Association between low alanine aminotransferase levels and sarcopenia in older adults: A cross-sectional study

DOI: https://doi.org/10.21203/rs.3.rs-2263366/v1

Abstract

Background

This study aimed to determine whether serum alanine aminotransferase (ALT) is a convenient tool to screen sarcopenia and frailty in clinical practice.

Methods

This cross-sectional and observational study included a total of 1333 residents from three communities in Chengdu, China. A bioimpedance analysis device was used to measure the appendicular skeletal muscle mass (ASM). Handgrip strength was measured with a digital handheld dynamometer. Gait speed was measured with a 6-m gait test. The sarcopenia was defined according to the Asian Working Group on Sarcopenia (AWGS) 2019. Biochemical variables including ALT were tested in the same laboratory. Other characteristics, including smoking status, alcohol drinking status, education level, and chronic comorbidities, were obtained through a face-to-face interview. We used logistic regression to evaluate the association between ALT levels and sarcopenia.

Results

Compared with the non-sarcopenia group, the sarcopenia group had a significantly lower body mass index (BMI), serum albumin levels, hemoglobin levels, calf circumference (CC), and ALT levels. Both men and women with sarcopenia or low handgrip strength had lower ALT levels than those without sarcopenia or low handgrip strength. Compared with the highest ALT quartile, the odds ratios (OR) for individuals in the lowest ALT quartile were found to be increased (OR 1.68, 95% confidence interval 1.13–2.49, P = 0.010), adjusting for age, sex, BMI, hemoglobin levels, CC, and serum albumin levels.

Conclusions

Low ALT levels were associated with sarcopenia onset involving low skeletal muscle mass and handgrip strength in older adults. ALT measurement could be used as a simple and preliminary tool to screen for frailty and sarcopenia.

Background

Sarcopenia is defined as age-related loss of skeletal muscle mass, which is usually diagnosed based on a combination of low appendicular skeletal muscle mass (ASM) and low muscle strength, and/or low physical performance [1, 2]. Frailty is defined as a condition wherein a person becomes more vulnerable to external stress owing to changes in organ function and decreased reserve with increasing age [3]. Both sarcopenia and frailty are associated with poor short-term and long-term outcomes in the older population. Sarcopenia and frailty have an overlapping role in the loss of muscle mass and decline in physical function, which are the common pathophysiological mechanisms of these conditions.

Serum alanine aminotransferase (ALT) level is a widely used index for evaluating liver function. It is well known that ALT is present in skeletal muscle and adipose tissue. ALT levels are generally elevated in association with components of metabolic syndrome, such as high body mass index (BMI), obesity, and high fasting glucose levels [47]. On the contrary, low-to-normal ALT levels have been reported to increase frailty, all-cause mortality, and cardiovascular mortality [8]. In a cohort study of community-dwelling healthy older men, decreased ALT levels were associated with frailty and reduced survival time, but the association between ALT levels and mortality disappeared when frailty and age were adjusted for in the survival analysis [9]. Moreover, the association between low ALT levels and frailty seemed to contribute to the relationship between low ALT levels and mortality. It has been thought that sarcopenia leads to frailty [3]. Currently, there is a need to determine the association between ALT levels in muscle mass and strength deterioration.

In the present study, we aimed to investigate the association between ALT levels and sarcopenia in the older population, to determine whether ALT measurement is a convenient tool for screening sarcopenia and frailty in clinical practice.

Methods

Study population

We conducted a cross-sectional and observational study between July 2019 and October 2020. We consecutively recruited older adults (aged ≥ 65 years) residing in three communities in Chengdu, China. We excluded individuals who met the following criteria: (1) presence of an implanted pacemaker; (2) clinically visible edema; (3) severe mental illness; (4) chronic kidney disease; (5) heart failure; (6) respiratory failure; (7) unable to cooperate with the researchers; (8) declined consent to participate in this study; (9) bone fracture, cerebrovascular accident, or surgery within the past three months; (10) any type of liver disease, biliary tract disease, acute infection, or tumor; and (11) ALT levels > 50 IU/L.

All participants signed a written informed consent form. Participants’ information was collected through face-to-face interviews conducted by trained nurses. The study protocol was approved by the Biomedical Ethics Committee of West China Hospital, Sichuan University.

Measurement of muscle mass

We used a bioimpedance analysis device (BIA; InBody 770; Biospace Co. Ltd, Seoul, Korea) to measure the ASM. A trained nurse guided the participants through the BIA test. The participants were asked to stand upright at least for 5 minutes before testing. Then they were asked to step on the footplate barefoot, with their heels on the rear sole electrodes and their hand holding the hand electrode. They were asked to keep their arms straight, without touching the sides of their body during the test. The appendicular skeletal muscle index (ASMI) was calculated using the following equation: ASMI (kg/m2) = ASM/height 2.

Measurement of handgrip strength

A trained nurse measured the participants’ handgrip strength (HGS) using a digital handheld dynamometer (EH101; Xiangshan Inc., Guangdong, China) to evaluate the HGS to the nearest 0.1 kg, according to the recommendation of the Chinese National Physical Fitness Evaluation Standard [10]. Before the test, each participant received detailed instructions on the procedure. The participants were asked to stand with their feet shoulder-width apart, with their elbows fully extended, and to hold the dynamometer in the neutral position with 90° flexion of the index finger, and squeeze the grip with full force for ≥ 3 s. During the test, the participants were asked to avoid contact between the dynamometer and the body, and verbal encouragement or visual feedback was not allowed. Three measurements were performed for each hand, with rest periods of ≥ 30 s between each measurement. HGS was determined as the maximum value out of the six measurements.

Measurement of gait speed

A trained nurse measured the gait speed (GS) by asking the participants to walk at their normal pace. They were asked to walk down a hallway through a 1-m acceleration zone, a 4-m central testing zone, and a 1-m deceleration zone. The nurse started the timer at the first footfall after the 0-m line and stopped the timer at the first footfall after the 4-m line. The duration was calculated to the nearest of 0.1 s. GS was calculated using the following equation: GS (m/s) = 4/time. The use of an assistive device (cane or walker) was allowed, if needed.

Definition of sarcopenia

According to the recommendation from the Asian Working Group on Sarcopenia (AWGS) 2019 (1), we defined sarcopenia based on the following indications: ① low skeletal muscle mass, defined as ASMI < 7.0 kg/m2 for men and ASMI < 5.7 kg/m2 for women, together with ② low muscle strength, defined s HGS < 28 kg for men and HGS < 18 kg for women, and/or ③ low physical performance, defined as GS < 1.0 m/s.

Measurements of biochemical variables

Fasting venous blood levels were measured by trained nurses. Serum levels of albumin, ALT, γ-glutamyl transferase (GGT), fasting glucose, and hemoglobin were determined in the same laboratory using the same standard methods and reference values.

Covariates

Information on the following variables was obtained through a face-to-face interview: age, sex, smoking status, alcohol drinking status, education level, and chronic comorbidities (hypertension, diabetes, chronic obstructive pulmonary disease, and coronary heart disease). Body height and weight were measured to the nearest 1 cm and 0.1 kg, respectively, using standard methods. BMI was calculated using the following equation: BMI (kg/m2) = body weight/height2. Calf circumference (CC) was measured using a millimeter-graded tape, with the participant in the supine position, with the left knee raised and the calf at a right angle to the thigh.

Statistical analysis

Data were analyzed using SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, USA), and R software, version 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria). Data of categorical variables are presented as numbers and percentages. Data of normally distributed continuous variables were tested using the Shapiro–Wilk test. Data of continuous variables are presented as mean and standard deviation or median and interquartile range, as appropriate. Between-group differences were analyzed using the two-sample independent t-test, one-way analysis of variance, Mann–Whitney U test, Kruskal–Wallis test, and chi-square test, as appropriate. The distributions of ALT, ASM, HGS, and GS were calculated from density plots. Multiple logistic regression analysis was performed to assess the relationship between ALT quartiles and sarcopenia onset after adjustment for covariates. A P-value of < 0.05 indicated statistical significance.

Results

The present study included 1,333 participants, of whom 311 were defined as having sarcopenia. The clinical characteristics of the population according to sarcopenia are shown in Table 1. Participants in the sarcopenia group were older than those in the non-sarcopenia group (68.0 ± 11.0 vs. 66.0 ± 8.0, respectively; p < 0.001). Compared with the non-sarcopenia group, the sarcopenia group had a significantly lower BMI (24.03 ± 3.10 and 23.53 ± 3.25, respectively; p < 0.05), serum albumin levels (46.12 ± 3.19 and 45.46 ± 4.07, respectively; p < 0.05), hemoglobin levels (143.42 ± 13.7 and 140.9 ± 15.4, respectively; p < 0.05), CC (34.2 ± 3.3 and 33.2 ± 3.4, respectively; p < 0.001), and ALT levels (21.37 ± 8.33 and 19.51 ± 8.71, respectively; p = 0.001). There was no difference between the two groups in the proportion of ever-smokers. However, the proportion of ever-drinkers was significantly higher in the sarcopenia group.

Table 1

Characteristics of the study population according to sarcopenia

Characteristics

Non-sarcopenia (n = 1,022)

Sarcopenia (n = 311)

p-value a

Age, years, median (IQR)

66.0 (8.0)

68.0 (11.0)

< 0.001

Women, n (%)

510 (49.9)

163 (52.4)

0.438

Ever-smoker, n (%)

187 (18.3)

70 (22.5)

0.099

Ever-drinker, n (%)

279 (27.3)

104 (33.4)

0.036

Education, n (%)

     

< 7 years

359 (35.1)

126 (40.5)

0.009

7–12 years

546 (53.4)

167 (53.7)

 

> 12 years

117 (11.4)

18 (5.8)

 

Hypertension, n (%)

255 (25.1)

80 (26.2)

0.704

Diabetes, n (%)

107 (10.6)

43 (14.1)

0.092

COPD, n (%)

79 (7.8)

22 (7.2)

0.729

CHD, n (%)

48 (4.7)

17 (5.6)

0.563

BMI, kg/m2

24.03 (3.10)

23.53 (3.25)

0.015

Serum albumin, g/L

46.12 (3.19)

45.46 (4.07)

0.003

ALT, IU/L

21.37 (8.33)

19.51 (8.71)

0.001

GGT, IU/L

19.0 (14.0)

20.0 (13.0)

0.764

Fasting glucose, mmol/L

5.90 (1.59)

6.02 (1.75)

0.229

Hemoglobin, g/L

143.42 (13.7)

140.9 (15.4)

0.007

CC, cm

34.2 (3.3)

33.2 (3.4)

< 0.001

Data are presented as mean and standard deviation if not specified.
Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; CC, calf circumference; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; GGT, gamma-glutamyl transferase; IQR, interquartile range.
a. Group differences were analyzed using the two independent-sample t-test, Mann-Whitney U test, and Chi-square test as appropriate.

Table 2 shows sex-specific differences in baseline characteristics according to ALT quartiles (Q1-Q4). In men, the age and proportion of ever-smokers decreased with increasing ALT quartiles. BMI, serum albumin, GGT, fasting glucose, hemoglobin levels, and CC showed an increasing trend with increasing ALT quartiles. The proportions of patients with chronic conditions did not differ among ALT quartiles. In women, BMI, GGT levels, and fasting glucose levels showed an increasing trend with increasing ALT quartiles. From the lowest to the highest ALT quartile, the proportion of patients with hypertension increased.

Table 2

Characteristics of the study population according to alanine aminotransferase quartiles

Men (n = 660)

 

Characteristics

ALT quartiles (IU/L)

p-value

Q1 (< 16)

(n = 160)

Q2 (16–21)

(n = 153)

Q3 (21–27)

(n = 168)

Q4 (≥ 27)

(n-179)

Age, years, median (IQR)

69.0 (11.0)

66.0 (11.0)

66.0 (9.0)

66.0 (8.0)

0.002

Ever-smoker, n (%)

74 (46.3)

63 (41.2)

51 (30.4)

54 (30.2)

0.003

Ever-drinker, n (%)

74 (46.3)

72 (47.1)

79 (47.0)

81 (45.3)

0.985

Hypertension, n (%) b

44 (27.7)

30 (19.9)

44 (26.3)

44 (24.9)

0.409

Diabetes, n (%) b

10 (6.3)

20 (13.2)

23 (13.9)

18 (10.2)

0.115

COPD, n (%) b

10 (6.3)

10 (6.6)

13 (7.8)

14 (7.9)

0.921

CHD, n (%) b

7 (4.4)

8 (5.3)

6 (3.6)

6 (3.4)

0.821

BMI, kg/m2

23.06 (2.88)

23.85 (2.85)

24.06 (2.89)

23.9 (2.93)

< 0.001

Serum albumin, g/L

45.35 (3.17)

46.30 (3.17)

46.42 (2.67)

46.05 (3.19)

0.012

GGT, IU/L

18.0 (10.0)

19.0 (15.0)

24.5 (18.8)

24.0 (20.0)

< 0.001

Fasting glucose, mmol/L

5.59 (1.43)

5.80 (1.35)

6.08 (1.54)

6.20 (2.18)

0.005

Hemoglobin, g/L

146.18 (13.70)

151.10 (13.30)

152.73 (13.02)

152.47 (12.56)

< 0.001

CC, cm

35.1 (2.9)

35.4 (2.5)

35.9 (2.8)

36.3 (3.0)

0.001

Women (n = 673)

 

Characteristics

ALT quartiles (IU/L)

p-value

Q1 (< 14)

(n-156)

Q2 (14–18)

(n = 157)

Q3 (18–24)

(n = 190)

Q4 (≥ 24)

(n = 170)

Age, years, median (IQR)

66.5 (9.0)

66.0 (9.0)

67.0 (9.0)

65.0 (7.3)

0.249

Ever-smoker, n (%)

17 (10.9)

15 (9.6)

23 (12.1)

22 (12.9)

0.787

Ever-drinker, n (%)

6 (3.8)

1 (0.6)

3 (1.6)

5 (2.9)

0.216

Hypertension, n (%) c

24 (15.6)

39 (25.0)

58 (31.2)

52 (30.8)

0.004

Diabetes, n (%) c

16 (10.4)

21 (13.4)

19 (10.2)

23 (13.6)

0.650

COPD, n (%) c

18 (11.7)

13 (8.3)

11 (5.9)

12 (7.1)

0.252

CHD, n (%) c

8 (5.2)

11 (7.0)

13 (7.0)

6 (3.6)

0.453

BMI, kg/m2

22.91 (3.23)

23.65 (3.08)

24.01 (3.39)

24.84 (3.36)

< 0.001

Serum albumin, g/L

45.87 (3.94)

46.38 (2.86)

45.52 (4.30)

45.82 (3.13)

0.181

GGT, IU/L

15.0 (7.0)

15.0 (8.0)

18.0 (10.0)

25.0 (10.0)

< 0.001

Fasting glucose, mmol/L

5.74 (1.36)

5.79 (1.10)

5.93 (1.76)

6.23 (1.83)

0.019

Hemoglobin, g/L

133.32 (10.66)

135.15 (9.62)

135.87 (10.10)

136.06 (10.35)

0.062

CC, cm

31.69 (2.59)

32.06 (2.65)

32.14 (3.04)

32.51 (2.79)

0.132

Data are presented as mean and standard deviation if not specified.
Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; CC, calf circumference; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; GGT, gamma-glutamyl transferase; IQR, interquartile range.
a. Group differences were analyzed using the one-way ANOVA, Kruskal-Wallis test, and Chi-square test as appropriate.
b. Missing data: n = 6.
c. Missing data: n = 8.

Sarcopenia is defined as low skeletal muscle mass and low handgrip strength and/or low GS. The ALT levels, ASM, and handgrip strength in both sexes are shown in Fig. 1. The association between ALT levels and sarcopenic diagnosis criteria was also explored (Fig. 2). Men with sarcopenia or low handgrip strength had lower ALT levels than those without sarcopenia or low handgrip strength. Similar results were found in women. The sarcopenia group and the low ASMI group had lower ALT levels than the non-sarcopenia group and the normal ASMI group. There was no significant difference in ALT levels among different gait speeds in either sex.

Logistic regression analysis was performed to determine the effect of ALT levels on the prevalence of sarcopenia. Logistic regression models were adjusted for age, sex, BMI, hemoglobin levels, CC, and serum albumin levels. Compared with the highest ALT quartile, the odds ratio (OR) for individuals in the lowest ALT quartile was found to be increased (OR 1.68, 95% confidence interval 1.13–2.49, P = 0.010; Fig. 3). Additionally, age increased the risk of sarcopenia, whereas CC decreased the risk.

Discussion

We investigated the association between ALT levels and sarcopenia onset in older individuals. Our study revealed that individuals with sarcopenia had lower BMI and ALT levels. In both men and women, BMI and fasting glucose levels increased with increasing ALT quartiles. A low ALT level was associated with low skeletal muscle mass and handgrip strength, which are major components of sarcopenia. After adjusting for age, sex, and nutritional confounders, low ALT level were found to be independently associated with sarcopenia.

Elevated serum ALT levels are usually used as a biomarker of hepatic dysfunction due to viral infection, alcohol intake, and medicine use. In addition, deterioration of ALT levels was observed in individuals with metabolic syndrome [11, 12] and obesity [4]. Previous studies reported that elevated ALT levels were associated with increasing BMI [5] and lean mass index [7], in accordance with the findings of our study. Furthermore, our findings regarding the relationship between ALT and fasting glucose levels were consistent with those reported in other studies. Both cross-sectional and longitudinal studies have demonstrated that ALT levels are positively related to impaired fasting glucose levels or diabetes [6, 1315]. One of the mechanisms whereby ALT levels are elevated in metabolic disorders is the direct release of ALT into the blood from adipose tissue and skeletal muscle [8]. Therefore, individuals with a low skeletal muscle mass will have ALT released into the blood from the skeletal muscle at a lower rate.

In the present study, low ALT levels were associated with a low skeletal muscle mass and handgrip strength. The association between low ALT levels and sarcopenia was still statistically significant after adjusting for the confounders. Consistent with the findings of the present study, cohort studies have shown that a reduced ALT level is a biomarker of sarcopenia and frailty [16, 17]. In older Korean diabetes patients, low ALT levels predicted a higher risk of low muscle strength with a cut-off ALT level of 18.5 IU/L [8]. Sarcopenia and frailty were predictors of reduced survival time in older adults. The Health ABC Study cohort showed that both quadriceps and handgrip strengths, rather than skeletal muscle mass, were more strongly related to mortality in the older population [18]. Some researchers have reported that low ALT levels are independently associated with a higher mortality risk in middle-aged adults [1921]. In the older population, a low ALT level predicted a longer hospitalization duration and an increased rate of mortality [17, 22]. It was speculated that the usefulness of ALT levels to predict adverse outcomes was mediated through their association with sarcopenia and frailty. Blood ALT levels may be an easily accessible tool for predicting sarcopenia, frailty, and aging.

This study had some limitations. First, our study had an observational and cross-sectional design. Therefore, further prospective studies are required to confirm and validate our results. Second, the study design did not rule out participants with hepatitis viral infection, which may influence ALT activity. Finally, metabolic factors contributing to muscle loss, such as fasting glucose, diabetes, and hypertension, were not adjusted for in the logistic regression analysis of ALT and sarcopenia.

Conclusions

In conclusion, the present study showed that low ALT levels were associated with sarcopenia onset involving low skeletal muscle mass and handgrip strength in older adults. Low ALT levels may be a strong biomarker for sarcopenia and frailty. Our study suggests that ALT measurement could be used as a simple preliminary tool to screen for frailty and sarcopenia and assess the health status of older adults.

Abbreviations

ASM: appendicular skeletal muscle mass

ALT: alanine aminotransferase

BMI: body mass index

ASMI: appendicular skeletal muscle index

HGS: handgrip strength

GS: gait speed

AWGS: Asian Working Group on Sarcopenia

GGT: γ-glutamyl transferase

CC: calf circumference

OR: odds ratio

Declarations

Acknowledgements

Not applicable. 

Funding

This study was partly supported by the National Natural Science Foundation of China (81501197), the Sichuan Province Science and Technology Support Program (2021YFS0138), the Chengdu Science and Technology Bureau (2021-YF05-00987-SN), the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20191010).

Author Contributions

YL led the development of the study concept, LL assisted with study design, data analysis, and manuscript writing. JL and JS helped in data analysis.

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request

Ethics Approval and Consent to Participate

The study protocol was approved by the Biomedical Ethics Committee of West China Hospital, Sichuan University (Reference number of ethical approval: 2018-325). All procedures involving human participants were in accordance with the declaration of Helsinki. All participants signed a written informed consent form. 

Consent for Publication

Not applicable.

Competing Interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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