Abstract
Objectives:
The objective of this study was to investigate the association between measures of body composition based on bioelectrical impedance analysis (BIA) and histologic severity of liver disease in a pediatric cohort with nonalcoholic fatty liver disease (NAFLD).
Methods:
This was a cross-sectional study of patients < 20 y old with histologically confirmed NAFLD followed in our Steatohepatitis Center from 2017 to 2019. Contemporaneous body-composition data were obtained using a multifrequency octopolar BIA device (InBody 370, InBody, Seoul, South Korea). BIA data collected were skeletal muscle mass, appendicular muscle mass, and percentage body fat. Skeletal and appendicular muscle mass were corrected for height (dividing by the square of height), generating their respective indices. Univariate linear and logistic regression, followed by multivariable logistic regression analyses, were used.
Results:
Of the 79 children included (27% female, 73% male; 38% Hispanic; median age, 13 y; median body mass index Z-score, 2.43), the median NAFLD Activity Score was 4 (interquartile range, 3–5). In multivariable regression analyses, the skeletal muscle mass index was negatively associated with hepatic steatosis after controlling for confounders (odds ratio, 0.76; 95% confidence interval, 0.62–0.93). Similarly, the appendicular muscle mass index was negatively associated with severity of hepatic steatosis severity (odds ratio, 0.69; 95% confidence interval, 0.53–0.90). In contrast, percentage body fat was not associated with hepatic steatosis. NAFLD Activity Score, lobular inflammation, ballooning scores, and fibrosis stage were not associated with measures of body composition.
Conclusions:
There is an inverse association between BIA-based measures of muscle mass and severity of hepatic steatosis in children with NAFLD. BIA data could further inform clinical decision making in this context
Keywords: NASH, Sarcopenia, Body composition, Bioelectrical impedance, NAFLD, Pediatrics
Introduction
Nonalcoholic fatty liver disease (NAFLD) has become a highly prevalent liver disease globally in both adults and children [1,2]. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommends screening all children ages 9 to 11 y who are overweight or obese for NAFLD [3]. This is in part due to the higher prevalence of NAFLD, which may be as high as 30% to 50%, in youth with obesity [4,5]. Interestingly, however, obesity does not always predict NAFLD, and NAFLD also develops in people who are lean [6,7]. For example, even in countries where the prevalence of obesity is less than 5%, such as India and Japan, the prevalence of NAFLD is still found to surpass 30% [8]. The development of NAFLD in people who are not obese suggests that body-composition changes may be more accurate predictors of the presence and severity of NAFLD than body mass index (BMI) is.
Body composition can be assessed in a variety of ways. Clinically, it is most often determined using bioelectrical impedance analysis (BIA) or dual-energy x-ray absorptiometry. From a clinical research perspective, cross-sectional imaging (e.g., computed tomography/magnetic resonance imaging [MRI]) is used as well. We have previously shown that MRI-based measures of muscle mass are inversely correlated, in children with NAFLD, with both MRI-based measures of hepatic steatosis (proton-density fat fraction) and steatosis severity seen on histology [9]. However, MRI scans are costly, and the interpretation of body-composition results is currently not automated, rendering this tool less practical for clinical use [10]. In terms of clinically available tools, standard dual-energy x-ray absorptiometry machines are not portable and involve a small degree of radiation exposure, which limits broad application in clinical settings, particularly when frequent assessments are considered. In contrast, BIA is useful because of its relatively low cost, portability, and accessibility for repeated measurements [11]. Although BIA is a practical method for measuring body composition, there have been no studies investigating the association between body composition assessed using BIA and severity of pediatric NAFLD. Should an association be confirmed, BIA could be used as an adjunct to clinical and biochemical markers to predict disease severity.
Therefore, the objective of this study was to investigate whether body-composition estimates obtained by multifrequency octopolar BIA are associated with histologic disease severity in children with biopsy-confirmed NAFLD.
Materials and methods
Participants and design
This was a cross-sectional study of people ages < 20 years of age with both histologically confirmed NAFLD and BIA data obtained within 6 mo of the liver biopsy. Participants were patients followed at the Steatohepatitis Center at Cincinnati Children’s Hospital Medical Center from January 1, 2017, to August 31, 2019. Patients with secondary cases of hepatic steatosis (e.g., genetic or medication-induced), evidence of other or concurrent liver diseases (e.g., autoimmune hepatitis, primary sclerosing cholangitis), and history of weight-loss surgery or liver transplantation were excluded. The study protocol was approved by the Research Ethics Committee of Cincinnati Children’s Hospital Medical Center before the initiation of any research-related activities.
Collection of clinical data
Clinical records were reviewed retrospectively to collect demographic and clinical characteristics (age, sex, ethnicity, anthropometric data) at the time of BIA. Race could not be verified in this retrospective analysis and therefore was not included; however, ethnicity data were verified at time of visit and were included. Prescribed medications including metformin, insulin, vitamin E, and statins at the time of BIA were collected. Similarly, the results of laboratory investigations obtained within 3 mo of the BIA (whichever was closest)—including serum levels of alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, alkaline phosphatase, fasting glucose, fasting insulin, hemoglobin A1C, homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profile—were collected. Diagnosis of type 2 diabetes mellitus (T2DM) was defined as hemoglobin A1C > 6.4%, oral glucose tolerance test with plasma glucose > 200 mg/dL at the 2-h mark, or confirmation of T2DM diagnosis by an endocrinologist found in the participant’s electronic medical record.
Body-composition measurements by BIA
At our institution, patients undergo BIA assessments at every clinic visit (3–6-mo intervals), for clinical purposes. BIA is performed using a stationary multifrequency octopolar BIA device (InBody 370, InBody, Seoul, South Korea). Participants stood on the scale foot pads (2 electrode contact points per foot) and held a handle in each hand (containing two electrode contact points per hand) for about 1 min. Height, sex, and age were entered into the device. BIA data reviewed for this study were skeletal muscle mass (SMM, in kilograms, which is reflective of total body skeletal muscle mass), appendicular muscle mass (AMM, in kilograms, which reflects lean mass of the upper and lower extremities), trunk muscle mass (TMM, in kilograms), and percentage body fat. SMM, AMM, and TMM were corrected for height (by dividing by the square of height), generating, respectively, the SMM, AMM, and TMM indexes.
Histology
The classification developed by the Nonalcoholic Steatohepatitis Clinical Research Network was used to score the severity of steatosis (0–3), lobular inflammation (0–3), hepatocyte ballooning (0–2), and fibrosis (0–4). The NAFLD Activity score (NAS) was calculated as the sum of scores for steatosis, lobular inflammation, and ballooning (range, 0–8) [12]. The biopsies were reviewed by experienced hepatopathologists at our institution.
Statistical analyses
Descriptive statistics (median and interquartile range for continuous variables, frequency and percentage for categorical variables) are used to present the demographic and clinical characteristics of the cohort. Univariate linear and logistic regression analyses, followed by multivariable logistic regression analyses, were used to determine the relationships between measures of body composition and histology, adjusting for possible confounders, such as age, sex, ethnicity (Hispanic versus non-Hispanic), T2DM, and BMI Z-score. Statistical analyses were performed using Stata MP version 14.2 (StataCorp, College Station, TX, USA) and SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Significance was set at a threshold of P ≤ 0.05.
Results
In this study, 79 children had concurrent histology and BIA data available. The median time from liver biopsy to BIA was 1 mo (0–4). Of the 79 participants, 73% were male and 27% were female; 38% were Hispanic, 19% were on metformin, and 6% had a diagnosis of T2DM. The median age was 13 y (11–16), and median BMI Z-score was 2.43 (2.11–2.63).
Histologically, the median steatosis score was 2 (1–3) and the median NAS was 4 (3–5). Twenty-four participants (30%) had an NAS score ≥ 5, and 20% had fibrosis stage ≥ 2 (median fibrosis score 1; interquartile range, 0–1). The remaining baseline clinical, laboratory, and histologic characteristics of the study cohort are shown in Table 1.
Table 1.
Demographic and baseline clinical, laboratory, histologic, and imaging characteristics (n = 79)
| Variable | Value |
|---|---|
| Age (y) | 13(11–16) |
| Male sex; n (%) | 58(73) |
| Ethnicity | |
| Hispanic; n (%) | 30 (38) |
| Non-Hispanic; n (%) | 49 (62) |
| BMI Z-score | 2.43(2.11–2.63) |
| Type 2 diabetes mellitus; n (%) | 5(6) |
| Medication use at time of BIA | |
| Metformin; n (%) | 15(19) |
| Insulin; n (%) | 1(1) |
| Vitamin E; n (%) | 16(20) |
| Statin; n (%) | 1(1) |
| Laboratory data | |
| ALT (U/L) | 97 (63–155) |
| AST (U/L) | 44 (33–72) |
| GGT (U/L) | 44(30–61) |
| ALP(U/L) | 184(109–312) |
| Fasting glucose (mg/dL) | 91 (84–95) |
| Fasting serum insulin (mU/L) | 15(23– 31) |
| HbA1c (%) | 5.3 (5.1–5.4) |
| HOMA-IR | 5.41 (3.14–7.06) |
| Cholesterol (mg/dL) | 158(129–181) |
| LDL-C(mg/dL) | 86 (63–106) |
| HDL-C (mg/dL) | 41 (33– 48) |
| Triacylgylcerols (mg/dL) | 136(97–196) |
| Histology data | |
| Steatosis score | 2(1–3) |
| Lobular inflammation score | 1(1–2) |
| Ballooning score | 0(0–1) |
| NAS | 4(3–5) |
| NAS ≥ 5; n (%) | 24 (30) |
| Portal inflammation score | 1 (1–1) |
| Fibrosis stage | 1 (0–1) |
| Fibrosis ≥ 2; n (%) | 16(20) |
| BIA data | |
| SMM index (kg/m2) | 10.4(9.1–12.2) |
| AMM index (kg/m2) | 7.8 (6.8–9.1) |
| TMM index (kg/m2) | 9.1 (8.1–9.9) |
| Percentage body fat (%) | 43.5 (38.9–48) |
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMM, appendicular muscle mass; AST, aspartate aminotransferase; BIA, bioelectrical impedance analysis; BMI, body mass index, GGT, γ-glutamyl transpeptidase; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; SMM, skeletal muscle mass; TMM, trunk muscle massData are presented as median (interquartile range) or n (%)
In univariate analyses, SMM, TMM, and AMM indexes and age were all negatively associated with histologic steatosis severity, whereas Hispanic ethnicity was directly linked to a higher steatosis score (Supplementary Table 1). Similarly, SMM index, AMM index, and age were negatively associated with NAS and fibrosis stage, and Hispanic ethnicity was associated with increased odds of a higher NAS or fibrosis stage (Supplementary Tables 2 and 3). There were no associations between percentage body fat and steatosis score, NAS, or fibrosis stage (Supplementary Table 1).
In multivariable regression analyses, SMM index was negatively associated with hepatic steatosis after controlling for age, sex, ethnicity, T2DM, and BMI Z-score (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.62–0.93). Similarly, AMM index was negatively associated with severity of hepatic steatosis (OR, 0.69; 95% CI, 0.53–0.90) after controlling for the same confounders. In contrast, percentage body fat was not associated with hepatic steatosis after controlling for the same confounders.
Beyond histologic steatosis, the various muscle mass components and percentage body fat were not associated with NAS, lobular inflammation, ballooning scores, or fibrosis stage in multivariable analyses (data not shown). The only significant term to predict NAS was Hispanic ethnicity (OR, 2.85; 95% CI, 1.22–6.69), and the only one to predict fibrosis stage was age (OR, 0.86; 95% CI, 0.76–0.98).
Discussion
In this pediatric cohort with biopsy-confirmed NAFLD, we demonstrated that muscle mass, specifically the SMM and AMM indices, was associated with histologic steatosis severity. Specifically, the lower the muscle mass, the more severe the hepatic steatosis. In contrast, BMI Z-score, the clinical variable that is monitored most closely in clinical practice, was not associated with any histologic outcome. This is an important finding that underscores, once more, the limitations of BMI [13,14]. Furthermore, our results demonstrate that the incorporation of body-composition measurements obtained by BIA can be a meaningful addition to the data obtained routinely to predict NAFLD severity in clinical practice. This may help with risk stratification of patients, as well as with decision making (e.g., when to proceed with a liver biopsy). Although steatosis may not be a significant driver of liver-related outcomes (as fibrosis has proven to be in adults [15]), it is a reflection of metabolic dysregulation and as such may be a predictor of long-term morbidity. Given the ease of BIA acquisition, there is merit to considering incorporating BIA into the clinical care of people with NAFLD.
Our finding of a negative association between SMM and severity of hepatic steatosis aligns with previously published adult and pediatric literature. Petta et al. report that sarcopenia (defined using BIA measurements) was negatively associated with hepatic steatosis after controlling for confounders in adults [16]. Similarly, in two recent pediatric studies, muscle mass measured by dualenergy x-ray absorptiometry was found to be lower in children with nonalcoholic steatohepatitis, and cross-sectional total psoas muscle surface area measured by MRI was negatively associated with histologic steatosis severity [9,17].
The pathophysiological links explaining the inverse association between muscle mass and hepatic steatosis are not completely understood. Chronic inflammation and insulin resistance are thought to feed the cycle of sarcopenia and hepatic steatosis [18–21]. Skeletal muscle is a major site for glucose homeostasis through the expression of the insulin-dependent transporter GLUT-4, as well as a site for fat oxidation. In the context of insulin resistance, there is proteolysis, muscle depletion, and loss of muscle mitochondria [22,23]. The developing sarcopenia furthers peripheral insulin resistance and limits the steatosis of fat that can normally occur in skeletal muscle. In turn, both of these complications increase the amount of fat that returns to the liver (from muscle and adipose tissue), worsening steatosis severity [24]. Insulin resistance increases the hepatic uptake of free fatty acids released from adipose-tissue lipolysis, impairs suppression of gluconeogenesis, and inhibits fatty-acid oxidation, which ultimately leads to hepatic steatosis. In addition, impairment of insulin signaling of the mammalian target of rapamycin pathway and inhibited growth hormone/insulin growth factor-1 axis may diminish the synthesis of muscle protein and muscle regeneration, which impairs lipid handling in the periphery, further increasing the burden on the liver [25]. In spite of those data, as well as the results of our study, it remains to be seen whether optimizing the muscle mass of children with NAFLD has a beneficial effect on their histology.
Beyond steatosis, BIA-obtained measures of body composition in our cohort were not associated with NAS or fibrosis, which is in contrast to studies previously reported in the adult literature. One study of 74 participants from Greece with BIA data found that non-alcoholic steatohepatitis was more common among those with “increased” versus “average” abdominal fat levels [26]. However, similar to our study, these investigators also found no association between body fat and fibrosis stage. Another study of 225 people from Italy reported that muscle mass by BIA was associated with fibrosis and steatosis severity, independent of hepatic and metabolic risk factors [16]. The differences between our study and these adult studies may have to do with the changes in body composition that occur with age, the significantly lower prevalence of T2DM in children than in adults (T2DM is also associated with sarcopenia), and the relatively low prevalence of advanced fibrosis (fibrosis stage ≥ 2) in children with NAFLD. Additional studies with larger numbers of participants across the spectrum of disease severity are needed.
Beyond muscle mass, we demonstrated that percentage body fat was not associated with histologic NAFLD severity, including steatosis severity. This may be due to the fact that BIA does not provide granular data regarding the exact location of the fat depots. This is a significant limitation, as the metabolic implications of visceral versus subcutaneous fat are different, with the former being associated with increased metabolic dysregulation compared to the latter [27]. Nonetheless, our findings are in agreement with two previous studies using cross-sectional abdominal imaging in pediatric patients with NAFLD. In a study of 86 children with NAFLD, Trout et al. report that the distribution of abdominal fat measured by MRI was not associated with the severity of hepatic steatosis quantified using proton-density fat fraction [28]. Similarly, Seth et al. [29] revealed the uncoupling between obesity and steatosis severity by showing that neither histologic steatosis severity nor liver proton-density fat fraction were associated with the severity of childhood obesity (categorized using BMI as overweight, obese class I, obese class II, obese class III [30]). The inability to demonstrate a link between fat mass and histologic steatosis severity may suggest that the ability to store fat in the periphery is a protective, adaptive mechanism that serves to prevent excess fat from returning to the viscera. Additional “hits,” such as insulin resistance, genetic predisposition, diet, and the microbiome may determine the function of this adaptive fat tissue, which in turn regulates fat return to the liver [23,27,31].
Limitations of our study include its retrospective design and cross-sectional nature, which did not allow for detection of a cause-and-effect relationship between muscle mass and histologic outcomes. The study cohort may have introduced selection bias, as all participants had undergone a liver biopsy, which is typically reserved for people who are thought to have more severe disease, and the results may therefore not be generalizable to people with mild NAFLD. Furthermore, we lacked information regarding muscle function, which is part of the definition of adult sarcopenia [32]. Therefore, similar to the previously published pediatric literature, we focused on muscle mass only. In addition, BIA was not obtained concurrently with the liver biopsy, suggesting that it is possible that the participants’ body composition changed in the intervening months. This is less likely, however, as the median time between both tests was only 1 mo. Lastly, our sample size, while large for a cohort with confirmed NAFLD, may have been small enough to introduce type 2 error, particularly regarding histologic outcomes that are less frequent in pediatric NAFLD, such as advanced fibrosis.
Conclusion
In this pediatric cohort with biopsy-confirmed NAFLD, we found that muscle mass measured by BIA was associated with histologic hepatic steatosis severity. Although these results are cross-sectional and do not prove a causative relationship between decreased muscle mass and severity of liver disease in pediatric NAFLD, they do suggest that the addition of BIA to the armamentarium of clinicians caring for people with NAFLD may be beneficial. Future studies should directly explore whether the interventions that enhance muscle mass can improve the liver histology of children with NAFLD.
Supplementary Material
Acknowledgments
S. O. was funded by NIH T32 DK007727. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no relevant financial disclosures and none of the authors have any potential conflicts of interest to declare.
Footnotes
Supplementary materials
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.nut.2021.111447.
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