This study showed that MHE was affected by skeletal muscle mass and suggests that skeletal muscle may play an important role in MHE. As a neuropsychiatric abnormality without overt clinical symptoms of HE [1–3], MHE is considered the primary status of overt HE [9]. MHE leads to deteriorations in QOL [4, 5] and impairment of driving skill for motor vehicles [10–16]. Moreover, MHE is associated with falls [17, 18], learning impairment [19] and poor prognosis [6, 18, 20]. In addition, MHE is reportedly related to the survival of patients with liver cirrhosis [6, 21]. Early detection of patients with MHE is therefore necessary.
In patients with cirrhosis, ammonia, as the main substance causing HE, is increased in serum, since its metabolism is attenuated in the liver. Ammonia metabolism by skeletal muscle can compensate for impaired hepatic metabolism [22–24]. Moreover, loss of skeletal muscle readily occurs in patients with cirrhosis due to alterations in protein turnover, energy disposal or metabolism [25]. Generally, skeletal muscle loss exacerbates deficiencies in detoxification of ammonia, inducing HE. Qureshi et al. reported that ammonia level correlates with the severity of HE [26]. Although the concentration of ammonia in our study showed no significant difference between patients with or without MHE, loss of skeletal muscle mass may affect the presence of MHE in patients with liver cirrhosis. In addition, Qiu et al. reported that hyperammonemia led to inhibition of protein synthesis through the increase in myostatin mediated by nuclear factor-κB [27]. These findings suggest that hyperammonemia and skeletal muscle loss might affect each other in a bi-directional manner.
Sarcopenia or muscle loss is considered a predictor of impaired QOL [28], postoperative major complication [29], prognosis [30–33] and physical disability [34]. Since advanced-stage HCC influences nutritional status, we excluded patients with HCC who did not meet Milan criteria [8] from the present study. Hanai et al. described sarcopenia as a predictor of MHE [35]. Moreover, several reports have shown that sarcopenia or muscle depletion affects the risk of overt HE or MHE [36–38]. These reports potentially support our result regarding patients without advanced HCC. According to the guidelines for sarcopenia in liver disease issued by the Japan Society of Hepatology, the proportion of sarcopenia in patients with cirrhosis varies within the range of 10–70% [7]. Because too few patients with sarcopenia were enrolled in our study, sarcopenia might not have been detected as a predictor of MHE. The exclusion criteria for advanced HCC in our study might have caused the discrepancy between our study and previous reports [35, 36]. With regards to cirrhotic patients without HCC or with HCC within Milan criteria, although the incidence of sarcopenia was quite low, we could predict the incidence of MHE in terms of muscle mass loss.
Mild cognitive impairment (MCI) was not completely excluded because of the difficulty detecting this pathology in clinical settings. To remove this bias, we additionally analyzed the incidence of MHE among subjects under 80 years old, to reduce the possibility of MCI. The incidence of MHE differed significantly between cases below and above the cut-off level of SMI in patients under 80 years old.
Although various drugs have been given for patients with MHE [39–43] to decrease ammonia levels or improve mental status, drugs that are effective against MHE are unclear. We showed that the concentration of BCAA correlated with the presence of MHE, suggesting that administration of BCAA may be a reasonable treatment for MHE, because of its potential efficacy ameliorating skeletal muscle mass loss.
Several limitations to this study must be considered. First, the number of patients enrolled in this study was small. Further analysis of a larger number of patients is needed to confirm the current findings. Second, we used skeletal muscle area at the L3 level for the evaluation of muscle mass. Although this SMI was previously reported to correlate with SMI as calculated using bioelectrical impedance analysis (BIA) [7], we did not evaluate skeletal muscle mass by BIA. Third, we used the NP-test to diagnose MHE. The Psychometric Hepatic Encephalopathy Score (PHES), Inhibitory Control Test (ICT), electroencephalography, critical flicker frequency, and Stroop EncephAlapp are also available to diagnose MHE, and the combination of these tests is reportedly more useful than single tests [2, 44] Although we used NP-tests as a simple method in the clinical setting, how many and which types of tests are best and are most reliable for diagnosing MHE remains unclear.