Sarcopenia was initially defined by Rosenberg as age-related loss of muscle mass and function 1, whereas Morley et al. 2 later refined the definition as loss of muscle volume and muscle strength in association with aging. The European Working Group on Sarcopenia in Older People (EWGSOP) has noted age-related muscle volume loss that appears in combination with low muscle strength and/or physical performance condition 3. Chronic diseases (e.g. heart failure, obstructive pulmonary disease, diabetes mellitus, kidney disease, connective tissue disease, tuberculosis infection, and other wasting conditions) have also been shown to be associated with secondary sarcopenia 3. However, little is known on the frequency and clinical features of sarcopenia, including muscle volume loss and reduced handgrip strength, in Japanese patients with chronic liver disease (CLD).
Recently, criteria and definitions of sarcopenia have been proposed by European 3 and Asian groups [Asia Working Group for Sarcopenia (AWGS)] 4. Measurement of handgrip strength is an easy and cost-effective method for the evaluation of muscle strength, whereas assessment of muscle volume by computed tomography (CT) findings, commonly used in screening for hepatocellular carcinoma (HCC), is considered to be suitable for Japanese CLD outpatients. The essential requisite for the diagnosis of sarcopenia is muscle volume loss in EWGSOP criteria, whereas it is decreasing muscle strength in AWGS criteria. However, there are few reports of the frequencies of muscle volume loss, decreasing muscle strength and sarcopenia diagnosed on the basis of cut-off values for handgrip strength, which are used in the criteria of handgrip strength presented by EWGSOP and AWGS, or muscle volume loss in those assessed by CT findings and difference in sex in CLD patients. For Japanese CLD patients, it is important to elucidate the frequency of sarcopenia as well as patients with presarcopenia for detecting high-risk cases requiring nutrition and/or exercise intervention to maintain quality of life and improve prognosis.
In the present study, we analyzed the clinical features of Japanese CLD patients with sarcopenia diagnosed on the basis of a combination of handgrip strength and muscle volume loss assessed by CT findings in patients with CLD.
Materials and methods
Patients and chronic liver disease
We enrolled 807 individuals with CLD [chronic hepatitis (CH), liver cirrhosis (LC); 67.1±10.0 years old; men 466, women 341] who were treated as outpatients at Ehime Prefectural Central Hospital from April to September 2015. The activities of daily living of all enrolled patients were self-reliant and HCC patients with extrahepatic metastasis or vascular invasion were excluded. Those positive for esophageal–gastric varices, showing collateral vessel formation, and/or with a platelet count under 10×104 cells/μl were considered to have LC and classified using the Child-Pugh classification (A, B/C).
Methods for measurement of muscle volume and handgrip strength
Muscle volume loss was determined using a previously reported index [psoas index (PSI): psoas muscle area of middle L3 level (cm2)/height (m)2; men=4.24 cm2/m2, women=2.50 cm2/m2) from CT findings 5. PSI was calculated manually with psoas muscle area at the middle L3 level from CT findings using personal computer software (Centricity Web DX, version 184.108.40.20617; GE Healthcare, Little Chalfont, UK). CT was performed for screening of HCC within 1 year of measuring handgrip strength and the findings were used for the evaluation of PSI (median 6 months). Handgrip strength was measured with the patient in a standing position using a hand dynamometer (TL110; Toei Light Co. Ltd, Saitama, Japan). The best values for both right and left handgrip strength out of a few measurements were averaged and used for analysis. We compared the patients using cut-off values for lowered handgrip strength presented by the AWGS 4 (AWGS/grip criteria; men=26 kg, women=18 kg) and the EWGSOP (EWGSOP/grip criteria; men=30 kg, women=20 kg) 3. Sarcopenia was diagnosed when the patient showed both muscle volume loss and reduced handgrip strength. Those who showed only reduced handgrip strength were categorized in the s-presarcopenia group, whereas patients with only muscle volume loss were categorized in the v-presarcopenia group. The clinical features of CLD and frequencies of lowered handgrip strength and presarcopenia were analyzed in association with each grade of CLD (CH, LC Child-Pugh A, LC Child-Pugh B/C). In addition, the relationships of levels of branched-chain amino acid (BCAA) (µmol/l), BCAA/tyrosine ratio, albumin (g/dl), BMI, and PSI with handgrip strength were analyzed. The elderly was defined as those of at least 65 years old. The serum level of BCAA was measured using a commercially available kit (Diacolour-BTR, Toyobo Co. Ltd, Osaka, Japan).
Informed consent to participate in the study was obtained from all patients. The study protocol was approved by the Institutional Ethics Committee of Ehime Prefectural Central Hospital (No. 27-26).
Values are expressed as the mean±SD. Statistical analyses were carried out using a χ 2-test, Fischer’s exact test, or Pearson’s test, as appropriate. All statistical analyses were carried out using SPSS, version 21 (IBM SPSS Japan Inc., Tokyo, Japan). A P-value less than 0.05 in Pearson’s test was considered to represent statistical significance. Furthermore, a P-value of less than 0.0166 was considered to represent statistical significance in comparisons between each of the three CLD groups (CH, LC Child-Pugh A, LC Child-Pugh B/C).
Clinical backgrounds of the 807 patients
The etiology of CLD in the 807 patients was hepatitis C virus in 511 patients, hepatitis B virus in 134 patients, hepatitis B and C virus in three patients, alcohol in 45 patients, and others in 114 patients. Furthermore, 381 patients were classified as CH, whereas 330 and 96 patients were LC Child-Pugh A and B/C, respectively (Child-Pugh B : C=83 : 13). Two hundred and fifty-six patients (31.7%) had a history of HCC or newly detected HCC. The average age of those classified as CH was 65.7±10.4 years, whereas that of those classified as LC Child-Pugh A and B/C was 68.4±8.9 and 69.8±10.6 years, respectively (Table 1).
The results of analysis for handgrip strength with the AWGS/grip criteria and EWGSOP/grip criteria
The results of handgrip strength measurements are shown in Fig. 1. For both sexes, as well as each generation and grade of CLD, a large number of patients showed handgrip strength lower than that reported for normal Japanese individuals 6 (Fig. 1a).
In all 807 patients, reduced handgrip strength on the basis of the AWGS/grip criteria was observed in 23.3% (sarcopenia and s-presarcopenia: 3.9 and 19.4%), 26.6% (sarcopenia and s-presarcopenia: 4.8 and 21.8%), and 56.3% (sarcopenia and s-presarcopenia: 16.7 and 39.6%) of those classified as CH, LC Child-Pugh A, and LC Child-Pugh B/C, respectively, whereas these respective values on the basis of the EWGSOP/grip criteria were 40.2% (sarcopenia and s-presarcopenia: 7.1 and 33.1%), 44.5% (sarcopenia and s-presarcopenia: 11.8 and 32.7%), and 70.9% (sarcopenia and s-presarcopenia: 21.9 and 49.0%). There was also a significant difference in the frequency of all patients with reduced handgrip strength between CH and Child-Pugh B/C and between Child-Pugh A and Child-Pugh B/C using both criteria (P<0.001) (Fig. 1b).
In men (n=466), reduced handgrip strength on the basis of the AWGS/grip criteria (<26 kg) was observed in 16.0, 21.0, and 44.1% of those classified as CH, LC Child-Pugh A, and LC Child-Pugh B/C, respectively, whereas these respective values were 33.0, 38.4, and 62.7% on the basis of the EWGSOP/grip criteria (<30 kg). Even in nonelderly male CH patients, reduced handgrip strength was found in 6.5 and 17.6% on the basis of the AWGS/grip and EWGSOP/grip criteria, respectively (Fig. 2a).
In women (n=341), reduced handgrip strength on the basis of the AWGS/grip criteria (<18 kg) was observed in 32.5, 34.8, and 75.7% of those classified as CH, LC Child-Pugh A, and LC Child-Pugh B/C, respectively, whereas these respective values were 49.1, 53.3, and 83.8% on the basis of the EWGSOP/grip criteria (<20 kg). Even in female nonelderly CH patients, reduced handgrip strength was found in 7.7 and 17.3% on the basis of the AWGS/grip criteria and EWGSOP/grip criteria, respectively (Fig. 2b). There were significant differences in the frequency of reduced handgrip strength between CH and Child-Pugh B/C and between Child-Pugh A and Child-Pugh B/C using both criteria in each sex (P<0.01).
Results of analysis for muscle volume
Distribution of PSI in both sexes
Distribution of PSI in both sexes is shown in Fig. 3a. Muscle volume loss as determined by PSI in all patients classified as CH, LC Child-Pugh A, and LC Child-Pugh B/C was observed in 11.8, 22.4, and 28.1%, respectively. There was a significant difference in the frequency of muscle volume loss between patients with CH and Child-Pugh A and between those with CH and Child-Pugh B/C (P<0.001) (Fig. 3b), whereas that in men with CH, Child-Pugh A, and Child-Pugh B/C was observed in 16.5, 28.2, and 40.7%, respectively, and in 5.9, 14.1, and 8.1, respectively, in women (Fig. 3c).
The results of analysis for sarcopenia, and frequencies of sarcopenia, s-presarcopenia, and v-presarcopenia
When the AWGS/grip criteria were used to determine handgrip strength, sarcopenia was diagnosed in 3.9, 4.8, and 16.7% of the patients classified as CH, LC Child-Pugh A, and LC Child-Pugh B/C, respectively, whereas these values were 7.1, 11.8, and 21.9%, respectively, when the EWGSOP/grip criteria were used. There were significant differences between the frequencies of sarcopenia in CH and Child-Pugh B/C and of those in Child-Pugh A and Child-Pugh B/C using both criteria (P<0.016, respectively) (Fig. 4a).
Our analysis of nonelderly patients (<65 years) showed that sarcopenia was diagnosed on the basis of the AWGS/grip criteria in 1.9, 0, and 11.8% of those classified as CH (n=160), LC Child-Pugh A (n=100), and LC Child-Pugh B/C (n=34), respectively, whereas the values on the basis of the EWGSOP/grip criteria were 3.8, 0.0, and 20.6%, respectively (Fig. 4b). However, in elderly patients, sarcopenia was diagnosed on the basis of the AWGS/grip criteria in 5.4, 10.9, and 19.4% of those classified as CH (n=221), LC Child-Pugh A (n=230), and LC Child-Pugh B/C (n=62), respectively, and these values on the basis of the EWGSOP/grip criteria were 9.5, 17.0, and 22.6%, respectively (Fig. 4c).
A comparison between each grade of CLD showed that the frequencies of patients with sarcopenia or either type of presarcopenia were greater in those in an advanced stage compared with the others (AWGS/grip criteria: 31.2, 44.2, and 66.7%, respectively; EWGSOP/grip criteria: 44.9, 55.2, and 77.1%, respectively) (P<0.016 for all) (Fig. 5). The numbers of women and the elderly were significantly higher among patients with s-presarcopenia than those with v-presarcopenia on the basis of both criteria (P<0.016, respectively) (data not shown). In an additional analysis, there were no significant differences in the frequencies of patients with sarcopenia or either type of presarcopenia in each grade between viral and nonviral CLD patients (data not shown).
Results of analysis for relationship between muscle and BCAA
BCAA was administered to 0% of the patients with CH, 14.8% (n=49) of those with LC Child-Pugh A, and 62.5% (n=60) of those with LC Child-Pugh B/C. For an analysis of patients who did not receive BCAA granule medication (n=698), the serum level of BCAA was measured in 655. Six hundred and sixty two of the 698 patients without BCAA granule medication were patients with CH and LC Child-Pugh A (94.8%). A correlation was found between handgrip strength and PSI (men: r=0.284, P<0.001; women: r=0.144, P=0.014), as well as serum level of BCAA with handgrip strength (men: r=0.238, P<0.001; women: r=0.189, P=0.002) and PSI (men: r=0.202, P<0.001; women: r=0.135, P=0.025). There was also a significant relationship between BMI and PSI (men: r=0.464, P<0.001; women: r=0.408, P<0.001), or between level of albumin and handgrip strength (men: r=0.207, P<0.001; women: r=0.209, P<0.001). In women, there was no significant correlation between BMI and handgrip strength (r=−0.023, P=0.801), or between level of albumin and PSI (r=0.085, P=0.150). In both sexes, BCAA/tyrosine ratio did not show a significant relationship with handgrip strength (men: r=0.075, P=0.145; women: r=0.058, P=0.339) or PSI (men: r=0.119, P=0.020; women: r=−0.012, P=0.849).
Sarcopenia is not only related to age but has also been shown to be associated with chronic disease conditions (secondary sarcopenia) 3. Prevention of progression to sarcopenia is an important issue for CLD patients in terms of both quality of life and prognosis as muscle wasting has been reported to be a significant predictor of survival in patients with LC 7. Those with CLD often require invasive treatment and sarcopenia has been reported to be a predictive factor 8–10. In consideration of those previous reports, it is very important to identify high-risk patients with CLD who are on the way to sarcopenia and establish easy methods for evaluation of such cases. Lauretani reported that handgrip strength has a strong relationship with lower extremity muscle power 11. Recently, AWGS provided a definition of sarcopenia for Asian individuals, which consists of decreased handgrip muscle strength and loss of muscle volume.
Along with the increasing importance of sarcopenia, several issues have emerged. First, the cut-off values used for each method of diagnosis differ depending on race and among presented studies. In addition, the modalities for the evaluation of muscle volume and muscle strength used in each criteria for sarcopenia are different. For example, dual-energy X-ray (DXA) 12,13 and bioelectrical impedance analysis (BIA) 14,15 findings have been used in past studies of sarcopenia in elderly Japanese with sarcopenia on the basis of the EWGSOP definition observed in 10.3–21.8% of men and 14.5–23.8% of women 14–16. Nonelderly patients with LC Child-Pugh B/C showed a high rate of sarcopenia assessed using the EWGSOP/grip criteria (20.6%) in the present study. However, these modalities (DXA and BIA) are not used in all institutions. In contrast, CT is widely available throughout Japan and commonly performed for screening of HCC in patients with CLD. CT could be used easily for the evaluation of muscle volume in the present study.
A decline in handgrip strength was observed even in CH and nonelderly patients in comparison with Japanese healthy individuals of the same age in the present study. The ratio of decline in handgrip strength in LC Child-Pugh B/C was significantly greater than that in the CH and LC Child-Pugh A patients (Fig. 1b), whereas the ratio of muscle volume loss was significantly lower in CH compared with the others (Fig. 3b). EWGSOP has stated that sarcopenia is diagnosed on the basis of muscle volume loss as the required factor plus reduced muscle strength and/or performance status 3. However, AWGS defines sarcopenia on the basis of reduced muscle strength as the required factor plus muscle volume loss 4. Our results, shown in Fig. 5, suggest that there are two types of patients who are on the way to sarcopenia: those who show muscle volume loss or loss of muscle strength as the first step to sarcopenia. Those positive for reduced handgrip strength or muscle volume loss alone are believed to be in a prestage of sarcopenia (presarcopenia). We found that the frequencies of sarcopenia, as well as s-presarcopenia and v-presarcopenia increased as CLD progressed (Fig. 5). Evaluations of handgrip strength and muscle area at the L3 level using CT may be easy to perform as screening for high-risk patients on the way to sarcopenia. In Japanese patients with CLD, evaluation of handgrip strength and muscle volume examination with CT for the diagnosis of sarcopenia are considered to be suitable because measurement of handgrip strength is easy and cheap, and CT has become common and is performed for screening of HCC.
In our previous study, a decreasing level of BCAA in serum was observed in CH patients 17. The present findings of a high incidence of v-presarcopenia and s-presarcopenia even in patients with CH may be related to these previous results. Patients with CLD who have presarcopenia must undergo an intervention with a nutritional and/or an exercise approach. Hayashi et al. 18 reported that 50 patients with sarcopenia and LC had a low energy intake of 30 kcal/ideal kg of body weight and took fewer numbers of steps. Resistance exercise has been reported to be effective for eliciting gains in lean body mass 19, whereas essential amino acids play a primary role in amino acid-induced stimulation of muscle protein anabolism 20,21. Børsheim et al. 22 also reported that diet supplementation with essential amino acids improved lean body mass, strength, and physical function in glucose-intolerant elderly individuals, whereas Kim et al. 23 found that exercise and amino acid supplementation was effective in enhancing muscle strength and improving muscle mass in elderly (>75 years old) women, and Hanai et al. 24 noted that BCAA granule supplementation improved the survival of LC patients with sarcopenia. In the present study, the serum levels of BCAA and albumin showed weak but significant correlations with handgrip strength and PSI in patients of both sexes who did not receive BCAA granule medication, but we also previously noted that disturbances in neuropsychiatric function as well as BCAA level were observed not only in patients with LC but also those with CH 25. BCAA levels, which decrease as a result of CLD progression as well as neuropsychiatric dysfunction, may play a role in the development of sarcopenia. Hayashi et al. 26 reported that the intensity of daily activities was lower in urban LC patients instead of a decrease in dietary intake and noted that lower skeletal muscle may result in an amino acid imbalance. Thus, BCAA supplementation as well as habitual exercise may be effective for prevention of sarcopenia and presarcopenia.
Our study has some limitations. This was a single-center investigation and a validation study will be needed. Furthermore, the differences between the modalities used for evaluation of muscle volume can lead to different results in terms of the frequency of sarcopenia; thus, analysis of correlations among those different modalities (e.g. DXA, BIA, CT) in terms of muscle volume loss will be needed. Differences between men and women should be considered for more detailed future analysis. Finally, the frequency of sarcopenia as well as s-presarcopenia and v-presarcopenia in the present patients with CLD, even those with CH and LC with Child-Pugh A, was not low. Evaluation of handgrip strength and determination of PSI on the basis of CT findings are considered to be an easy and suitable method for the detection of sarcopenia and presarcopenia in Japanese patients with CLD.
Conflicts of interest
There are no conflicts of interest.
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