In this study, we investigated the association between NAFLD as measured using FLI, a validated surrogate marker, and the incidence of asthma in a large, representative sample of the Korean population. NAFLD was associated with an increase in the incidence of asthma and in most clinical subgroups except alcohol drinkers, an increase in the incidence of asthma was observed with an increase in the FLI score. Furthermore, as the FLI score increased, the utilization of asthma-related health care services such as hospitalization days and outpatient visits also increased.
In current study, the incidence of asthma was slightly higher in the middle group (30 ≤ FLI < 60) compared to the highest FLI group. However, as a result of confirming the hazard ratios, it was found that asthma incidence increased as FLI increased, and the same result was obtained in the analysis using other types of FLI categories and HIS, another surrogate marker of NAFLD. Therefore, our findings support the possibility of NAFLD influencing the occurrence of asthma.
NAFLD is highly prevalent worldwide, and it is known that NAFLD occurs along the lines of MetS progression24. Similar to MetS, the association of NAFLD with extrahepatic complications such as cardiovascular disease, chronic kidney disease and insulin resistance are well known3,4,24. Because potential associations with other diseases including atrial fibrillation and periodontitis have recently been suggested, there is increased interest in the effect of NAFLD on multiple organs 5,25.
Numerous studies have reported a correlation between MetS and impairment of lung function. Of the MetS components, robust epidemiological data linking abdominal obesity with the incidence and exacerbation of asthma are available26. Other factors such as dyslipidemia, hyperglycemia, and hypertension have also shown to be independently associated with asthma. Waist circumference and insulin resistance were revealed independent risk factors for asthma in a large Norwegian adult asthma cohort, and high triglyceride (TG) level and insulin resistance were independently associated with asthma incidence in a cross-sectional study of children aged 4–12 years in West Virginia9,27.
Given the above results, a relationship between asthma and NAFLD may be suspected. Therefore, we evaluated the association between these two diseases using a large population after excluding known risk factors such as diabetes, hyperlipidemia, hypertension, and smoking exposure and confirmed the independent association of NAFLD with asthma incidence. To the best of our knowledge, this is the first study to confirm the association between asthma incidence and NAFLD. However, the magnitude of association was not very high, and the following explanation of our results may be considered.
Because the study used health insurance data, asthma patients of all severity levels were included because it was not possible to determine the control status or severity level. Given that less than 10% of all asthma patients were diagnosed with severe asthma, it is believed that a number of mild asthmatic patients were included, which could have diluted the association.
The association between NAFLD and asthma incidence identified in this study may be explained by several pathophysiological mechanisms underlying the two diseases. First, in patients with NAFLD, elevated levels of circulatory TG and free fatty acids have been observed. Excess fat increases the production of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 through the activation of innate immune responses such as pattern recognition receptor28,29. Excess fatty acid is also involved in the production of reactive oxygen species by inducing endoplasmic reticulum stress30. Increased proinflammatory cytokines and oxidative stress may cause airway epithelial damage and airway inflammation, which may affect asthma development31,32. Second, insulin resistance, which plays a key role in the development of fatty liver disease, leads to excessive insulin secretion in the blood. Insulin is thought to contribute to airway hypersensitivity and airway remodeling by causing epithelial damage and smooth muscle proliferation in the airway33. In addition, hyperinsulinemia was reported to have been involved in enhancing airway responsiveness through parasympathetic stimulation in an asthma mouse model 34.
Similar to the above-mentioned observations, our study also confirmed that an increase in age, weight, or poor lipid profile affects the incidence of asthma. Daily physical activity tended to have a positive effect on the suppression of asthma.
Furthermore, we analyzed the correlation between FLI and asthma-related healthcare service utilization, and the number of patients who experienced hospitalization was higher in the group with low FLI, but the number of hospitalizations per patient, number of days of hospitalization, and outpatient frequency increased with higher FLI. The discrepancy between the incidence of asthma and asthma-related hospitalization may have been influenced by the fact that the severity of asthma was not reflected in this study. In fact, the increase in the number of hospitalizations per patient, the number of days of hospitalization, and intensive care unit admission in the high FLI group in this study may also suggest a possible association between FLI and asthma severity. In a study of more than 70,000 adolescents in Brazil published by Kuchinir et al., a significant association was reported between MetS and asthma control35. In a similar vein, progression of NAFLD may also affect the severity of asthma. Further research is needed that reflects the severity of asthma.
As another important point, in this study, women showed a stronger correlation between FLI and asthma incidence than men. Several previous studies reported a higher correlation between obesity and asthma in women36,37, but others provided conflicting results38. Some studies have reported the correlation between metabolic abnormality and the occurrence of asthma9,39, but few studies have investigated gender differences. There are several possible mechanisms for differences in the association between asthma incidence and FLI by gender. It is thought that the female sex hormone estrogen may be involved in Th2 inflammation and airway hypersensitivity40. It has also been suggested that the level of leptin, an adipokine with pro-inflammatory effect, is high in women independently of body fat mass41. Overlapping genetic foci associated with asthma and obesity have been reported, and genetic differences are thought to have an effect42,43, but it is still unclear.
Currently, NAFLD is a disease of increasing global concern, several guidelines recommend regular screening in patients with chronic conditions such as obesity, diabetes mellitus, and MetS44. In addition to weight reduction, oral hypoglycemic agents are currently being used in an attempt to treat NAFLD44. Based on the results of the current study, improvement of NAFLD through such interventions is expected to have a positive effect on asthma. Further studies are needed in the future.
This study has some limitations. First, the incidence of asthma may be overestimated because asthma patients may asymptomatic or have symptoms but do not need medical care for years. To minimize this error, all patients who were diagnosed with asthma or were prescribed asthma-related medication within two year before the index year were excluded based on previous studies45. However, the duration of two year may not have been sufficient. However, since the focus of current study was not on the asthma incidence rate itself, but on the identification of the correlation between asthma incidence and fatty liver, it seems that the effect on the outcome was not significant. Second, in this study, determination of NAFLD status did not involve imaging tests such as abdominal ultrasonography or magnetic resonance imaging, which are currently first-line diagnostic methods. However, the FLI used in the current study was validated as a predictor of NAFLD in several existing studies in both Asian and Western populations19,21,22,46. In addition, health checkups in various countries currently do not include imaging tests. Therefore, we think that FLI, which can be easily obtained from data obtained from health checkups, may rather comprehensively reflect the presence of hepatic steatosis in the general population. Third, we were unable to include family history of allergic disease, allergen exposure, and atopic status known as asthma risk factors in this study due to the nature of health insurance data. Finally, the generalizability of our study findings is limited to the Korean population. Further studies will be needed for other ethnic groups.
In conclusion, the results of this study suggest that NAFLD, which was measured using the FLI, was associated with an increase in asthma incidence in healthy Korean population, especially in women. It was also confirmed that progression of NAFLD may affect the severity of asthma. These findings suggest that clinicians should be aware of the higher risk of asthma among patients with NAFLD. Further research on the impact of NAFLD management on the incidence and severity of asthma is needed.