Study design and patients
The participants were 117 older patients with CLD, aged 60 years or above, who were admitted to the Division of Gastroenterology and Metabolism, Hiroshima University Hospital, between April 2014 and September 2018, and agreed to undergo physical therapy under the care of a physical therapist. Patients with neuromuscular diseases, those with motor diseases and complaining of excessive pain, and those diagnosed with dementia were excluded. Patients were given the choice to opt-out. All measurements were taken as part of routine clinical management and the data were reviewed retrospectively. This study was conducted with the approval of the Ethics Review Committee of Hiroshima University Hospital (Permission No. E-583).
Clinical and laboratory assessment
The attributes of patients including sex, age, height, weight, body mass index (BMI), body fat percentage, etiology, FIB-4 index, presence of chronic hepatitis, LC, encephalopathy, ascites, HCC, hypertension, the presence or absence of dyslipidemia, diabetes mellitus, and blood data [hemoglobin, platelets (PLTs), total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, prothrombin time, ammonia, and hemoglobin A1c)] were extracted from the medical records. The data of muscle mass, grip strength, lower extremity strength, and gait speed measured as assessments of motor function were also extracted from the medical records.
Muscle mass
The muscle mass of the extremities was measured using a body impedance assessment device (InBody720; InBody Co., Ltd., Seoul, Korea). The skeletal muscle mass index (SMI), which is calculated as the limb muscle mass divided by the square of height, was used as defined in the Japan Society of Hepatology (JSH) and Asian Working Group for Sarcopenia (AWGS) criteria for diagnosing sarcopenia.8,9,11
Muscle strength
Muscle strength was assessed in the upper and lower extremities. Grip strength was measured in the upper limbs, and knee extension force (KEF) was measured in the lower limbs.
Grip strength was measured in 0.5 kg units using a grip strength meter (Smedley-type grip strength meter; Matsuyoshin Medical Instruments Co., Tokyo, Japan). The posture at the time of measurement was standing, with the elbows extended and the upper limbs lowered. Two measurements were taken on each side, and the average of the maximum values on each side was considered.
KEF was measured with a belt-mounted handheld dynamometer (µTas F-1; Anima, Tokyo, Japan). The patients were asked to be in the end-seated position, with the trunk upright, and the lower leg fixed to the belt with the knee joint flexed at 90º. The maximum isometric knee extension strength was measured. Two measurements were taken on each side, and the average of maximum values on each side was considered. KEF was divided by body weight and lower limb muscle mass, respectively, and adjusted to account for differences in body size.14,15
Gait speed
The participants were asked to walk for 10 m, plus 3 m before beginning the walk and 3 m after completing the walk, for deceleration. The time taken for walking 10 m was measured using a stopwatch. The distance and time taken were converted into speed, which was considered for the analysis. The patients were not allowed to use a walking aid and were instructed to walk as usual under normal walking conditions at a comfortable speed.8,9 Measurements were taken twice, and the average of the two measurements was considered for the analysis.
Sarcopenia
The criteria for sarcopenia defined by AWGS 20199 and JSH11 were used in this study. The AWGS 2019 diagnostic criteria for muscle mass loss and decreased muscle strength or gait speed correspond to sarcopenia. The AWGS 2019 criteria for loss of muscle mass are an SMI of < 7.0 kg/m2 in men and < 5.7 kg/m2 in women, and the criteria for muscle weakness are a grip strength of < 28 kg in men and < 18 kg in women, with a decreased gait speed of < 1.0 m/s.9
The JSH diagnostic criteria for loss of muscle mass and muscle weakness correspond to sarcopenia. The JSH criteria for muscle mass loss are defined as an SMI of < 7.0 kg/m2 in men and < 5.7 kg/m2 in women, and the criteria for muscle weakness are defined as a grip strength < 26 kg in men and < 18 kg in women.11
Liver fibrosis
As a representative biomarker that can determine the pathological progression of CLD, we used the FIB-4 index, which can assess the degree of liver fibrosis. The FIB-4 index was calculated using the values of PLT, AST, and ALT by the following formula16–18:
FIB-4 index = [(AST [U/L] × age) / (PLT [10 9 /L] × √ALT [U/L])]
In this study, the cut-off point for determining the pathological progression of liver fibrosis was set at 3.25, based on previous studies.17,18 Thus, an FIB4 index of > 3.25 was defined as severe-degree liver fibrosis (SLF), while that of < 3.25 was defined as low-degree liver fibrosis (LLF).
Statistical analysis
The Mann–Whitney U test was used for the continuous variables, and the chi-square test was used for the ordinal and nominal variables, to compare the two groups of SLF and LLF by sex. Logistic regression analysis was used to analyze the factors associated with a decrease in gait speed in men with CLD. The objective variable was a decrease or no decrease in gait speed (< 1.0 m/s), and the explanatory variables were age, BMI, FIB-4 index, and KEF/weight by a forced entry method. The KEF/weight was multiplied by 100 at the time of input, referring to a previous study.19
The CLD patients in this study were further subclassified into categories hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver injury (Alc), NAFLD, and others according to the etiology, and multiple comparisons were made using the Steel-Dwass test for continuous variables and Fisher’s exact test for nominal variables.
Statistical processing was performed using JMP® 14 (SAS Institute Inc., Cary, NC, USA). All hypothesis tests were two-tailed, and the significance level was set at 5%.