THE DIETARY MANAGEMENT OF PHENYLKETONURIA BY ANITA MACDONALD A thesis ...

289 Pages·2007·4 MB·English

THE DIETARY MANAGEMENT
OF PHENYLKETONURIA
BY
ANITA MACDONALD
A thesis submitted to the Faculty of Medicine and Dentistry
of The University of Birmingham
for the degree of
DOCTOR OF PHILOSOPHY
Department of Reproductive and Child Health
School of Medicine
Faculty of Medicine and Dentistry
The University of Birmingham
August 1999
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ABSTRACT
Dietary Management of Phenylketonuria
A wider understanding of the impact of each of the dietary components on blood
phenylalanine concentrations in PKU may lead to improvements in management.
Knowledge of the effects of such rigorous diet therapy on feeding behaviour is also
important. In a series of studies, the effect of a number of dietary factors on plasma
phenylalanine control and of diet on feeding behaviour was systematically investigated.
The key findings were: 1) there is wide variability in plasma phenylalanine concentrations
which were not reflected in a single early morning phenylalanine measurement; 2) plasma
phenylalanine concentrations were more influenced by the timing and dosage of protein
substitute than by total energy or excess natural protein intake from ‘freely’ allowed foods;
3) repeated 4 hourly administration of protein substitute throughout 24-hours markedly
reduced phenylalanine variability and led to lower phenylalanine concentrations; 4) ‘free’
use of fruits and vegetables containing phenylalanine between 51-100 mg/100g did not
adversely affect plasma phenylalanine control; and 5) feeding problems were common, with
almost 50% of young children with PKU exhibiting at least 3 feeding problems. These
findings in PKU are important in the understanding of feeding behaviour; the interpretation
of plasma phenylalanine concentrations; they increase and rationalise the range of ‘free’
foods; and will reduce 24-hour plasma phenylalanine variability, and thus, possibly increase
dietary phenylalanine tolerance.
I
ACKNOWLEDGEMENTS
This work would not have been possible without the help and encouragement of many
individuals and groups. In particular, I would like to thank:
Mrs Pat Briscoe, for typing numerous drafts of this manuscript with such skill, patience
O
and humour. All your work and support is particularly appreciated.
Professor Ian Booth and Dr George Rylance for excellent supervision. They both helped
O
in very different ways, but both provided much needed expertise, a critical eye, and lots
of matter of fact encouragement.
All my patients and their parents whose enthusiasm and support was superb. The
children were all stars!
The West Midlands Support Group for PKU, the NSPKU, and the Birmingham
Children’s Hospital (BCH) Centenary Fund for providing financial support for
blood tests.
Kate Hall, Russell Denmeade and all the staff in the BCH screening laboratory for
analysing numerous blood samples.
Di Asplin for supplying all the blood taking equipment and providing invaluable nursing
support.
Dr Gill Harris for giving help and advice with the feeding problem study.
Mr Paul Davies for providing excellent statistical advice and support.
All the BCH dietitians for allowing me to go part time to complete this research.
Finally, my husband John MacDonald. I am sure without his constant practical help,
patience and fortitude this thesis would not have been completed, particularly when the
going was tough. He has done every thing possible to support me and I cannot thank him
enough. He has been, as always, fantastic!
Thank you all so much
II
CONTENTS
Page
ABSTRACT I
ACKNOWLEDGEMENTS II
CONTENTS III
LIST OF FIGURES IX
LIST OF TABLES XV
ABBREVIATIONS XVII
Chapter 1 Introduction 1
1.1 Background information 3
1.2 History 3
1.3 Classification of PKU 8
1.4 Does outcome in early-treated PKU relate to quality of 9
control of blood phenylalanine?
1.4.1 Effect on IQ 10
1.4.2 Outcome measures other than IQ 13
1.5 What should blood phenylalanine concentrations be in PKU? 20
1.6 Is the structure of the existing diet capable of consistently 24
maintaining blood phenylalanine concentrations within
target ranges?
1.7 Other dietary factors which may affect control in PKU 30
1.7.1 Protein substitutes 30
1.7.2 Energy 37
1.8 What do PKU children actually eat? 38
1.9 What is the effect of PKU diet on normal eating behaviours? 38
1.10 Summary 39
1.11 Summary of questions addressed in PhD thesis 40
III
Page
Chapter 2 Factors affecting the variation in plasma 43
phenylalanine in patients with phenylketonuria
on diet
2.1 Introduction 45
2.2 Subjects and methods 45
2.2.1 Subjects 45
2.2.2 Methods 46
2.3 Statistical analyses 50
2.4 Results 51
2.4.1 Dietary intake 51
2.4.2 Blood phenylalanine results 55
2.5 Summary 60
Chapter 3 A prospective, cross-over trial assessing the 75
impact of new potato exchange allowances
on blood phenylalanine concentrations in PKU
3.1 Introduction 77
3.2 Subjects and methods 77
3.2.1 Subjects 77
3.2.2 Study design 78
3.3 Statistical analyses 82
3.4 Results 82
3.4.1 Dietary intake 82
3.4.2 Plasma phenylalanine concentrations 83
3.5 Summary 83
IV
Page
Chapter 4 A prospective, cross-over trial investigating the 93
effect of free use of fruits and vegetable containing
intermediate amounts (51-100 mg/100g) of
phenylalanine on control in PKU
4.1 Introduction 95
4.2 Subjects and methods 95
4.2.1 Subjects 95
4.2.2 Study design 97
4.3 Statistical results 101
4.4 Results 101
4.4.1 Part 1 and 2 : Addition of fruit and vegetables containing 101
phenylalanine 5 1-75 mg/100g
4.4.2 Part 1,2 and 3 : Addition of fruit and vegetables containing 102
phenylalanine 76-100 mg/100g
4.5 summary 104
Chapter 5 24-hour plasma phenylalanine variability in PKU 117
5.1 Introduction 119
5.2 Subjects and methods 119
5.2.1 Subjects 119
5.2.2 Methods 120
5.3 Statistical analyses 122
5.4 Results 122
5.4.1 Plasma phenylalanine concentrations 122
5.4.2 Dietary intake 124
5.5 summary 127
V
Page
Chapter 6 Part A. The effects of altered timing of administration 145
of protein substitute on variability of plasma
phenylalanine concentrations
6.1 Introduction 147
6.2 Subjects and methods 147
6.2.1 Subjects 147
6.2.2 Study design 148
6.3 Statistical analyses 152
6.4 Results 152
6.4.1 Subjects withdrawn from the study 152
6.4.2 Effect of administration of protein substitute protocol on 24 h 152
plasma phenylalanine pattern
6.4.3 Changes between highest and lowest phenylalanine 154
concentrations observed
6.4.4 Effect of time since giving dose of protein substitute and 154
change in plasma phenylalanine concentrations
6.4.5 Phenylalanine concentrations outside the MRC 155
recommended guidelines
6.4.6 Within subject reproducibility of plasma phenylalanine 155
concentrations on day 6 and day 7 of each study period
6.4.7 Protein and energy intake 156
6.5 Summary 159
Part B. The effects of frequent administration of 173
protein substitute on plasma phenylalanine
concentrations
6.6 Introduction 175
VI
Page
Subjects and methods 175
6.7
Subjects 175
6.7.1
Study design 177
6.7.2
Statistical analyses 177
6.8
6.9 Results 177
6.9.1 Effect of administration of protein substitute protocol on 24 h 177
plasma phenylalanine pattern
6.9.2 Changes between highest and lowest phenylalanine 179
concentrations observed
6.9.3 Energy and protein intake 179
180
6.10 Summary
Chapter 7 Abnormal feeding behaviours in phenylketonuria 187
7.1 Introduction 189
7.2 Subjects and methods 190
7.2.1 Subjects 190
7.2.2 Methods 191
7.3 Statistical analyses 193
7.4 Results 193
7.4.1 Feeding assessment questionnaire 193.
7.4.2 Video analysis 194
7.4.3 Dietary assessments 195
7.4.4 Protein substitute administration 195
VII
Page
7.4.5 Anthropometry 196
7.5 Summary 196
Chapter 8 Discussion
8.1 Principal findings 213
8.2 Interpretation and implication of research results 214
8.2.1 Variability in blood phenylalanine concentrations 214
8.2.2 Dietary factors affecting variability in blood phenylalanine
concentrations 218
8.2.3 Rationalisation of allocation of fruit and vegetables in PKU diet 226
8.2.4 Effect of diet on feeding behaviour in young children with PKU 229
8.3 Potential drawbacks of individual studies 223
8.4 Unanswered questions and future research 238
8.5 Conclusion 240
Appendix 1 Feeding assessment Form 24 1
Appendix 2 Protein substitute questionnaire 253
Appendix 3 Video analysis category system 263
References 269
Publications 285
VIII