Summary
Background
The estimated worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) in adults is 25%; however, prevalence in young adults remains unclear. We aimed to identify the prevalence of steatosis and fibrosis in young adults in a sample of participants recruited through the Avon Longitudinal Study of Parents and Children (ALSPAC), based on transient elastography and controlled attenuation parameter (CAP) score.
Methods
In this population-based study, we invited active participants of the ALSPAC cohort to our [email protected]+ clinic at the University of Bristol (Bristol, UK) between June 5, 2015, and Oct 31, 2017, for assessment by transient elastography with FibroScan, to determine the prevalence of steatosis and fibrosis. FibroScan data were collected on histologically equivalent fibrosis stage (F0-F4) and steatosis grade (S0-S3); results with an IQR to median ratio of 30% or greater were excluded for median fibrosis results greater than 7·1 kPa, and CAP scores for steatosis were excluded if less than ten valid readings could be obtained. Results were collated with data on serology (including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase) and exposures of interest: alcohol consumption (via the Alcohol Use Disorder Identification Test for Consumption [AUDIT-C] and the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for alcohol use disorder), body-mass index (BMI), waist-to-height ratio, socioeconomic status (based on predefined ALSPAC markers), and sex. We used logistic regression models to calculate odds ratios (ORs) for the effect of exposures of interest on risk of steatosis and fibrosis, after dichotomising the prevalences of fibrosis and steatosis and adjusting for covariates (excessive alcohol intake [hazardous drinking, AUDIT-C score ≥5; or harmful drinking, evidence of alcohol use disorder], social class, smoking, and BMI).
Findings
10 018 active ALSPAC participants were invited to our [email protected]+ clinic, and 4021 attended (1507 men and 2514 women), with a mean age of 24·0 years (IQR 23·0–25·0). 3768 CAP scores were eligible for analysis. 780 (20·7% [95% CI 19·4–22·0]) participants had suspected steatosis (S1–S3; ≥248 dB/m), with 377 (10·0%) presenting with S3 (severe) steatosis (≥280 dB/m). A BMI in the overweight or obese range was positively associated with steatosis when adjusted for excessive alcohol consumption, social class, and smoking (overweight BMI: OR 5·17 [95% CI 4·11–6·50], p<0·0001; obese BMI: 27·27 [20·54–36·19], p<0·0001). 3600 participants had valid transient elastography results for fibrosis analysis. 96 participants (2·7% [95% CI 2·2–3·2]) had transient elastography values equivalent to suspected fibrosis (F2–F4; ≥7·9 kPa), nine of whom had values equivalent to F4 fibrosis (≥11·7 kPa). Individuals with alcohol use disorder and steatosis had an increased risk of fibrosis when adjusted for smoking and social class (4·02 [1·24–13·02]; p=0·02).
Interpretation
One in five young people had steatosis and one in 40 had fibrosis around the age of 24 years. The risk of fibrosis appears to be greatest in young adults who have harmful drinking patterns and steatosis. A holistic approach to the UK obesity epidemic and excessive drinking patterns is required to prevent an increasing health-care burden of adults with advanced liver disease in later life.
Funding
Medical Research Council UK, Alcohol Change UK, David Telling Charitable Trust.
Introduction
The disease is recognised as a spectrum of conditions, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), and ultimately cirrhosis. Worldwide, NASH prevalence in adults is estimated to be 6% in developed countries, with up to 40% of these individuals progressing to advanced fibrosis.
In the UK, NASH-related cirrhosis is among the most common indications for liver transplantation.
An increased pool of steatotic donor livers has ramifications for recipients, with primary graft non-function and dysfunction increasingly associated with graft steatosis.
Prospective cohort population studies in an adolescent setting (17–18 years) have estimated the prevalence of NAFLD to be between 2·5% and 12·8% in developed countries from liver ultrasound data.
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Although liver biopsy is considered the gold standard for NAFLD assessment, it is unethical in large population studies, because of a risk of serious adverse events following the procedure.
Evidence before this study
Non-alcoholic fatty liver disease (NAFLD) affects approximately a quarter of adults in developed countries, a substantial proportion of whom are at risk of developing liver failure and liver cancer, and an increased risk of death related to heart disease. One of the largest studies to analyse prevalence of NAFLD in young adults used data from the National Health and Nutrition Examination Survey. The estimated prevalence of suspected NAFLD in adults aged 18–35 years was 25%, under the criteria for NAFLD of an alanine aminotransferase concentration greater than 30 IU/L in men and greater than 19 IU/L in women, and a body-mass index greater than 25 kg/m2; however, these criteria are broad. To date, no study has used imaging to screen young adults and establish the true prevalence of NAFLD in this sparsely studied age group.
Added value of this study
This study is, to the best of our knowledge, the first to determine the prevalence of NAFLD in young adults with use of transient elastography, in an age group in which NAFLD burden is poorly characterised. The added value of our use of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort is that, as the most phenotyped birth cohort worldwide, this group of young adults has already been assessed for NAFLD between the ages of 17 and 18 years, which acts as a comparator.
Implications of all the available evidence
We identified that around 20% of young adults in our cohort had steatosis of grade S1 or higher around the age of 24 years. One in 40 also had evidence of liver fibrosis, with participants at greatest risk of fibrosis being those with harmful drinking patterns and evidence of steatosis. Patients identified with steatosis and early fibrosis as young adults might present in earlier decades of life with advanced liver disease, placing increased strain on inpatient and transplant services. This outcome could have wide implications in the context of the national obesity epidemic in the UK. Increased public health interventions are required to tackle the obesity epidemic and excessive drinking in young adults, to attenuate their risk of NAFLD and alcohol-related liver disease, and therefore reduce the health-care burden of advanced liver disease.
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To date, no population studies have looked into the prevalence of fibrosis and steatosis in young adults assessed by transient elastography.
In the current study, we aimed to identify the prevalence of steatosis and fibrosis in young adults from the unselected, general population birth cohort of ALSPAC by use of transient elastography.
Results
10 018 active ALSPAC participants were invited to our [email protected]+ clinic. Of those who were invited, 4021 (40·1%) attended (figure 1). Characteristics of participants who attended the clinic are shown in table 1. This population had a mean age of 24·0 years (IQR 23·0–25·0), with a range of 22–26 years, and comprised 1507 men and 2514 women. In total, 421 (10·5%) participants were excluded. Reasons for exclusion were not accepting the transient elastography session (n=107), withdrawal of consent from the current study (n=38), insufficient information for fibrosis or CAP measurement (n=182), or a transient elastography result with an IQR to median ratio of 30% or greater (n=94; figure 1).
Figure 1Participant flow chart
*182 with insufficient data for fibrosis measurement and 108 with insufficient data for CAP measurement; reasons included not achieving ten valid scan measurements or missing data.
Table 1Characteristics of ALSPAC participants who attended the [email protected]+ clinic
Data are n (% of available data), median (IQR), or mean (SD). ALSPAC=Avon Longitudinal Study of Parents and Children. AUDIT-C=Alcohol Use Disorder Identification Test-C. BMI=body-mass index.
In our check of current medications, no participants reported having viral hepatitis or to be taking nucleos(t)ide analogues or direct-acting antivirals. Autoimmune hepatitis requiring azathioprine, and overlap syndrome with autoimmune hepatitis and primary sclerosing cholangitis requiring prednisolone, mycophenolate mofetil, or ursodeoxycholic acid were reported in less than five participants each, but these individuals were not excluded on the basis of this being a general population study. 23 participants were taking insulin for type 1 diabetes. No participants were known to have type 2 diabetes.
in analysed participants (n=3768)
Data are n (% of available data), mean (SD; normally distributed variables), or median (IQR; non-normally distributed variables); numbers reflect available data and therefore do not always reflect the total population (data missing on 512 participants across all categories). AUDIT-C=Alcohol Use Disorder Identification Test-C. BMI=body-mass index.
Figure 2Distribution of BMI categories across steatosis grade
Steatosis grade was derived from measurement of controlled attenuation parameter. Percentages represent obese participants at each grade.
Table 3Exposures associated with the presence of steatosis in analysed participants (n=3768)
OR=odds ratio. BMI=body-mass index. AUDIT-C=Alcohol Use Disorder Identification Test-C.
in analysed participants (n=3600)
Data are n, mean (SD; normally distributed variables), or median (IQR; non-normally distributed variables); numbers reflect available data and therefore do not always reflect the total population (data missing on 526 participants across all categories). Any analysed groups with less than five participants are expressed as n<5 in line with the ALSPAC confidentiality policy (percentages not provided for the same reason). AUDIT-C=Alcohol Use Disorder Identification Test-C. BMI=body-mass index.
Table 5Exposures associated with the presence of fibrosis in analysed participants (n=3600)
OR=odds ratio. CAP=controlled attenuation parameter.
Discussion
which found a prevalence of 25% in people aged 18–35 years, albeit with a different assessment modality. In our study, BMI and adiposity were independent predictors of steatosis despite adjusting for excessive alcohol consumption. To the best of our knowledge, the prevalence of steatosis detected with CAP measurement in our birth cohort is one of the first attempts to assess prevalence of NAFLD in young adults in the UK.
Although 96 participants were identified with suspected F2–F4 fibrosis, these cases cannot be solely attributed to NAFLD. No associations were found between steatosis and metabolic syndrome, harmful alcohol use (ie, alcohol use disorder), or fibrosis; however, participants with steatosis and alcohol use disorder had a four times greater risk of developing fibrosis, when adjusted for confounders. These patients could represent participants with both alcohol-related and non-alcoholic fatty liver disease.
890 adults (mean age 53 years) were assessed for NAFLD with transient elastography and CAP, with similar cut-off values for fibrosis stage and steatosis grade. They identified 428 (48·1%) of their population to have NAFLD, 27·4% of whom had type 2 diabetes or impaired fasting glucose. Of the 890 participants, 28 (3·1%) had NAFLD and evidence of advanced fibrosis (≥F3). By comparison, only 1·5% of our cohort had F3–F4 fibrosis. Although no ALSPAC participants had known type 2 diabetes, HOMA-IR in participants with steatosis (≥S1) in Petta and colleagues’ study was similar to that in our S3 group (3·2 vs 3·6).
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However, this ability is lost when attempting to differentiate between F0 and F1 fibrosis. As a result, this population study could under-report the number of participants with fibrosis as we cannot comment on those with early F1 fibrosis.
Additionally, the proportion of positive laboratory reports for acute or chronic hepatitis B is 6·8 per 100 000 of the population in the southwest region.
Furthermore, in our large population study, the gold standard method of liver biopsy was not ethically viable. Therefore, the definitive cause of fibrosis was only speculated to be NAFLD in participants with steatosis in the absence of harmful alcohol consumption.
This previous analysis used ultrasound to assess steatosis, and did not include mild (S1) steatosis in its definition of NAFLD. Ultrasound has been superseded in clinical practice by transient elastography and CAP measurement for assessment of fibrosis and quantification of steatosis. Therefore, the prevalence of NAFLD could have been under-reported previously in this cohort. A similar population-based cohort study in Australia that used ultrasound assessment reported a prevalence of 12·8% for NAFLD.
Ultrasound has greater than 90% sensitivity to detect steatosis of 30% or more, which corresponds to high S1 and low S2 steatosis.
13·2% of our participants had S2–S3 steatosis, and therefore a substantial increase in the prevalence of NAFLD in the ALSPAC birth cohort seems to have occurred between 18 to 24 years, despite differences in methods used for detection.
This study did not collect data on grams of alcohol consumed by participants. To compensate for these missing data, we risk-stratified our participants using AUDIT-C scores and evidence of alcohol use disorder into the categories of hazardous and harmful drinking. As a result, the true number of participants with excessive alcohol consumption might be under-reported. Similarly, we did not have data on physical activity to comment on its effect as a predictor of steatosis and fibrosis. However, physical activity relates closely to our key exposures of obesity and adiposity, both of which were shown to be positively associated with steatosis around the age of 24 years.
Although our study found no association between social class and increased steatosis and fibrosis, we acknowledge that participants that continue to attend our clinics tend to have higher-level educational attainment, introducing a selection bias.
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Furthermore, the southwest region of England has the third lowest adult prevalence of obesity in the UK, at 23%.
Therefore, this study might underestimate the prevalence of NAFLD in young adults for the whole of the UK, and particularly for regions such as northeast England, where the prevalence of adult obesity is 30%.
Interestingly, this prevalence in young men was despite proportionally more female participants having obesity than male participants (15·0% vs 10·7%), which contrasts with national data from Cancer Research UK, showing that the prevalence of adult obesity is higher in men than women. Part of this discrepancy could be due to a slightly greater proportion of men in our cohort having increased adiposity compared with women, based on waist-to-height ratio (28·6% vs 27·5%). These findings are consistent with another large epidemiological study of electronic health records, which identified male sex as an independent risk factor for NASH and NAFLD.
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We found no association between the severity of steatosis or fibrosis and socioeconomic status. Furthermore, no association was identified between smoking and suspected NAFLD, despite smoking being a well recognised risk factor for the development of NAFLD.
However, most studies looking at the association of smoking with NAFLD have been in middle-aged adults (aged 40–60 years), and the effects of smoking might have been too premature to be apparent in the young adults of our birth cohort.
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However, chronic alcohol consumption in the context of NAFLD has been associated with increased risk of hepatocellular carcinoma.
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In 2019, a cohort study of UK and US patients with alcohol-related hepatitis that short-term mortality was two times greater in patients with obesity.
Ultimately in our study, we did not identify any protective effect of alcohol consumption on steatosis, and at least seven participants had suspected fibrosis in the setting of alcohol-related liver disease with steatosis.
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Evidence exists for steatosis or non-alcoholic fatty liver progressing to fibrosis, with concurrent diabetes a strong risk factor.
We are not aware of any patients with confirmed type 2 diabetes in our cohort of young adults, but the mean HOMA-IRs for all the steatosis groups were indicative of insulin resistance (≥1·68). Although no association was seen between HOMA-IR and increasing fibrosis stage in participants with suspected NAFLD, HOMA-IR was associated with increasing CAP score, supporting the concept that insulin resistance is a major facilitator of steatosis in the context of NAFLD.
In conclusion, this study provides evidence that the obesity epidemic is affecting the future health of young adults in the UK, by increasing their risk of NASH-related cirrhosis, hepatocellular carcinoma, and complications of metabolic syndrome. Crucially, these outcomes can be avoided with stringent public health measures, starting with increased awareness of NAFLD among the general population. We identified participants in our cohort with NAFLD-related fibrosis, but the strongest association with increased severity of fibrosis was found in participants with harmful alcohol consumption and hepatic steatosis.
KWMA analysed data and wrote the manuscript. GSF helped with data interpretation, advised on statistical analysis, and reviewed the manuscript. GH collected and interpreted data. AJP and FHG provided clinical input for data interpretation and reviewed the manuscript. JH advised on statistical analysis, reviewed the manuscript, and supervised KWMA. MH advised on statistical analysis, reviewed the manuscript, and supervised KWMA and the project.
We declare no competing interests.
Acknowledgments
We are extremely grateful to all the families who took part in this study, to the midwives for their help in recruiting participants, and to the whole Avon Longitudinal Study of Parents and Children team, including the interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. We are also thankful to Professor Nick Sheron at the Institute of Hepatology, Foundation for Liver Research, Kings College London (London, UK), who contributed to the original study design for the [email protected]+ clinic. This publication is the work of the authors, who serve as guarantors for the contents of this paper. The UK Medical Research Council (MRC) and Wellcome Trust (102215/2/13/2) and the University of Bristol (Bristol, UK) provide core support for the Avon Longitudinal Study of Parents and Children. This work was undertaken with the support of the MRC and Alcohol Research UK (MR/L022206/1), and the David Telling Charitable Trust. We also acknowledge support from The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement, a UK Clinical Research Collaboration (UKCRC) Public Health Research Centre of Excellence (joint funding [MR/KO232331/1] from the British Heart Foundation, Cancer Research UK, the UK Economic and Social Research Council, the MRC, the Welsh Government, and the Wellcome Trust, under the UKCRC); the UK National Institute for Health Research (NIHR) School of Public Health Research, the NIHR Health Protection Research Unit in Evaluation, and the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust (Bristol, UK); and the University of Bristol.
