Abstract
Association between pulmonary function tests (PFTs) and non-alcoholic fatty liver disease (NAFLD) has been reported in adult studies; however, there is lack of pediatric studies. Our study aimed to evaluate PFTs in children with NAFLD. A total of 137 children with NAFLD and 100 healthy children of matched age and sex were included in the study. Different PFTs including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, residual volume (RV), and total lung capacity (TLC) were performed for all included children. Lipid profile, insulin resistance, fasting and postprandial glucose level, and high sensitive C reactive protein (hs-CRP) were measured. FEV1 %, FVC %, FEV1/FVC ratio, RV, and TLC were significantly lower in the patient group compared with the control group (P < 0.05), while RV and hs-CRP were significantly higher in children with NAFLD. Restrictive lung dysfunction was the commonest pulmonary dysfunction detected in children with NAFLD (21.9%). PFT indices were significantly correlated with grade and duration of NAFLD, insulin resistance, waist circumference, and hs-CRP. Regression analysis revealed that insulin resistance and hs-CRP were independently associated with decreased PFT indices.
Conclusion: PFT indices were impaired in children with NAFLD and this impairment was independently associated with insulin resistance and hs-CRP.
What is Known: • Pulmonary function tests (PFTs) abnormalities are common in adults with nonalcoholic fatty liver disease (NAFLD). • Studies involving PFTs abnormalities in pediatric NAFLD are lacking. | |
What is New: • It is the first study that assessed PFT in pediatric patients with NAFLD. • PFTs abnormalities are present in children with NAFLD. • Insulin resistance and high sensitive C reactive protein are independently associated with the decline of PFTs in children with NAFLD. |
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Introduction
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver diseases, characterized by excessive hepatic fat accumulation (steatosis) in the absence of significant alcohol consumption [1]. It became one of the most common causes of chronic liver disease in children worldwide. A significant proportion of patients progress to non-alcoholic steatohepatitis (NASH), hepatic necrosis, cirrhosis, and hepatocellular carcinoma [2].
NAFLD is thought to be a hepatic manifestation of more widespread and underlying metabolic dysfunction and is strongly associated with a number of metabolic conditions such as insulin resistance, dyslipidemia, cardiovascular disease, and central obesity [2,3,4,5,6,7]. NAFLD is associated with various extrahepatic complications such as cardio-metabolic diseases, chronic kidney disease, and sarcopenia through increased low-grade systemic inflammation mechanism [8,9,10,11,12]. Low-grade systemic inflammation plays a causal role in the development of NAFLD [13, 14].
Recently, the association between lung function and metabolic conditions attracts the attention of researchers. Previous studies have demonstrated that impaired lung function is associated with an increase in low-grade inflammation, increased risk of diabetes, cardiovascular disease, and metabolic syndrome [15,16,17].
Few studies reported impaired lung function in adult with NAFLD but these studies are lacking in pediatrics [18, 19]. Our study aimed to evaluate the PFTs in children and adolescents with NAFLD and to correlate the findings with various clinical, laboratory, and ultrasonographic data.
Methods
This prospective cross section study was carried out at Pediatric and Gastroenterology departments, Tanta University Hospital between June 2016 and April 2020. The study included 137 children and adolescent with ultrasound-proven NAFLD for more than 3 years. One hundred healthy subjects of matched age and sex selected from the siblings of included patients served as a control group. The study was conducted in accordance with the principles of the Declaration of Helsinki. At the start of the study, all parents were informed about the study and signed a written consent after approval to participate in the study. The study was approved by local Ethical Committee of our faculty of medicine.
Inclusion criteria
Children and adolescents below 18 years with ultrasound-proven NAFLD for more than 3 years who can perform PFTs.
Exclusion criteria
Children with other chronic liver disease, children with chest infection within the previous 2 weeks, children with viral hepatitis, e.g., hepatitis B or C, pregnant adolescent, alcohol consumption, chronic chest disease such as bronchial asthma, patients with diabetes mellitus, ex or current smokers, children with cardiac disease, children with systemic disease that can affect PFTs, and children who cannot perform PFTs.
All included patients underwent thorough clinical examination including anthropometric measurements such as height, weight, waist circumference (WC), hip circumference (HC), waist to hip ratio (W/H), and body mass index (BMI). BMI was calculated as weight (kg)/(height in meters)2. Blood pressure was measured at the left arm three times consecutively with 1-min intervals after at least 5-min rest in the seated position; the three readings were averaged for analysis. Chest x-ray was also performed to exclude chest pathology.
All laboratory investigations including hepatitis B and C markers were drawn. All subjects were assessed, after overnight fasting for at least 10 h, for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). They were measured on an automatic analyzer (Hitachi 7080; Tokyo, Japan). Fasting glucose, 2 h post-prandial glucose level, and fasting serum insulin were also measured. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated according to the equation HOMA-IR = fasting serum glucose (mmol/L) × fasting serum insulin (mU/mL) / 22.5 [20] and values ≥ 2.5 indicate insulin resistance. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), complete blood count, and high sensitive C-reactive protein (hs-CRP) were measured according to standard protocols.
Liver ultrasonography
Liver ultrasonography was carried out by an expert radiologist who was not a part of the study using an Acuson S2000 system (Siemens) with linear and convex transducers 4–14 MHz to diagnose the presence of NAFLD and to define its stage. Grade 0 was defined as normal liver echo-texture with absent steatosis, grade I was defined as slight and diffuse increase in fine parenchymal echoes with normal visualization of diaphragm and portal vein borders which means mild steatosis, grade II was defined as moderate and diffuse increase in fine echoes with slightly impaired visualization of diaphragm and portal vein borders which means moderate steatosis, and grade III was defined as fine echoes with poor or no visualization of diaphragm, portal vein borders, and posterior portion of the right lobe which means severe steatosis [21]. Intra-observer variability was good with intraclass correlation coefficient (ICC) of 92% (95%CI: 88–95%).
Pulmonary function tests
PFTs in the form of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, residual volume (RV), and total lung capacity (TLC) were measured in all included children [22]. FEV1, FVC, and FEV1/FVC were measured using spirometry (Erich Jaeger GmbH, Hoechberg, Germany), while RV and TLC were measured using whole-body plethysmography. PFTs were repeated for 3 times and the best value was recorded. Data were recorded as the percentage of predicted values for age, gender, and height [23].
All our included children were classified into one of the four out of five classes according to the American Thoracic Society [24]. The four classes are normal pattern where all PFT parameters were normal, obstructive pattern which is characterized by decreased FEV1/FVC below the fifth percentile of the predicted value with normal or elevated TLC, restrictive pattern which is characterized by decreased TLC below the fifth percentile of the predicted value with normal FEV1/FVC, and mixed pattern (obstructive and restrictive abnormalities) which is characterized by decreased FEV1/FVC and TLC below the fifth percentile of predicted value.
The primary outcome was to assess the PFTs in children and adolescents with NAFLD. The secondary outcome was to correlate PFTs with various clinical, laboratory, and ultrasonographic data.
Statistical analysis
Power analysis was performed using G*Power program that showed that 97 patients in every group were required to achieve a power of 90% with α=0.05 to detect a difference of 4 in the mean of FEV1. All statistical analysis was performed with the SPSS Statistical Package (version 21; SPSS Inc., Chicago, IL). Normal distribution of the data was tested using Shapiro-Wilk test. Normally distributed data were expressed as means ± SD, whereas variables with a skewed distribution were reported as median and interquartile range. Comparisons of means between the two groups were performed using Student’s t test. Comparisons of medians between the two groups were performed using Wilcoxon-Mann-Whitney test, while comparison of categorical variables between the two groups was performed using Chi-square test. Correlation between PFTs and other variables was performed using Spearman correlation test. After adjusting for body mass index, age, and sex, multiple linear regression analysis was performed to identify factors that were independently associated with decreased lung function. P < 0.05 was considered statistically significant.
Results
This study includes 137 children and adolescents with NAFLD patients and 100 healthy children as a control group. BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), WC, HC, and W/H ratio were significantly higher in children with NAFLD compared with the control group. Similarly, triglycerides level, LDL, AST, ALT, GGT, and hs-CRP were significantly higher in children with NAFLD compared with the healthy control group, while HDL was significantly lower in children with NAFLD compared with the healthy control group. All glycemic parameters were significantly higher in children with NAFLD compared with the healthy control (fasting plasma glucose 6.2 ± 1 vs 5.5 ± 1.2 mmol/L, 2 h PG 8.2 ± 1.9 vs 7.2 ± 2.7 mmol/L, HbA1c 5.8 ± 0.9 vs 5 ± 0.8, HOMA-IR 2.08 vs 1.51, respectively), putting into considerations that all patients with overt DM were excluded from the start (Table 1).
Most pulmonary function indices including FEV1, FVC, FEV1/FVC, and TLC were significantly lower in children with NAFLD than those in healthy control. However, RV was significantly higher in children with NAFLD than the controls. Lung function was normal in all children of the control group, while in children with NAFLD, 78 patients (56.9%) had normal lung functions, 7 patients (5.1%) had obstructive pattern, 30 patients (21.9%) had restrictive pattern, and 22 patients (16.1%) had mixed obstructive and restrictive pattern (Table 2).
Table 3 shows a significant negative correlation between grades of steatosis and FEV1, FVC, and TLC but a significant positive correlation between grades of steatosis and RV. The table also revealed the presence of a significant negative correlation of duration of NAFLD with the FEV1 and FVC, but it had a positive correlation with RV. The table also revealed significant negative correlations between levels of hs-CRP and FEV1, FVC, and TLC. On the other hand, levels of hs-CRP had a positive correlation with RV. WC had significant negative correlations with FEV1 and FVC but a significant positive correlation with RV. Moreover, HOMA-IR had significant negative correlations with FEV1 and FVC but a significant positive correlation with RV.
Table 4 shows multiple linear regression analysis of the factors that independently associated with decreased PFT in children with NAFLD. It revealed that HOMA-IR and hs-CRP were independently associated with the decrease of FEV1, FEV, and RV. At the same time, multiple linear regression analysis revealed that the duration of NAFLD and WC was not independently associated with decrease of PFTs.
Discussion
Many previous studies performed in adult population documented the association of impaired PFTs with NAFLD irrespective of whether the subjects were smokers or not [25, 26]. Furthermore, emerging evidence has shown that both NAFLD and impaired lung functions were commonly associated with metabolic comorbidities [27]. To our best knowledge, this is the first study that evaluated PFTs in children and adolescents with NAFLD.
Our study confirmed that all measured PFTs (FEV1, EVC, FEV1/FVC ratio, and TLC) in patients with NAFLD were significantly lower than those of the healthy controls. Of interest, restrictive lung pattern was the most common associated lung lesion with NAFLD (21.9%). Obstructive lung pattern is rare and occurs only in 5.1% of the patients, while mixed lung lesion occurs in 16.1% of the patients.
Pulmonary affection that occurs in children and adolescents with NAFLD consists merely of subclinical abnormal lung function as none of our patient had any chest complaint. This reflects the importance of PFTs in detection of latent lung affection in NAFLD patients before it turns into a manifest disease.
The underlying mechanisms of impaired lung function in NAFLD remain unclear. However, insulin resistance may play a role as it is closely associated with both NAFLD and reduced lung function [28, 29]. Interestingly, NAFLD is also associated with insulin resistance in skeletal muscle that reduces glucose utilization and induces abnormal fat metabolism which may impair mitochondrial adenosine triphosphate production and reduce skeletal muscle strength [12, 30]. Good respiratory skeletal muscle contraction is needed for forced respiration during spirometry, so a decline of lung function is expected due to decreased skeletal muscle strength and mass in patients with NAFLD [30, 31]. Furthermore, we observed a significant negative correlation between PFTs and insulin resistance as measured by HOMA-IR. It has been documented that insulin resistance plays an important role in the development of NAFLD [32, 33]. Metabolic risk factors which are associated with insulin resistance such as BMI, blood pressure, FBG, WC, and lipid profile may be responsible for the association of impaired lung function with NAFLD.
Interaction between inflammatory process and metabolic pathways in NAFLD patients may be another underlying mechanism that links impaired pulmonary function and NAFLD [34]. A strong association between lung function tests and inflammatory markers has been reported in several previous studies [35, 36]. Low-grade systemic inflammation plays an important role in the development of NAFLD; thus, the inflammatory process may associate reduced lung function with NAFLD. In our study, there were significant higher serum levels of hs-CRP in children with NAFLD compared with the control group. Increased serum hs-CRP, a marker of systemic inflammation, has been positively associated with lung function decline [15]. Moreover, we reported that serum levels of hs-CRP were significantly inversely correlated with the indices of PFTs in children with NAFLD.
Another possible explanation for this association between impaired PFTs and NAFLD is the central obesity. Our patients with NAFLD had higher WC compared with healthy control which may mechanically decrease chest wall compliance. Central obesity increases abdominal pressure that restricts the descent of the diaphragm and limits lung expansion thereby causing restriction of lung inflation [27]. The inverse correlation between central obesity measured by WC and PFTs was demonstrated in our study as well as previous studies [37, 38].
Our study also showed that impaired lung function was significantly associated with grades and duration of NAFLD. This was in agreement with the results of previous studies in adults [19, 26]. Increased severity and duration of NAFLD are associated with increased systemic inflammation that can explain decreased lung function in these patients. Interestingly, regression analysis revealed that only HOMA-IR and hs-CRP were the only independable factors associated with PFT. This raises the importance of insulin resistance and systemic inflammatory mechanisms in explaining the decline of PFTs in children with NAFLD.
Limitation of the study
The diagnosis of NAFLD was based on ultrasonic examination and elevated ALT not liver biopsy; however, liver ultrasound is the most widely used noninvasive technique to detect NAFLD in clinical studies with high sensitivity and specificity to diagnose NAFLD and its grade. Serial PFT measurements in the patient group to detect impact of disease progression on PFT results were not performed.
Conclusion
PFTs indices were impaired in children and adolescents with NAFLD and this impairment was independently associated with insulin resistance and hs-CRP.
Data availability
Available when required.
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D.E., S.G., and S.H. collected the study data, wrote, revised, and approved the manuscript. H.E. and S.M. performed the statistical analysis, collected the study data, wrote, revised, and approved the manuscript.
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Local ethics committee of Faculty of Medicine, Tanta University, approved the study. The study is in accordance with the ethical standards of institutional research committee and with the 1964 Helsinki declaration and its later amendments.
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An informed consent was obtained from the parents of all subjects of the study before enrollment.
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El Amrousy, D., El Ashry, H., Maher, S. et al. Pulmonary function test abnormalities in children and adolescents with non-alcoholic fatty liver disease. Eur J Pediatr 180, 1693–1699 (2021). https://doi.org/10.1007/s00431-021-03941-3
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DOI: https://doi.org/10.1007/s00431-021-03941-3