PEM is a poor prognosis factor in chronic liver disease [1, 2, 11, 12] and has been associated with abdominal fluid retention, hepatic encephalopathy, rupture of esophageal gastric varicose veins, hepato-renal syndrome, sarcopenia, and decreased quality of life (QOL) [2, 13, 14]. In Japan, according to the treatment guidelines for liver cirrhosis of the Japanese Gastroenterological Society, EM is defined as a npRQ <0.85, %AC <95%, or FFA >660 μEq/L . However, compared with PM, which is diagnosable based on albumin values alone, it is difficult to measure the parameters that are used to diagnose EM in all patients. Therefore, EM is often underdiagnosed, particularly in early-stage CLDs such as chronic hepatitis and Child–Pugh A cirrhosis. In this study, we focused on EM and examined the simple items that are easy to use in daily clinical care as indicators of EM.
Measurement of the npRQ using indirect calorimetry is an established method for the diagnosis of EM. In patients with cirrhosis, EM is associated with a decrease in glycogen storage caused by increased energy consumption at rest and liver atrophy. The sugar ratio, which is an energy source during early morning fasting, decreases and the lipid ratio increases. As a result, EM occurs . Increased insulin resistance and increased blood concentrations of glucagon, catecholamines, and cortisol are also involved in reducing the utilization efficiency of carbohydrates as an energy substrate. A previous study using the npRQ revealed that age >64 years, AST >40 IU/L, branched-chain amino acid to tyrosine ratio ≤5.2, and increased serum hyaluronic acid levels were associated with PEM[3, 17]. However, npRQ measurement is costly and can only be carried out in a limited number of facilities. Therefore, a simple substitute marker for the diagnosis of EM is required, and %AC and FFA have been reported to be useful correlates of npRQ measurement[18, 19]. In this study, we used %AC or FFA to diagnose EM, as we were not able to measure npRQ at our facility.
%AC is a method that is used for evaluating muscle mass based of body measurements and is employed as a parameter of nutritional assessment. %AC is correlated with the skeletal muscle mass measurements of the whole body in the elderly, as obtained from dual-energy X-ray absorptiometry . A decrease in AC is a poor prognosis factor for healthy elderly people, and a decrease in AC over time is associated with a deterioration of the activities of daily living in the elderly Japanese people . The survival of patients whose AC was in the 10th or lower percentile was significantly shorter [18, 21]. Although the measurement error is minimized by the standardization of the methods of measurement, the measurer must be an expert who is familiar with the procedure. The measurement error is large in cases involving thick subcutaneous fat ; moreover, we should consider the measurement errors resulting from fluid retention in patients with decompensated cirrhosis [22, 23].
FFA accounts for approximately 5% of total lipids, and its blood concentrations are regulated by uptake into the liver through the action of the hormone-sensitive lipase and lipoprotein lipase (LPL) enzymes . Plasma levels of FFA were correlated with npRQ (r = −0.39, P < 0.001), and the FFA value that predicted a npRQ of 0.85 was 660 μEq/L. In patients with cirrhosis, decreased liver processing of FFA and increased LPL activity result in increased FFA levels [25, 26]. FFA is associated with hepatic encephalopathy and the onset of dementia in patients with cirrhosis [19, 24, 27-30]. FFA decreases with dietary intake, exercise, and use of hypoglycemic agents, but it increases with fasting, smoking, aging, growth hormone, and catecholamines . Therefore, it is necessary to consider the patient’s background when diagnosing EM based on FFA.
In this study, we report for the first time that Child–Pugh grade and increased levels of γ-GTP, AST, and ALT may suggest EM in patients with CLDs. Our facility cannot measure npRQ and FFA using the in-house testing system, and we believe this report is useful for the simple enclosurement of patients with EM. In patients with CLDs, Child–Pugh grade B or C, and high levels of γ-GTP, AST, or ALT were risk factors for EM, and patients who were positive for 0, 1, 2, or 3 of the items developed EM in 16%, 35%, 59%, and 57% of cases, respectively. In patients with Child–Pugh grade A in whom the levels of γ-ATP, AST, or ALT were measured, those positive for 0, 1, or 2 of the items developed EM in 16%, 32%, and 67% of cases, respectively.
The blood concentration of cytokines is reported to be significantly higher in patients with cirrhosis than in non-cirrhosis patients because of abnormal intestinal flora, bacterial translocation resulting from portal hypertension, and a decrease in reticuloendothelial function [32, 33]. The secretion of cytokines is mainly due to the infiltration of lymphocytes into the liver as a result of inflammation and liver damage. In particular, the tumor necrosis factor-α (TNF-α), interleukin (IL)-1, or IL-6, inhibits glucose oxidation, thus affecting fat combustion, and is associated with EM in patients with cirrhosis [32, 34-39]. In cases of inflammation and liver damage showing high values of γ-GTP and transaminases, blood cytokine levels are expected to increase, and the frequency of EM expected to increase.
For the treatment of malnutrition in patients with cirrhosis, guidelines such as ESPEN and ASPEN have been proposed [1, 11, 40]. Patients with EM showed increased AC and reduced FFA after 1 month of diet management . After the administration a LES to patients with EM, a decrease in FFA and an improvement in QOL were observed [14, 41-43]. In this study, FFA values were significantly higher in cases without a LES compared with those with a LES (453 ± 307 vs. 278 ± 359 μEq/L, P = 0.031) (Figure 5). Further research is needed regarding the relationship between changes in FFA, %AC, treatment intervention, and prognosis.
This study had some limitations. It was conducted at a single facility and included a small number of cases, with few cases of Child–Pugh grade B or C. Furthermore, the relationship between ethiology, physical activity, and EM could not be investigated. Among the 43 cases in which both FFA and %AC were measured, there were 19 cases in which the results regarding the judgement of EM based on FFA and %AC differed. Three cases had %AC ≥95% and FFA >660μEq/L, and all of whom were female and were diagnosed with myopenia based on CT imaging. Conversely, the remaining 16 cases had %AC<95% and FFA ≤660, 13 of whom were male. The diagnosis of EM based on %AC alone in women or FFA alone in men can be difficult, and measurements of both %AC and FFA should be performed whenever possible. In addition, EM cases tended to have radiological attenuation of iliopsoas muscle, low subcutaneous fat mass index (SFMI), and low visceral fat mass index (VFMI) in this study. The radiological attenuation of iliopsoas muscle, SFMI, and VFMI are findings suggesting low BMI, muscle atrophy, and fat infiltration. Detailed studies by sex including imaging should be conducted in the future.
In clinical practice, it is difficult to measure npRQ, %AC, and FFA in all cases of CLDs. This is the first report to predict EM using low-cost, and simple standardized test items, such as γ-GTP, AST, and ALT levels. Nevertheless, it will be necessary to accumulate additional case data for further analysis.