Non-alcoholic fatty liver disease across the lifespan: The effects of early-life nutrition on adult disease Pubblico
Sekkarie, Ahlia (Spring 2021)
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing in children, hinting that it may have early-life origins. Supporting this hypothesis, animal studies have shown that maternal diets are associated with hepatic fat in offspring. The association between prenatal and early childhood nutrition and later NAFLD in humans, as well as the natural history of NAFLD throughout childhood, have not been well characterized.
In this dissertation, I examine the association between early-life nutrition and adult NAFLD using secondary data from two longitudinal birth cohorts. In aim 1, I examine the effect of improved protein-energy nutrition from conception to two-years on NAFLD prevalence in mid-adulthood in the Guatemalan Institute of Nutrition of Central America and Panama (INCAP) cohort. In aim 2, I utilize the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort to examine the effect of (a) maternal free sugar intake and nutritional status and (b) early childhood high free sugar and sugary beverage intake on hepatic steatosis at 24 years. In aim 3, I use the ALSPAC cohort to determine whether hepatic enzymes throughout childhood and adolescence are associated with hepatic steatosis in young adulthood.
There was a high prevalence of NAFLD in mid-adulthood in the INCAP cohort. Early-life protein-energy supplementation was not significantly associated with NAFLD. In the ALSPAC cohort, maternal diabetes, overweight, obesity, and excess gestational weight gain, were positively associated with hepatic steatosis in adult offspring, although the relationship was mediated by body mass index at 24 years. Free sugar and sugary beverage intake at three years were positively but weakly associated with adult hepatic steatosis. Higher alanine aminotransferase concentration in adolescence, but not prior to puberty, was positively associated with hepatic steatosis at 24 years.
While I did not find that early-life diet and nutrition had strong independent effects on adult NAFLD, the work in this dissertation makes an important contribution to the limited body of research on the dietary and nutritional predictors of NAFLD. There is a need for further longitudinal studies on the causes of NAFLD throughout the life course.
Table of Contents
Chapter 1: Introduction. 1
1.1 References 3
Chapter 2: Background. 4
2.1 Definition and Epidemiology of NAFLD.. 4
2.2 Developmental Origins of NAFLD.. 5
2.2.1 Undernutrition. 6
2.2.2 Overnutrition. 7
2.2.3 Biological mechanism.. 10
2.3 High-sugar diets and sugary beverages 11
2.4 Screening for NAFLD in children. 13
2.5 Summary, specific aims, and hypotheses. 14
2.6 References 16
Chapter 3: Extended Methods. 26
3.1 Overview of Parent Studies. 26
3.1.1 INCAP. 26
3.1.2 ALSPAC.. 27
3.2 Nutrition Assessment Methods: 28
3.2.1 Improved protein-energy nutrition. 28
3.2.2 Food frequency questionnaire. 29
3.2.3 Non-milk extrinsic sugars 30
3.2.4 Sugary beverages. 31
3.2.5 Maternal nutritional status. 32
3.3 NAFLD Assessment Methods. 33
3.3.1 The NAFLD Liver Fat Score and Percent 35
3.3.2 Transient elastography. 36
3.3.3 Hepatic enzymes. 37
3.4 Statistical Analyses 38
3.4.1 Missing data. 39
3.4.2 Difference in Difference models. 42
3.4.3 Mixed models 44
3.4.4 Logistic models. 44
3.5 References 48
Chapter 4: Prevalence of NAFLD in Guatemala following exposure to a protein-energy nutrition intervention in early life. 53
4.1 Abstract 54
4.2 Introduction. 55
4.3 Material and methods. 56
4.3.1 Study population. 56
4.3.2 Data collection and lab assays. 57
4.3.3 Variable specification. 58
4.3.4 Statistical analysis. 59
4.4 Results. 60
4.5 Discussion. 61
4.6 References 65
4.7 Tables & Figures. 69
Chapter 5: Associations of maternal diet and nutritional status with offspring hepatic steatosis in the Avon Longitudinal Study of Parents and Children. 73
5.1 Abstract 74
5.2 Introduction. 75
5.3 Methods: 76
5.3.1 Study population. 76
5.3.2 Assessment of maternal nutrition. 76
5.3.3 Assessment of liver outcomes. 78
5.3.4 Covariates. 78
5.3.5 Inclusion/Exclusion. 79
5.3.6 Statistical analysis. 79
5.4 Results. 80
5.5 Discussion. 82
5.6 References 86
5.7 Tables & Figures. 92
Chapter 6: Association between free sugar and sugary beverage intake in early childhood and adult NAFLD in a population-based UK cohort 100
6.1 Abstract 101
6.2 Introduction. 102
6.3 Methods. 103
6.3.1 Study population. 103
6.3.2 Assessment of three-year free sugar intake. 104
6.3.3 Assessment of liver outcomes. 105
6.3.4 Covariates. 105
6.3.5 Inclusion/exclusion. 106
6.3.6 Statistical Analysis. 106
6.4 Results. 106
6.5 Discussion. 108
6.6 References 112
6.7 Tables & Figures. 116
Chapter 7: ALT trends through childhood and adolescence associated with hepatic steatosis at 24 Years: A population-based UK cohort study. 124
7.1 Abstract 125
7.2 Introduction. 126
7.3 Materials & Methods. 127
7.3.1 Study design and population. 127
7.3.2 Assessment of liver outcomes. 128
7.3.3 Covariates. 129
7.3.4 Inclusion/Exclusion. 129
7.3.5 Statistical Analysis. 129
7.4 Results. 130
7.5 Discussion. 132
7.6 References 135
7.7 Tables & Figures. 139
Chapter 8: Conclusions. 149
8.1 Key conclusions & discussion. 149
8.1.1 Protein-energy supplementation in an undernourished population. 149
8.1.2 Prenatal and early childhood overnutrition. 151
8.1.3 Pediatric hepatic enzyme levels association with adult NALD.. 152
8.1.4 Limitations & Strengths. 153
8.2 Public health implications. 154
8.3 Future directions for research. 155
8.4 References 158
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