphoid leukaemias 516
Myeloproliferative neoplasms 517
Myelodysplasia 517
Non-Hodgkin lymphoma 517
Haemostasis 518
Introduction 518
The coagulation cascade 518
Laboratory tests of coagulation 518
Prothrombin time 519
Activated partial thromboplastin time 519
Fibrinogen and thrombin time 519
D-dimer concentration 519
Specific factor assays 520
Interpretation of coagulation tests 520
Haemophilia 520
Disseminated intravascular coagulation 520
Blood Transfusion 521
Introduction 521
Blood group antigens 521
ABO blood group 521
Rh blood group 521
Other important blood groups and antibodies 521
Laboratory transfusion tests 522
Blood grouping and antibody screen 522
ABO and D grouping 522
Antibody screening 522
Antibody identification panels 522
Crossmatching (compatibility testing) 522
Electronic crossmatch 522
Immediate spin crossmatch 523
Full crossmatch 523
Investigation of suspected transfusion reaction 523
Haemolytic disease of the newborn 523
Blood products 524
Red cells 524
Platelets 524
Fresh frozen plasma 524
Cryoprecipitate 524
Factor concentrates 524
Risks of transfusion 524
Regulations 525
Conclusion 525
Acknowledgements 525
Further reading 525
Chapter 27: Biochemical aspects of anaemia 526
Introduction 526
The formation, structure and function of the normal red cell 526
Formation 526
Structure of the red cell 527
Function of the red cell 528
Anaemia 528
Anaemias associated with a reduction in red cell production 528
Iron deficiency anaemia 528
Iron physiology 528
Iron requirements 530
Iron absorption 530
Iron transport and storage 530
Causes of iron deficiency anaemia 530
Clinical consequences of iron deficiency 531
Laboratory determination of iron status 531
Red cell parameters 531
Hypochromic red cells 531
Serum iron 531
Serum ferritin 531
Serum iron binding capacity, transferrin and transferrin saturation 531
Serum transferrin receptor 531
Hepcidin 531
Bone marrow aspiration 531
The megaloblastic anaemias resulting from vitamin B12 and folate deficiency 531
Folate metabolism 532
Folate requirements 532
Absorption of folate 532
Causes of folate deficiency 532
Features of folate deficiency 532
Laboratory determination of folate status 532
Vitamin B12
532
Structure of vitamin B12 532
Source of vitamin B12 532
Vitamin B12 requirements 532
Absorption of vitamin B12 532
Causes of vitamin B12 deficiency 534
Features of vitamin B12 deficiency 534
Laboratory determination of vitamin B12 status 534
Serum vitamin B12 534
Serum methylmalonate and homocysteine 535
Deoxyuridine suppression test 535
Antibody tests 535
Schilling test 535
Anaemias due to reduction in red cell production: inherited causes 535
Anaemias associated with reduction in red cell production: acquired causes 535
Anaemia of chronic disease 535
Aplastic anaemia 535
Myelodysplasia 535
Malignant infiltration of the bone marrow 535
Anaemias associated with increased red cell loss 535
Bleeding 535
Haemolysis 535
Laboratory features of haemolysis 536
Causes of haemolytic anaemias 536
Inherited haemolytic anaemia 536
Membrane defects 536
Enzyme defects 537
Disorders of the pentose phosphate pathway and related enzymes of glutathione metabolism 537
Disorders of anaerobic glycolysis 539
Disorders of nucleotide metabolism 539
Acquired haemolytic anaemias 539
Immune haemolytic anaemias 539
Non-immune haemolytic anaemias 539
Infections 539
Traumatic and microangiopathic disorders 539
Acquired disorders of the red cell membrane 540
Diagnosis of haemolysis 540
Clinical evidence 540
Laboratory investigations 540
Laboratory investigations for the presence of haemolysis 540
Red cell morphology 540
Total and unconjugated bilirubin 540
Haptoglobin 540
Haemopexin 541
Methaemalbumin 541
Free haemoglobin 541
Haemosiderinuria 541
Red cell survival 541
Laboratory investigations for the cause of haemolysis 541
Coombs test (direct antiglobulin test) 541
Tests for abnormal haemoglobin 541
Osmotic fragility tests 541
The autohaemolysis test 541
Flow cytometry 542
Tests for enzyme deficiencies 542
Glucose 6-phosphate dehydrogenase 542
Pyrimidine 5'-nucleotidase 542
Red cell metabolites 542
Glycolytic intermediates 542
Conclusion 543
Acknowledgements 543
Further reading 543
Chapter 28: The porphyrias: inherited disorders of haem synthesis 544
Introduction and overview 544
Biochemistry of haem synthesis 544
Overview of the porphyrias 545
Molecular genetics of the porphyrias 545
Porphyrias presenting with acute attacks 549
The autosomal dominant acute porphyrias 549
Pathophysiology of acute attacks 549
Clinical presentation of acute attacks 549
Chronic complications 550
Diagnosis of acute porphyria 550
Management of an acute attack 550
Supportive treatment 550
Specific treatment 551
Preventing acute attacks 551
Severely affected patients 551
Managing asymptomatic relatives of patients 552
Family studies 552
Safe prescribing 552
Specific situations 553
Pregnancy 553
Anaesthesia 553
Rare forms of acute porphyria 553
AA dehydratase deficiency porphyria 553
Homozygous acute porphyrias 553
The cutaneous porphyrias 553
Bullous porphyrias 553
Pathophysiology of skin lesions 554
Skin symptoms and signs 554
Biochemical features and diagnostic approach 554
Individual disorders 555
Porphyria cutanea tarda 555
Hepatoerythropoietic porphyria 556
Congenital erythropoietic porphyria 556
Erythropoietic protoporphyria and X-linked dominant protoporphyria 557
Skin symptoms and signs 557
Treatment 558
Chronic complications and their management 558
Secondary disorders of porphyrin metabolism 558
Conclusion 559
Further reading 559
Internet resources 560
Chapter 29: The haemoglobinopathies 561
Introduction 561
The structure and function of haemoglobin 561
The genetic control of haemoglobin synthesis 562
The thalassaemias 563
a Thalassaemia 563
ß Thalassaemia 564
Structural haemoglobin variants 565
Sickle cell anaemia 566
Other structural haemoglobin variants 567
Laboratory diagnosis of haemoglobinopathies 568
Conclusion 570
Further reading 570
Chapter 30: Immunology for clinical biochemists 571
The immune system 571
Introduction 571
Immune responses 571
Antigens 572
Clonality 572
The innate immune system 572
The adaptive immune system 573
Lymphoid tissue 573
Cells 573
Neutrophils 575
Basophils and eosinophils 576
Monocytes 577
Lymphocytes 577
Antigen recognition 577
Immunoglobulins 577
T cell receptors 580
Human leukocyte antigens (HA) 580
Antigen presentation 581
Cellular immune activation 581
Complement 581
The complement system 581
Activation via the alternative pathway 581
Activation via the classical pathway 581
Activation via the lectin pathway 581
Regulation of the complement pathways 581
Acute phase proteins 582
Cytokines 583
Inflammatory cytokines 585
Mechanisms of immunological damage 585
Type I hypersensitivity 585
Type II hypersensitivity 586
Type III hypersensitivity 586
Type IV hypersensitivity 586
Conclusion 586
Diseases of the immune system 586
Introduction 586
Immune deficiency 586
Development of immunity in humans 586
Infection and immune deficiency 587
Investigation of patients with suspected immune deficiency 587
Primary immunodeficiencies 588
B ymphocyte (humoral) system 588
IgA deficiency 588
Common variable immunodeficiency (CVID) 588
X-linked agammaglobulinaemia 589
T ymphocyte (cell-mediated immunity) system 589
Severe combined immunodeficiencies (SCID) 589
DiGeorge syndrome 589
X-linked hyper-IgM syndrome/CD40 ligand deficiency 589
Phagocytic (polymorphonuclear and mononuclear) system 590
Chronic granulomatous disease 590
Leukocyte adhesion defect types I and II 590
Complement system 590
C1 Esterase inhibitor deficiency 590
Transient hypogammaglobulinaemia of infancy 590
Secondary immune deficiency 590
Protein loss 590
Splenectomy 591
Allergies 591
Investigation of patients with allergies 591
Anaphylaxis 592
The investigation of anaphylaxis 593
Autoimmune diseases 593
Autoimmune endocrine diseases 594
Thyroid 594
Pancreas 594
Adrenals 594
Autoimmune polyendocrine syndromes (APS) 594
Autoimmune diseases of the gut 594
Autoimmune liver diseases 595
Autoimmune skin diseases 596
Autoimmune kidney diseases 596
Autoimmune articular diseases 596
Rheumatoid arthritis (RA) 596
Other connective tissue diseases 598
Antinuclear antibodies 598
Antibodies to double-stranded DNA 598
Antibodies to extractable nuclear antigens 598
Antinuclear antibodies in pregnancy 598
Antiphospholipid antibodies 598
Lymphoid malignancies 599
B lymphocytes and monoclonal proteins 599
Clinical significance of monoclonal proteins 599
Prevalence of monoclonal proteins 600
Laboratory investigation of paraproteins 600
Identification of paraproteins 600
Typing of monoclonal immunoglobulins in serum and urine 602
Immunofixation 602
Quantitation of monoclonal components 603
Cryoproteins 604
2 -Microglobulin 605
B cell malignancies 605
Myeloma 605
Solitary plasmacytoma 606
Waldenström macroglobulinaemia 606
Lymphomas, chronic lymphocytic leukaemia and heavy chain diseases 606
Monoclonal gammopathy of unknown significance (MGUS) 607
Transient paraproteinaemia 607
Serum free light chains (SFC) 607
Amyloidosis 607
Infection and sepsis 608
Diagnosis and monitoring of infections 609
C-reactive protein and markers of the acute phase response 609
Transplantation 610
Organ transplantation 610
Stem cell transplantation 611
Conclusion 611
Further reading 612
Appendix 30.1: Immunological investigations 613
Quantification of total immunoglobulin concentrations 613
IgG subclasses 613
Quantification of specific antibody responses 613
Quantification of IgE 613
Complement 613
Enumeration of cell numbers 613
Functional assays 613
Neutrophil function tests 614
Autoantibodies 614
Chapter 31: Metabolic bone disease 615
Bone biology 615
Anatomy of bone 615
Macroscopic 615
Microscopic 615
Bone matrix proteins 616
Collagen 616
Non-collagenous proteins 617
Osteocalcin 617
Other bone proteins 617
Cellular elements of bone 618
Osteoblasts 618
Osteocytes 618
Osteoclasts 619
Bone remodelling and its regulation 619
Biochemical markers of bone turnover 620
Markers of bone formation 620
Alkaline phosphatase 620
Osteocalcin 621
Procollagen 1 extension peptides 622
Markers of bone resorption 622
Hydroxyproline 622
Glycosylated hydroxylysine 622
Collagen cross-links 622
Collagen telopeptides 623
Tartrate-resistant acid phosphatase 624
New markers 624
Variation in bone turnover markers 624
Osteoporosis 624
Causes of osteoporosis 625
Investigation and diagnosis 626
Clinical risk factors for fracture 626
Bone densitometry 626
Biochemical investigation 627
Other investigations 628
Treatment 628
Lifestyle modifications 628
Calcium and vitamin D 628
Pharmacological management 628
Bisphosphonates 628
Hormone replacement therapy 629
Selective oestrogen receptor modulators 629
Parathyroid hormone 629
Other pharmacological treatments 629
Biochemical responses to treatments 630
Osteomalacia 631
Calciopenic osteomalacia 631
Vitamin D deficiency 631
Defects in 1,25-dihydroxyvitamin D synthesis or action 632
Laboratory investigation 632
Responses to therapy 633
Phosphopenic osteomalacia 633
Laboratory investigation 634
Treatment 634
Hypophosphatasia 634
Osteomalacia and acidosis 634
Defective osteoblast function and osteomalacia 634
Chronic kidney disease – mineral and bone disorder 635
Aetiology 635
Parathyroid hormone–calcitriol–FGF23 axis 635
Aluminium retention 636
Calcium 636
Phosphate 637
Parathyroid hormone 637
FGF23 637
Alkaline phosphatase 637
Other markers of bone turnover 637
Aluminium 637
Radiology, scintigraphy and densitometry 638
Bone histology 638
Clinical features 636
Investigations 636
Treatment 638
Hyperparathyroidism 638
Vitamin D derivatives 638
Phosphate metabolism 638
Parathyroidectomy 638
Calcimimetic agents 639
Aluminium toxicity 639
Bone disease after renal transplantation 639
Bone disease in primary hyperparathyroidism 639
Clinical, biochemical and histological features 639
Treatment 640
Paget disease of bone 640
Epidemiology 640
Aetiology 640
Natural history 640
Pathology 641
Clinical features 641
Investigations 641
Radiology 641
Biochemical tests 641
Bone turnover markers 641
Plasma and urinary calcium 642
Responses to treatment 642
Bone turnover and bone disease in children 643
Genetic bone diseases 643
Osteogenesis imperfecta 643
High bone mass 645
Osteopetrosis 645
Progressive diaphyseal dysplasia 645
Familial or idiopathic hyperphosphatasia (juvenile Paget disease) 645
Other disorders 645
Familial expansile osteolysis and related disorders 645
Fibrogenesis imperfecta ossium 645
Polyostotic fibrous dysplasia 645
Conclusion 645
Further reading 646
Appendix 31.1:
646
Appendix 31.2:
646
Chapter 32: Biochemistry of articular disorders 647
Introduction 647
The articular system 647
Disorders of the articular system 648
Osteoarthritis (OA) 648
Inflammatory arthritis 648
The connective tissue diseases 649
Aches and pains 649
Crystal arthritis 650
Hyperuricaemia and gout 650
Asymptomatic hyperuricaemia 651
Acute gout 651
Chronic tophaceous gout 652
Diagnosis 652
Treatment 652
Calcium pyrophosphate deposition (CPPD) 653
Basic calcium phosphate deposition disease 653
Other crystals found in synovial fluid 654
Articular involvement in Endocrine and Metabolic diseases 654
Diabetes mellitus 654
Other endocrine disorders 654
Haemochromatosis 654
Alkaptonuria 654
Laboratory testing in articular disease 654
Anaemia in rheumatoid arthritis 654
The acute phase response 655
Examination of synovial fluid 655
Rheumatoid factor 655
Other autoantibody tests 655
Conclusion 656
Further reading 656
Chapter 33: Muscle disease 657
Introduction 657
Functional anatomy and physiology of muscle 657
Diseases of muscle and their investigation 661
Biochemical investigation of muscle disease 662
Routine’ biochemical studies 662
Plasma creatine kinase activity 662
Statin induced elevation of creatine kinase 664
Other enzymes measurable in plasma 664
Myoglobinuria 664
Investigation of muscle disease 664
Non-metabolic, genetically determined myopathies 664
Metabolic, genetically determined myopathies 665
Disorders of carbohydrate metabolism 665
Dynamic/functional tests 665
Histocytochemistry 665
Biochemical investigations 665
Defects of the respiratory chain 666
Dynamic/functional tests in blood 666
Histocytochemistry 666
Biochemical investigations 666
Measurement of mitochondrial oxidations 666
Measurement of activity of individual respiratory chain complexes 667
Molecular biology techniques 667
Defects of fatty acid oxidation 667
Dynamic/functional tests 668
Intermediary metabolites and metabolic fuels in blood. 668
Measurement of plasma, tissue and urine carnitine concentrations 668
Measurement of dicarboxylic acids and acylglycines in urine 668
Specific biochemical investigation 668
Measurement of flux through ß -oxidation 668
Measurement of carnitine transport and enzyme activity 668
Conclusion 670
Acknowledgements 670
Further reading 670
Appendix 33.1:
670
Chapter 34: Investigation of cerebrospinal fluid 671
Introduction 671
Cerebrospinal fluid physiology 672
Formation 672
Composition 672
Analysis of cisternal or ventricular fluid 672
Investigations relevant to physiology and pathophysiology 672
Sampling and pressure 672
Appearance 672
Cells 672
Glucose 673
Lactate 673
Proteins 673
Assessment of blood–brain barrier permeability and reduced fluid flow 675
Intrathecal immunoglobulin synthesis 675
Cerebrospinal fluid protein index 675
Oligoclonal bands 675
Brain-specific proteins 676
Cerebrospinal fluid oto- and rhinorrhoea 677
Haem pigments and ferritin 677
Examination of CSF for haem and bilirubin 678
Neopterin 678
ß2-Microglobulin ( ß2M) 678
C-reactive protein (CRP) 678
Enzymes in CSF 678
Markers of inflammation 678
Non-biochemical investigations 679
Biochemical investigations in CNS disorders 680
Acute infections 680
Chronic infections 680
Haemorrhage and obstruction 681
Inherited metabolic diseases 681
Malignancy 681
Dementia 681
Cerebrospinal fluid analysis in demyelinating diseases 682
Conclusion 682
Acknowledgement 683
Further reading 683
Chapter 35: Biochemical aspects of psychiatric disorders 684
Introduction: psychiatry as a clinical discipline 684
Investigations in psychiatry 685
The classification of psychiatric disorders 685
The aetiology of psychiatric disorders 686
Biochemical investigations in psychiatric disorders 686
Psychiatric manifestations of organic disease 687
Acute confusional state (delirium) 687
Anxiety 687
Dementia 688
Depression 689
Introduction 689
Depression and thyroid function 689
Depression and adrenal function 689
Depression in the metabolic syndrome and diabetes 690
Post-traumatic stress disorder 690
Schizophrenia 690
Endocrine and metabolic manifestations of psychiatric disease 691
Abnormalities of the hypothalamo–pituitary–adrenal axis 691
Abnormalities of the hypothalamo– pituitary–thyroid axis 691
Abnormalities of the hypothalamo–pituitary–gonadal axis 691
Abnormalities of growth hormone secretion 692
Abnormalities of prolactin secretion 692
Other metabolic abnormalities 692
Metabolic complications of psychotropic drugs 692
Lithium 692
Drugs causing hyperprolactinaemia 692
Drugs causing hyponatraemia 692
Drugs causing hyperglycaemia and hyperlipidaemia 693
Drugs interfering with hepatic function 693
Future developments 693
Conclusion 693
Further reading 693
Chapter 36: Biochemical aspects of neurological disease 694
Introduction 694
Encephalopathy 694
Toxic and metabolic encephalopathy 696
Carbon monoxide 696
Alcohol 696
Opioids 696
Thiamin (vitamin B1) deficiency 697
Vitamin B12 deficiency 697
Liver failure 697
Chronic kidney disease and established renal failure 697
Respiratory failure 697
Cardiorespiratory failure 698
Disorders of glucose metabolism 698
Hyponatremia 698
Hypernatraemia 698
Hypercalaemia 698
Septic encephalopathy 698
Autoimmune encephalopathy 699
Dementia 699
Spinal cord disorders 699
Vitamin B12 deficiency (subacute combined degeneration of the spinal cord) 699
Folate deficiency 700
Copper deficiency 700
Vitamin E deficiency 700
Hepatic myelopathy 700
Hexosaminidase A deficiency 700
Adrenomyeloneuropathy 700
Peripheral neuropathy 700
Small fibre painful axonal neuropathy 702
Diabetic neuropathies 702
Symmetrical polyneuropathies 702
Focal and multifocal neuropathies 702
Pathophysiology of diabetic neuropathy 702
Polyol pathway 702
Non-enzymatic glycation 703
Oxidative stress 703
Immune mediated neuropathies 703
Acute inflammatory neuropathies and variants 703
Chronic inflammatory demyelinating polyneuropathies and variants including paraproteinaemic neuropathies 703
Monoclonal gammopathy of unknown significance 703
Multiple myeloma 703
Waldenström macroglobulinaemia 704
POEMS syndrome 704
Chronic kidney disease and established renal failure 704
Liver disease 704
Endocrine disturbances 704
Hypothyroidism 704
Hyperthyroidism 704
Acromegaly 704
Nutritional peripheral neuropathies 704
Vitamin
704
Thiamin (vitamin B1) deficiency 705
Vitamin B6 (pyridoxine) deficiency 705
Vitamin E deficiency 705
Niacin (vitamin B3), pantothenic acid (vitamin B5) and folic acid deficiencies 705
Chronic hypophosphataemia 705
Copper deficiency 705
Neuropathy associated with bariatric surgery 705
Strachan syndrome 705
Metabolic neuropathies 705
Refsum disease (heredopathica atactica polyneuritiformis) 705
Porphyric neuropathy 706
Fabry disease (angiokeratoma corporis diffusum a -galactosidase deficiency)
Cerebrotendinous xanthomatosis (cholestanolosis) 706
Tangier disease 707
Amyloidosis 707
Mitochondrial disorders 707
Paraneoplastic neuropathies 707
Movement disorders 708
Parkinsonism 708
Tremor 709
Dystonia 709
DYT1 dystonia (Oppenheim dystonia) 709
Dopa-responsive dystonia (DRD) 709
Wilson disease 709
Chorea 710
Myoclonus 710
Tics 710
Ataxia 710
Friedreich ataxia 710
Ataxia with isolated vitamin E deficiency 710
Abetalipoproteinemia 711
Ataxia telangiectasia 711
Early onset ataxia with oculomotor apraxia and hypoalbuminemia 711
Fragile X-associated tremor/ataxia syndrome 711
Hexosaminidase deficiency (GM2 gangliosidoses) 711
Cerebrotendinous xanthomatosis (cholestanolosis) 711
Neuronal ceroid lipofuscinosis 712
Coeliac disease 712
Inflammatory disorders of the central nervous system 712
Conclusion 712
Acknowledgement 712
Further reading 712
Internet resources 712
Chapter 37: Ipids and disorders of lipoprotein metabolism 713
Introduction 714
Lipids 714
Sterols 714
Cholesterol 714
Cholesterol and membranes 714
Phytosterols 715
Fatty acids 715
Triglycerides 715
Phospholipids 715
Eicosanoids 716
Sphingolipids 716
Nuclear lipids 717
Lipoproteins 717
Chylomicrons 718
Very low density lipoproteins 719
Intermediate density lipoproteins 719
Low density lipoproteins 719
High density lipoproteins 719
Lipoprotein(a) 719
Lipoprotein X 719
Apolipoproteins 719
Apolipoprotein A 720
Apolipoprotein A-I 720
Apolipoprotein A-II 720
Apolipoprotein A-IV 720
Apolipoprotein A-V 720
Apolipoprotein B 720
Apolipoprotein B-100 720
Apolipoprotein B-48 720
Apolipoprotein C 720
Apolipoprotein C-I 721
Apolipoprotein C-II 721
Apolipoprotein C-III 721
Apolipoprotein D 721
Apolipoprotein E 721
Apolipoprotein M 721
Apolipoprotein(a) 721
Cholesterol absorption 721
Sitosterolaemia 722
Triglyceride digestion 722
Bile acid metabolism 722
Lipoprotein metabolism 722
Assembly of apolipoprotein B-containing lipoproteins 722
Exogenous pathway 724
Lipolysis in adipose tissue 724
Endogenous pathway 724
Hepatic cholesterol trafficking 725
High density lipoprotein metabolism 725
Assembly of lipoproteins 725
Cholesterol efflux 726
Reverse cholesterol transport 726
Enzymes involved in lipoprotein metabolism 727
Lecithin cholesterol acyltransferase 727
Lipases 727
Lipoprotein lipase 727
Hepatic lipase 727
Endothelial lipase 727
Lipase maturation factor 1 728
Pancreatic triglyceride lipase 728
Hormone sensitive lipase 728
Carboxyl ester lipase 728
Lysosomal acid lipase 728
Wolman disease 728
Cholesteryl ester storage disease 728
Phospholipase A2 728
Acyl-CoA:cholesterol acyltransferase 729
Transfer proteins involved in lipoprotein metabolism 729
Cholesteryl ester transfer protein (CETP) 729
Phospholipid transfer protein (PTP) 729
Fatty acid transport proteins 729
Receptors involved in lipoprotein metabolism 729
The D receptor 729
D receptor-related protein 730
Scavenger receptor class B type 1 730
Other scavenger receptors 730
Peroxisome proliferator-activated receptor family 731
Other nuclear receptors 731
Other proteins involved in lipoprotein synthesis, transport and metabolism 731
Microsomal triglyceride transfer protein 731
ATP binding cassette transporter family 731
Proprotein convertase subtilisin kexin 9 731
Sterol regulatory element binding proteins 732
Sortilins 732
Glycosylphosphatidylinositol-anchored HD-binding protein 1 732
Angiopoietin-like protein 3 732
Classification of lipoprotein disorders 732
The primary dyslipoproteinaemias 734
Hypobetalipoproteinaemia 734
Abetalipoproteinaemia 735
Chylomicron retention disease 735
Familial hypobetalipoproteinaemia 735
Familial combined hyperlipidaemia 735
Familial hypertriglyceridaemia 735
Chylomicronaemia syndrome 736
Lipoprotein lipase deficiency 736
Apo C-II deficiency 736
Familial lipoprotein lipase inhibitor 736
Classic familial hypercholesterolaemia (FH) 737
Familial defective apolipoprotein B-100 (FDB) 738
Gain of function mutation in PCSK9 738
Autosomal recessive hypercholesterolaemia 738
Remnant hyperlipoproteinaemia 736
Familial hypercholesterolaemia 737
Polygenic hypercholesterolaemia 739
Dysalphalipoproteinaemias 739
Abnormal apolipoprotein A structure 739
Apo A-I deficiency 739
Disorders of HD metabolism 739
Tangier disease 739
Familial lecithin–cholesterol acyltransferase deficiency 740
Fish eye disease 740
Hepatic triglyceride lipase deficiency 740
Cholesterol ester transfer protein deficiency 740
Acquired hyperlipidaemias 740
Diabetes mellitus 740
Hypothyroidism 741
Nephrotic syndrome 741
Chronic kidney disease 741
Renal transplantation 742
Liver disease 742
Alcohol 742
Drug-related hyperlipidaemia 742
Acquired hypolipidaemia 743
Investigation of lipid disorders 743
Total cholesterol 743
Triglycerides 743
High density lipoprotein cholesterol 743
Low density lipoprotein cholesterol 743
Non-HD-cholesterol 744
Apolipoproteins 744
Apolipoprotein A-I 744
Apolipoprotein B 744
Apolipoprotein E 744
Lipoprotein(a) 744
Post-heparin lipolytic activity 744
Lipoprotein separation techniques 744
Ultracentrifugation 744
Lipoprotein electrophoresis 745
Genotyping 745
Treatment of hyperlipidaemia 745
Conclusion 747
Acknowledgement 747
Further reading 747
Chapter 38: Clinical biochemistry of the cardiovascular system 748
Introduction 748
Cardiovascular disease 748
Role of the laboratory 750
Cardiac muscle structure and biochemistry 751
Arterial structure and function 752
Atherosclerosis 752
Theories of early atherogenesis 752
The response-to-injury hypothesis 752
The lipid oxidation hypothesis 752
The fibrofatty lesion 754
The complicated plaque/plaque rupture 754
Acute myocardial damage 755
Biomarkers of acute myocardial damage 755
Troponins 756
High-sensitivity troponins 757
Other causes of elevated cTn 757
Creatine kinase-MB (CK-MB) 758
Myoglobin 759
Heart-type fatty acid binding protein (H-FABP) 759
Other 759
Tests for other causes of chest pain 759
Heart failure 760
Natriuretic peptides 760
Critical values 760
Non-HF factors influencing NPs 760
Clinical utility 760
Cardiovascular risk factors 761
Cardiovascular risk assessment 761
Unmodifiable risk factors 762
Age 762
Gender 762
Race 763
Family history 763
Genetic factors 763
Low birth weight 763
Potentially modifiable risk factors 763
Smoking 763
Lipids and lipoproteins 763
Thrombogenesis, rheology and clotting factors 764
Hypertension 764
Obesity 764
Impaired glucose tolerance and diabetes 765
Metabolic syndrome 765
Physical activity 765
Psychological factors 765
Inflammation and infection 766
Relative importance of coronary risk factors 766
Dietary factors 767
Salt 767
Simple sugars 767
Ethanol 767
Fish and fish oils 767
Soy protein 767
Fatty acids 767
Plant sterols 768
Fibre 768
Fruit and vegetables, tea and coffee 768
Dietary pattern 768
Hypertension 768
Definition 768
Cause 769
Primary hypertension 769
Secondary hypertension 770
Kidney disease 770
Endocrine disease 770
Laboratory assessment of hypertension 770
Investigation for secondary causes 770
Renovascular hypertension 770
Primary aldosteronism (hyperaldosteronism) 771
Forms of PA 772
Biochemical investigation 773
Confounding factors 773
Posture 773
Time of day 773
Drugs 773
Dietary sodium 773
Plasma potassium 773
Phase of menstrual cycle 773
Renal impairment/elderly patients 773
Other conditions 773
Localization 773
Phaeochromocytoma 774
Biochemical investigation 774
Localization 775
Management 775
Malignant hypertension 775
Hypertension in pregnancy 775
Management of hypertension 775
Conclusion 776
Further reading 776
Atherogenesis 776
Myocardial injury 776
Heart failure 776
Cardiovascular risk factors and prevention 776
Hypertension 776
Appendix 1: Protocol for investigation of aldosteronism: screening and confirmatory tests 776
Patient preparation 776
Screening procedure 777
Interpretation of results of screening test 777
Confirmatory tests 777
Saline suppression test 777
Procedure 777
Interpretation 777
Fludrocortisone suppression test 777
Procedure 777
Interpretation 777
Chapter 39: Therapeutic drug monitoring 778
Introduction 778
Pharmacokinetics and pharmacodynamics 778
Adherence 778
Absorption 779
Distribution 779
Elimination (metabolism and excretion) 779
Protein binding 780
Pharmacodynamic factors 780
Which drugs should be measured? 780
Use of therapeutic drug monitoring 782
Appropriate clinical question 782
Accurate patient information 783
Appropriate sample 783
Accurate analysis 785
Relevant clinical interpretation 785
Effective action taken 785
Provision of a therapeutic drug monitoring service 786
Staff 786
Turnaround time 786
Point-of-care testing 786
Reporting 786
Units 786
Quality assurance 787
Continuing education 787
Pharmacodynamic monitoring, biomarkers and pharmacogenetics 787
Integrating information 788
Individual drugs 788
Analgesic/anti-inflammatory drugs 788
Aspirin (acetylsalicylic acid) 788
Value of monitoring: 788
Antiarrhythmics and cardiac glycosides 788
Amiodarone 788
Value of monitoring: 788
Digoxin and digitoxin 788
Value of monitoring: 789
Disopyramide 789
Value of monitoring: 789
Flecainide 789
Value of monitoring: 789
Procainamide 789
Value of monitoring: 789
Anticonvulsants (antiepileptics) 789
Carbamazepine/oxcarbazepine 789
Value of monitoring: 789
Ethosuximide 789
Value of monitoring: 789
Phenobarbital/primidone 790
Value of monitoring: 790
Phenytoin 790
Value of monitoring 790
Valproate 790
Value of monitoring 790
Newer anticonvulsant drugs 790
Value of monitoring 791
Antidepressants and antipsychotic drugs 791
Tricyclic antidepressants (amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, trimip ... 791
Value of monitoring 791
Selective serotonin release inhibitors (SSRIs) (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertralin ... 791
Value of monitoring 791
Lithium 791
Value of monitoring 791
Other antidepressants 791
Value of monitoring 791
Antipsychotic drugs 791
Value of monitoring 791
Antimicrobial drugs 792
Aminoglycosides (amikacin, gentamicin, tobramycin) 792
Value of monitoring 792
Glycopeptides (vancomycin and teicoplanin) 792
Value of monitoring 792
Chloramphenicol 792
Value of monitoring 792
Antifungal drugs 792
Value of monitoring 793
Antitubercular drugs 793
Value of monitoring 793
Antiretroviral drugs 793
Value of monitoring 793
Value of monitoring 794
Antineoplastic drugs 793
Methotrexate 794
Value of monitoring 794
Bronchodilator drugs 794
Theophylline/caffeine 794
Value of monitoring 794
Immunosuppressants 794
Ciclosporin 795
Value of monitoring 795
Sirolimus 795
Value of monitoring 795
Tacrolimus 795
Value of monitoring 795
Mycophenolic acid 795
Value of monitoring 796
Opiate and opioid drugs 796
Methadone/buprenorphine 796
Value of monitoring 796
Morphine 796
Value of monitoring 796
Acknowledgement 796
Further reading 796
General pharmacokinetics 796
Analytical methods 796
Antiarrhythmics/cardiac glycosides 796
Anticonvulsants 796
Antidepressants/antipsychotics 796
Antimicrobial drugs 796
Antifungal drugs 796
Antitubercular drugs 797
Antiretrovirals 797
Antineoplastic drugs 797
Immunosuppressants 797
Methadone/buprenorphine 797
Appendix 39.1:
797
Chapter 40: Poisoning 798
Introduction 798
Aetiology of poisoning 799
Intrauterine 799
Neonates 799
Infants 799
Childhood 799
Adult life 799
Types of lesion in poisoning 799
Diagnosis and management of poisoning: general principles 800
Diagnosis 800
Management 802
Respiratory support 802
Cardiovascular support 802
Central nervous system complications 802
Body temperature 804
Renal complications 804
General supportive care 805
Intestinal decontamination 805
Antidotes 805
Elimination techniques 806
Specific poisons 806
Paracetamol (acetaminophen) 806
Mechanisms 806
Toxic dose 806
Clinical features 806
Management 806
Salicylate 807
Mechanisms 807
Clinical features 807
Laboratory measurements 807
Management 808
Chloroquine 809
Digoxin 809
Clinical features 809
Management 809
Iron 809
Toxicity 809
Clinical features 809
Analysis 809
Treatment 809
Chelation therapy 809
Other metals 809
Organophosphates 810
Toxicity 810
Clinical features and management 810
Alcohols and glycols 810
Ethanol (ethyl alcohol) 810
Methanol (methyl alcohol) 811
Ethylene glycol 811
Drug and substance abuse 811
Amfetamines 812
3,4-Methylenedioxymetamfetamine (MDMA) 812
Heroin (diamorphine) 813
Lysergic acid diethylamide (SD) 813
Cocaine 813
Cannabis 813
Solvents 814
Benzodiazepines 814
Theophylline 814
Clinical features 814
Management 814
Antidepressants 814
Tricyclic antidepressants 814
Clinical features 814
Management 814
Monoamine oxidase inhibitors 815
Toxicity 815
Management 815
Other antidepressants 815
Lofepramine 815
Trazodone 815
Venlafaxine 815
Fluvoxamine, fluoxetine, sertraline, paroxetine 815
Citalopram 815
Lithium 815
Toxicity 815
Clinical features 815
Management 815
Cyanide 816
Carbon monoxide 816
Toxicity 816
Clinical features 816
Methaemoglobinaemia 816
Causes 816
Symptoms 817
Management 817
Plant and fungal toxins 817
Conclusion 818
Acknowledgement 818
Further reading 818
Appendix 40.1:
818
Chapter 41: Metabolic effects of tumours 819
Introduction 819
Neuroendocrine Tumours 819
Carcinoid tumours 819
Clinical presentation 819
Metabolism of serotonin 820
Laboratory investigation 820
Diagnostic imaging 821
Treatment 821
Multiple endocrine neoplasia 821
Multiple endocrine neoplasia type 1 821
Parathyroid disease 821
Gastroenteropancreatic neuroendocrine tumours 822
Pituitary tumours 822
Foregut carcinoid tumours 822
Adrenal tumours 822
Tumourigenesis in MEN1 822
Diagnosis of MEN1 822
Genetic screening 823
Biochemical screening 823
Surveillance of MEN1 patients and carriers 823
Diagnosis 823
Imaging 824
Treatment 824
Surveillance 824
Multiple endocrine neoplasia type 2 823
Other familial syndromes associated with multiple endocrine neoplasia 824
Metabolic Changes in Malignancy 824
Introduction 824
Paraneoplastic syndromes 825
Neurological paraneoplastic syndromes 825
Humoral paraneoplastic syndromes 825
Adrenocorticotropin 825
Vasopressin 825
PTH-related peptide 825
Tumour-induced osteomalacia 827
Other paraneoplastic syndromes and features of malignant disease 827
Haematological sequelae 827
Hyperuricaemia 827
Cancer cachexia 827
Changes in metabolism 828
Treatment 829
Endocrine Sequelae of Tumours and their Treatment 829
Effects on somatic growth 829
Reproductive consequences of therapy 830
Conclusion 831
Further reading 831
Chapter 42: Tumour markers 832
Introduction 832
Evaluation of the clinical utility of tumour markers 832
Tumour marker requests and the responsibilities of the clinical laboratory 836
Reasons for requesting tumour markers 836
Choice of tumour marker test 836
Pre-analytical requirements 836
Analytical requirements 837
Reporting of tumour marker results 838
Tumour Markers in the Management of Specific Cancers 838
Bladder cancer 838
Breast cancer 838
Screening and diagnosis 839
Prognosis 839
Monitoring 839
Cervical cancer 840
Screening and diagnosis 840
Prognosis 840
Monitoring 840
Choriocarcinoma 840
Colorectal cancer 840
Screening 840
Diagnosis 841
Prognosis and staging 841
Monitoring 841
Monitoring of advanced disease 842
Cautions and caveats 842
Genetic pre-screening for hereditary non-polyposis colon cancer 842
K-RAS mutation detection 842
Gastric cancer 842
Gastrointestinal stromal tumours (GIST) 842
Germ cell tumours 843
Screening 843
Diagnosis 843
Prognosis 844
Monitoring 844
Long-term surveillance 845
Gestational trophoblastic neoplasia 845
Hydatidiform moles 846
Invasive moles 846
Choriocarcinoma 846
Placental site trophoblastic tumours 846
Screening 846
Diagnosis 846
Prognosis 846
Monitoring 846
Hepatocellular carcinoma (primary liver cancer) 846
Screening of high-risk groups 847
Diagnosis 847
Prognosis 847
Monitoring 847
Lung cancer 847
Screening 848
Differential diagnosis 848
Prognosis 848
Monitoring 848
Epidermal growth factor receptor and K-RAS mutation analysis 848
Melanoma 848
BRAF mutation analysis 848
Neonatal and paediatric tumours 848
Germ cell tumours in childhood 849
Hepatoblastoma 849
Neuroblastoma 849
Ovarian cancer 849
Screening 849
Diagnosis 850
Prognosis 850
Detection of residual disease 850
Monitoring 850
Long-term surveillance 851
Pancreatic cancer 851
Prostate cancer 851
Screening and diagnosis 851
Management 852
Analytical and reporting requirements 852
Testicular cancer 852
Thyroid cancer 853
Screening, diagnosis and prognosis 853
Monitoring 853
Analytical and reporting requirements 853
Cancers of unknown primary 853
Summary 853
Chapter 43: Molecular clinical biochemistry 855
Introduction 855
Genes and gene expression 855
What is a gene? 855
The Human Genome Project 856
The ‘Encode’ project 856
Gene expression 857
Mutation, the source of diversity and disease 857
Genesis of an individual: the formation of gametes 860
Genes in families and populations 861
The variable expression of genetic disease 862
The techniques of genetic analysis 863
Detection of specific sequences in DNA 863
Use of proteins that recognize DNA sequences: restriction endonucleases 863
Hybridization: probes and the polymerase chain reaction (PCR) 863
Detection of mutations 866
Detecting known mutations 866
Scanning or screening methods 868
Tracking of mutant genes 869
Next generation sequencing 870
The applications of DNA analysis 871
Diagnosis of index cases 871
Prenatal diagnosis 871
Screening 872
Screening of individuals 872
Population screening 872
Pharmacogenetics 872
Inherited diseases – some examples 873
Single gene disorders 873
1 -Antitrypsin deficiency 873
Cystic fibrosis 874
Muscular dystrophy 875
Huntington disease 876
Multifactorial and polygenic disease 877
Atherosclerosis 877
Familial hypercholesterolaemia 877
Apolipoprotein E genotypes 878
Cancer genetics 878
Oncogenes and suppressor genes 878
Multiple endocrine neoplasia (MEN) 880
Gene therapy 880
Stem cells in gene therapy 881
Gene therapy in cancer 882
Conclusion 882
Acknowledgements 882
Glossary 882
Further reading 884
Background 884
Internet resources 884
Journals 884
Chapter 44: Forensic biochemistry 885
Introduction 885
Samples and sampling 886
Poisoning with endogenous agents 887
Hydroxybutyrate 887
Insulin 888
Magnesium 888
Sodium 889
Post-mortem biochemistry 889
Vitreous humour 890
Specific diagnostic problems 891
Anaphylaxis/anaphylactoid reactions 891
Diabetes 891
Drowning 891
Hypothermia/hyperthermia 891
Inflammation 893
Sudden death 893
Further reading 893
Up-to-date reviews on post-mortem biochemistry 893
Practical guidance on post-mortem samples and sampling 893
Clinical and post-mortem diagnosis of disorders of glucose metabolism 893
Reviews on post-mortem diagnosis of anaphylaxis, hyperthermia/hypothermia and sepsis 893
Index 894
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...
| Erscheint lt. Verlag | 5.3.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Biochemie | |
| ISBN-10 | 0-7020-5478-X / 070205478X |
| ISBN-13 | 978-0-7020-5478-5 / 9780702054785 |
| Haben Sie eine Frage zum Produkt? |
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