Assessing age differences in the magnitudes of the association between potential risk factors and NAFLD will provide critical clinical information pertinent to the diagnosis and prognosis of NAFLD. The importance of evaluating the variability of risk factors for NAFLD spans the age spectrum. NAFLD is the most common liver disease in children and the leading indicator for liver transplantation in adults over the past decade . While prior studies have sought to assess risk factors and develop predictive models, none have evaluated the need for age-specific modeling. This study observed that the association between patient characteristics and NAFLD varies across the age spectrum. We observed a gradient of the magnitude of association with increasing age for several risk factors, suggesting that future work should carefully consider age as a modifier when building predictive or prognostic models. To our knowledge, this is the first descriptive study to look at whether an association between patient characteristics and NAFLD varies by age in a large, nationally representative sample of the US population.
Previous studies of age and NAFLD have generally focused on age-specific trends in prevalence or age-restricted analyses. NAFLD prevalence in the US from 1988 to 1994 was reported as ~ 19.0% in the general population aged 20–74 years, based on NHANES respondents . Individual studies have studied the prevalence of NAFLD within different age groups. In a study limited to older participants, researchers found the prevalence rates were ~ 40.3% for those between the age of 60 and 74 years old and ~ 39.2% for those over the age of 74 years . Another study with patients between 28–70 (mean age: 54.6) years found the NAFLD prevalence to be ~ 46% . These studies highlight an association between NAFLD and age but do not address whether NAFLD prognosis or risk factors vary. A study looked at the prevalence of NAFLD in children aged 9–17 years with obesity. They found that one-third of boys and one-fourth of girls had NAFLD .
Publications from the early 2000s discussed gender influences on NAFLD; their conclusion had variable NAFLD prevalence in males and females. However, males consistently had a higher prevalence than females in these studies [20–25]. Our results were consistent with the literature where males had a higher prevalence than females. However, our calculated NAFLD prevalence ratio for males and females increased with increasing age. The increase in prevalence ratio suggests an increase in NAFLD prevalence of males and females with increasing age was not proportional. A possible explanation for the observation can be that pre-menopausal women may benefit from estrogen's protective effects when it comes to developing NAFLD. Recent research has shown that the prevalence of NAFLD is higher in males than in females during reproductive years. After menopause, females are suggested to have a higher prevalence than males .
Obesity has been considered a significant risk factor for NAFLD . Results from our study show a unique relationship between body weight, NAFLD, and age. Studies have suggested that the epidemic of pediatric obesity is driving the pediatric NAFLD prevalence [7, 28]. Participants who were younger than the age of 19 and obese had 47 times higher risk of developing NAFLD than normal-weight participants of the same age. For other age groups, the prevalence ratio continued to be the highest obese participants. Our results are consistent with the literature suggesting that obesity is a significant risk factor for NAFLD. However, a recently published study concluded that nonobese NAFLD patients carry a higher mortality than obese NAFLD patients . This suggests that it is essential to screen high-risk groups, even if obesity is not present.
Our results showed serum albumin was 4.4 g/dL for those younger than 18 and 4.2 g/dL for those over 18. In the literature, serum albumin is reported to decrease in patients with hepatic fibrosis. One study showed that serum level for albumin in patients with mild fibrosis was 4.4g/dL and albumin level for patients with intensive fibrosis was 4.2 g/dL [30, 31]. Serum bilirubin has been studied for its cytoprotective effects and reducing the risks of NAFLD. Our findings were consistent with the notion that total bilirubin may be protective against NAFLD .
NAFLD is associated with liver-related morbidity, cardiovascular disease, diabetes mellitus, and adulthood mortality in adults. Though the short term morbidity and mortality due to NAFLD are attenuated in the younger population, the increased lifetime consequences of chronic NAFLD with childhood-onset them at a higher risk of complications during their lifetime . Younger populations have vulnerabilities to environmental influences and have exposures that are unique opportunities for interventions and modification of risks. For example, maternal preconception obesity/gestational diabetes and early feeding practices like high sugar consumption during vulnerable developmental stages are susceptibilities unique to early life. NAFLD present in children and adolescents also may differ histologically from adults . For example, Type 2 NAFLD is more commonly found in children/young people and is associated with more significant fibrosis and progressive disease. Type 2 NAFLD refers to the periportal distribution of steatosis, inflammation, and fibrosis. In comparison, Type 1 NAFLD refers to steatosis, inflammation, and fibrosis surrounding the central vein .
Algorithms have been developed to identify and characterize NAFLD relying on diagnoses, laboratory measures, biometrics, and demographics. These algorithms use different data inputs and thresholds to rule out potential NAFLD cases . For example, the Fatty Liver Index (FLI) is used to predict fatty liver in the general population by using parameters like BMI, triglycerides (TG); waist circumference (WC); and gamma-glutamyl transferase levels . The Hepatic Steatosis Index (HSI) is an alternative algorithm relying on aspartate aminotransferase, alanine aminotransferase; BMI; and diabetes mellitus . Other algorithms include the lipid accumulation product, visceral adiposity index, and triglyceride and glucose index, which use a combination of parameters like gender; TG; WC; glucose; BMI, and HDL [38–40]. These algorithms have a sensitivity that ranges from 46–96% and specificity that ranges from 40–92%, depending on the cut-off point and algorithm used . There has been work done to improve the algorithms to fit the population. For example, USFLI adds to the FLI to predict hepatic steatosis more accurately in the multiethnic U.S. population [11, 36]. By accounting for additional parameters like race, age, insulin, and glucose, they improved the algorithm's sensitivity and specificity. For USFLI, the diagnostic accuracy of ≥ 30 cut-point was 62% sensitivity, 88% specificity, 5.2 likelihood ratio of positive, and 0.43 likelihood ratio of negative . Despite the differences seen between younger and older NAFLD patients, the algorithms commonly used to identify NAFLD have not taken age into account as an effect modifier.
Our study's main strength was the dataset used, which contained both self-reported data and laboratory collected value to assess the relationship between individual characteristics and NAFLD. Additionally, our population-based estimates of prevalence are representative of the U.S. non-institutionalized population and collected in standardized ways by trained professionals. Along with using a robust data source, we used a validated algorithm for NAFLD diagnosis. One of the study's limitations is that the data used does not represent the institutionalized U.S. population who may have a different prevalence of NAFLD. The USFLI algorithm is a validated algorithm that accurately predicts the presence of steatosis but does not predict the severity of NAFLD. While algorithms are used to indicate NAFLD's presence, they are not the gold standard diagnostic tool. Future studies should utilize biopsy or imaging confirmed NAFLD cases. Lastly, the study design is cross-sectional, limiting us from analyzing NAFLD progression in individuals over time.