Muscle mass and cellular membrane integrity assessment in patients with nonalcoholic fatty liver disease

SUMMARY

OBJECTIVE:

To evaluate the association between muscle mass depletion and compromising of the cell membrane integrity and clinical–anthropometric characteristics in patients with nonalcoholic fatty liver disease.

METHODS:

This observational study evaluated waist circumference, body mass index, and waist-to-height ratio in patients with nonalcoholic fatty liver disease. Skeletal mass index corrected by weight and impairment of cell membrane integrity were assessed using bioelectrical impedance analysis.

RESULTS:

In 56 patients, muscle mass depletion was observed in 62.5% and cell membrane impairment in 28.6%. The metabolic syndrome and elevated aspartate aminotransferase were the only clinical factors associated with mass depletion (p<0.05). The linear regression analysis showed association between skeletal mass index and waist-to-height ratio and waist circumference, after adjustments (p<0.05). The phase angle value was not different between those with and without mass depletion, and also it did not have correlation with skeletal mass index and clinical parameters (p>0.05).

CONCLUSIONS:

The prevalence of mass depletion and cell membrane impairment was higher in patients with nonalcoholic fatty liver disease. The muscle mass depletion was associated with central obesity, aspartate aminotransferase elevated, and metabolic syndrome; however, the phase angle is not associated with clinical and anthropometric data.

KEYWORDS:
Non-alcoholic fatty liver disease; Skeletal muscle; Bioelectrical impedance; Obesity; Central obesity

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases in the world, and evidence points that body composition is directly related to the pathogenesis of NAFLD¹. Thus, visceral obesity is listed as the main factor promoting metabolic changes, since it leads to an imbalance between adipokine secretion, with an increase in inflammatory cytokines and, consequently, influencing insulin resistance (IR) and oxidative stress².

However, muscle mass (MM) has also gained prominence in several diseases, including NAFLD³. It seems that the connection between the liver, adipose tissue, and muscle occurs through the expression of insulin receptors in these tissues, in view of the anabolic role of insulin, in the presence of IR in myocytes, protein catabolism increases, resulting in MM depletion and, consequently, in sarcopenia⁴.

The integrity of the cell membrane can be assessed by bioelectrical impedance analysis (BIA) and identified with the phase angle (PA) value. PA has been studied in several clinical conditions and found that the higher the PA values, the better the integrity of the membrane and thus the better cellular function. Studies show that low PA values are correlated with prognosis of chronic obstructive pulmonary disease, peritoneal dialysis, hemodialysis, and liver cirrhosis, being used as an indicator of nutritional status and prognosis of mortality⁵–⁸.

The aim of this study was to assess whether there is an association between MM reserve, impaired cell membrane integrity, and clinical–anthropometric characteristics in patients with NAFLD.

METHODS

Study design and sample

A cross-sectional, observational study was performed with patients followed up at a nonalcoholic steatohepatitis outpatient clinic. The sample was obtained for convenience between March 2016 and 2017. Inclusion criteria: patients of either sex above 18 years and below 60 years of age. Patients with special needs or diseases that made it difficult to perform anthropometric measurements and ethanol intake ≥140 g/week; patients with thyroid disease, hepatitis A, B, and C, autoimmune disease, Wilson's disease, or hemochromatosis and pregnant and lactating women were not included.

Clinical evaluation

Patients were screened by a team of nutritionists and previously trained students, using a semistructured questionnaire to identify demographic, clinical, and nutritional data.

Abdominal ultrasonography was used to measure intrahepatic fat, being performed by a single evaluator.

Anthropometric evaluation

Weight and height measurements were obtained with a digital scale (Leader, 200 kg capacity and 100 g precision) and coupled stadiometer⁹. The body mass index (BMI) was calculated, and overweight with BMI ≥ 25.0 kg/m²¹⁰.

Central obesity was identified when waist circumference (WC) ≥ 80 cm for women and ≥ 94 cm for men¹¹ and waist-to-height ratio (WhtR) >0.5¹².

Muscle mass

MM was measured using BIA (Biodynamics 450^®)¹³. The skeletal mass index (SMI) adjusted for weight was calculated¹⁴,¹⁵.

Muscle mass depletion was defined when SMI <37% for men and <28% for women¹⁶.

Cell membrane impairment

The cell membrane impairment was evaluated by the PA identified in the BIA, and the cutoff point ≤ the 25th percentile obtained in the statistical analysis of this sample was adopted.

Laboratory evaluation

The registered tests were alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (AF), blood glucose, insulin, and triglycerides. IR was calculated by homeostasis model assessment for insulin resistance (HOMA-IR)¹⁷. Metabolic syndrome was classified according to the International Diabetes Federation¹¹.

Statistical analysis

The statistical software SPSS version 21.0 was used for data analysis. The patients were grouped according to the MM evaluated, and to compare the means between groups by the Student's t-test and the proportions by Pearson's chi-square or Fisher's exact tests. Pearson's correlation was used to analyze the correlation between parametric variables and MM. Associations between MM and continuous variables were assessed by simple and multiple linear regression analyzes. For the multiple linear regression model, variables with p value <0.20, obtained in the bivariate analysis, were considered. The hierarchical selection method was used to construct the regression models and calculate the adjusted determination coefficient (R²), with a 95% confidence interval (95% CI). The level of significance was p<0.05.

RESULTS

General characteristics

All eligible patients were included in the study. Fifty-six patients with NAFLD, with a mean age of 47.7 ± 8.6 years and predominantly females (67.9%), were participated. Of note, 91.1% of the patients were presented with overweight and central obesity. A higher frequency of physically inactive individuals (56.3%), hypertensive individuals (33.9%), and grades II and III steatosis (67.9%) was observed. In a subgroup of 21 patients, 38.1% had IR (Table 1).

Table 1
Clinical and demographic characteristics in a group of patients with nonalcoholic fatty liver disease treated at a referral clinic.

		Total	Muscle Mass		p**
			Depletion	Adequate
Sex, n (%)
	Male	18 (32.1)	11 (31.4)	7 (33.3)	0.883
	Female	38 (67.9)	24 (68.6)	14 (66.7)
Age (years) $\overline{\text{χ}}$ (SD)		47.7 (8.6)	47.3 (9.3)	48.6 (7.4)	0.573a
Race
	Whites	3 (5.4)	1 (2.9)	2 (9.5)	0.246b
	Not whites	53 (94.6)	34 (97.1)	19 (90.5)
Weight (kg) $\overline{\text{χ}}$ (SD)		78.9 (14.7)	83.5(15.2)	71.3 (10.2)	0.002a
BMI (kg/m2) $\overline{\text{χ}}$ (SD)		30.6 (4.8)	32.4 (4.9)	27.7 (3.1)	<0.001a
WHtR $\overline{\text{χ}}$ (SD)		0.62 (0.07)	0.64 (0.08)	0.58 (0.05)	0.001a
WC (cm) $\overline{\text{χ}}$ (SD)		99.1 (11.1)	103.2(10.8)	92.4 (8.1)	<0.001a
Phase angle $\overline{\text{χ}}$ (SD)		7.3 (2.3)	7.7 (2.7)	6.8 (1.2)	0.102
Physical activity**, n (%)
	Yes	18 (56.3)	12 (57.1)	6 (54.5)	0.888
	Not	14 (43.8)	9 (42.9)	5 (45.5)
Comorbities, n (%)
	IIDM	16 (28.6)	11(68.8)	5 (31.3)	0.541
	Dyslipidemia	16 (28.6)	12 (75)	4 (25)	0.360b
	SHA	19 (33.9)	11 (64.9)	13 (35.1)	0.610
Grade steatosis, n (%)
	Grade I	18 (32.1)	11 (31.4)	7 (33.3)	0.833
	Grades II–III	38 (67.9)	24 (68.6)	14 (66.7)
ALT, n (%)
	Normal	47 (88.7)	29 (85.3)	18 (94.7)	0.402b
	Increased	6 (11.3)	5 (14.7)	1 (5.3)
AST, n (%)
	Normal	41 (78.8)	22 (66.7)	19 (100)	0.004b
	Increased	11 (21.2)	11 (33.3)	0 (0.0)
GGT, n (%)
	Normal	38 (73.0)	22 (66.7)	16 (84.2)	0.209b
	Increased	14 (27.0)	11 (33.3)	3 (15.8)
FA, n (%)
	Normal	38 (82.6)	23 (76.7)	15 (93.8)	0.230b
	Increased	8 (17.4)	7 (23.3)	1 (6.3)
TG, n (%)
	Normal	31 (59.6)	19 (57.6)	12 (63.2)	0.693
	Increased	21 (37.5)	14 (42.4)	7 (36.8)
GLICEMIA, n (%)
	Normal	36 (69.2)	21(63.6)	15 (78.9)	0.353b
	Increased	16 (30.8)	12 (36.4)	4 (21.1)
HOMA-IR*, n (%)
	Normal	13 (61.9)	8 (57.1)	5 (71.4)	0.656b
	Increased	8 (38.1)	6 (42.9)	2 (28.6)
Metabolic syndrome***
	Yes	24 (46.2)	19(57.6)	5 (26.3)	0.029
	No	28 (53.8)	14(42.4)	14 (73.7)

• ^*
  21 patients
• ^**
  Pearson's χ² test
• ^***
  52 patients
• ^a
  Student's t- test
• ^b
  Fisher's exact test. BMI: body mass index; WHtR: waist-to-height ratio; WC: waist circumference; IIDM: type 2 diabetes mellitus; SAH: systemic arterial hypertension; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyltransferase; FA: alkaline phosphatase; TG: triglycerides; HOMA-IR: insulin resistance index.

Muscle mass and cell membrane impairment

MM depletion was found in 62.5% of the population patients with NAFLD and cell membrane impairment in 28.6%.

The values of BMI, WHtR, and WC were higher in the group with MM depletion when compared to the group without depletion (p<0.05). MS was present in 57.6% of patients with MM depletion (p=0.03). However, the same finding was not obtained with the HOMA-IR (Table 1). Only AST was related to MM depletion (p=0.004) (Table 1).

PA showed no difference in relation to MM depletion and none association or correlation with anthropometric, clinical, and biochemical data (p>0.05) (Table 1).

We observed a moderate negative linear correlation between the WHtR and the SMI, in addition to the weak negative correlation with the BMI and WC and SMI (p<0.05) (Figure 1).

Figure 1
Correlation between: (A) BMI and SMI (r= -0.493; p<0.001); (B) WC and SMI (r= -0.312; p=0.019); (C) WhtR and SMI (r= -0.536; p≤0.001) in patients with nonalcoholic fatty liver disease.

Regression analysis

In the analysis of simple linear regression between SMI as independent variables, it was observed that there was a significant relation between WHtR, WC, and BMI with SMI (β= -48.74, 95%CI -69.67 – -27.81; β= -0.194, 95%CI -0.353 – -0.035; β= -0.695, 95%CI -1.029 − -0.360, respectively).

Multiple linear regression demonstrated that anthropometric parameters were associated with the dependent variable in all models. It is evident that the WHtR is a much stronger predictor in the depletion of MM. Note that the association of central obesity indicators (WHtR and WC) and total body mass improves the prediction of change in SMI, explaining 43.0% of this (Table 2).

Table 2
Linear regression selected from anthropometric variables associated with skeletal muscle mass index in a group of patients with nonalcoholic fatty liver disease treated at a referral clinic.

Skeletal muscle mass index (%)
	Model 1				Model 2				Final model
Variable	β adjusted	P	CI	R2	β adjusted	P	CI	R2	β adjusted	P	CI	R2
WHtR	−0.54	<0.001	−69.67 – -27.81	0.29	−1.08	<0.001	−138.8 – -58.50	0.38	−0.79	0.004	−118.9 – -24.02	0.43
BMI	–	–	–		–	–	–		−0.59	0.048	−1.650 – -0.006
WC	–	–	–		0.63	0.006	0.115–0.657		0.90	0.001	0.241 – 0.860

• Model 1: adjusted by the BMI and WC variables; Model 2: adjusted by the BMI variable; Model 3: adjusted by BMI, WC, and WHtR. WHtR: waist-to-height ratio; BMI: body mass index; WC: waist circumference; CI: confidence interval.

DISCUSSION

More than half of the patients with NAFLD evaluated in this study had MM depletion and approximately one-third cell membrane impairment. The cell membrane impairment does not seem to be associated with the clinical and anthropometric characteristics of these patients; however, skeletal MM was associated with metabolic syndrome, elevated AST, and central obesity indicators (WHtR and WC).

The MM depletion had also a high prevalence in a study with Caucasian patients with NAFLD, using the same cutoff points adopted in the present study¹⁸ and studies with Asian patients with NAFLD¹⁹,²⁰. Koo et al.²¹ observed that the occurrence of nonalcoholic steatohepatitis (NASH) may be associated with MM depletion.

In patients with NAFLD, a reduction in the MM can synergistically increase visceral fat.²² The association of central obesity with the reduction in MM was the main finding in this study, corroborating with data from the literature²⁰,²³.

IR has been identified as the link between MS and NAFLD²⁴. Furthermore, it is also suggested as a key factor in the genesis of sarcopenia, since when there is IR in myocytes, less activation of mTOR (target of rapamycin in mammals) occurs, leading to an imbalance between the synthesis and increase of protein catabolism and, consequently, depleting to MM⁴. Although the association between IR and MS is reported²⁵,²⁶, the same result was found only for MS in the present study.

Some studies observed that MM depletion affects the severity of liver disease, with worsening fibrosis¹⁹,²⁵. It is noted that there is an inverse relationship between MM and ALT and AST levels in patients with NAFLD, independently of obesity²⁶,²⁷. In this study, AST was the only liver enzyme to be associated with MM and such findings were similar to the studies by Moon et al.²³) and Petta et al.¹⁸

Studies that assess the correlation of PA with muscle 8 and other anthropometric and biochemical parameters are scarce. Petta et al.¹⁸ calculated the PA in Italian patients with NAFLD and found the mean PA similar to that of the present study (6.9±1.0). This cohort adopted the cutoff point of PA<5.4 to define sarcopenia, obtaining a prevalence of 5.7%.

The main positive points of this study include the use of practical, low-cost, and easy-to-use methods in clinical practice to assess MM and central adiposity. So far, most of the studies published have been carried out on the Eastern population who have different eating habits, lifestyle, and body composition than the Western population. However, the small sample size, the absence of liver biopsy, and loss of data in variables, such as IR, are the factors, which robust statistical analyses, however, tried to minimize the limitation of this study.

In conclusion, the high prevalence of MM depletion found in the patients with NAFLD is a cause for concern, considering the association with high AST and what has already been described in the literature regarding the progression of the disease to steatohepatitis and fibrosis in the presence of MM depletion. One-third of patients with NAFLD also had impaired cell membrane integrity and it is known that this integrity is important for maintaining adequate cell function. However, further studies are needed to better assess this condition in patients with NAFLD.

The findings of this study reinforce the importance of evaluating the indicators of central adiposity and MM in patients with NAFLD, considering that the indicators of central obesity remained independently associated with MM depletion.

• Funding: This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq [MCTI/CNPQ/Universal 14/2014] and institutional support from the Universidade Federal da Bahia.
• ETHICAL STATEMENT
  The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the research ethics committee of the School of Nutrition of the Federal University of Bahia (Opinion nº 774.353 / 2014). Informed consent was obtained from all participants. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/)

ACKNOWLEDGMENT

The authors thank all the patients involved in this study for their cooperation and the nutrition students, namely, Geisa de Jesus Santos and Jilmara Fiuza de Oliveira

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Publication Dates

• Publication in this collection
  19 Nov 2021
• Date of issue
  Sept 2021

History

• Received
  13 Feb 2021
• Accepted
  20 July 2021