Letter to the Editor: Improving the reliability of functional capacity testing in liver cirrhosis: A novel assessment direction

Abstract

I am delighted to read the intriguing observational study published in the recent issue of the World Journal of Hepatology by Corrêa et al. In this study, 6-minute walking test (6MWT) was assessed in patients with liver disease and showed significant reliability. Therefore, such physical exercise requires more objective rather than subjective variables, e.g., shortness of breath, walking distance, heart rate, etc. Therefore, this letter to the editor will add objective testing in different directions to document the inter-rater reliability of 6MWT. These tests include the determination of the levels of exerkines (myokines) following 6MWT in patients with liver cirrhosis (LC). The compatibility between laboratory findings and the functional capacity following 6MWT will improve the reliability of this test; otherwise, more research is important to prove the benefit and reliability of 6MWT in improving the functional capacity in LC.

Key Words: Liver cirrhosis; 6-minute walking test; Myokines

Core Tip: The six-minute walking test (6MWT) is useful in the assessment of functional capacity in a wide variety of diseases, including liver cirrhosis (LC). The development of sarcopenia is one cause of the deterioration of functional capacity in LC, and it is linked to a decline in the regulators of muscle growth. Therefore, the determination of the exerkine (myokine) levels, e.g., irisin, myostatin, and follistatin, as a supplement to the 6MWT, is of value in supporting the assessment of the functional capacity in LC.

TO THE EDITOR

I am delighted to read the intriguing observational study entitled “Intra-rater reliability of the 6-min walk test in people with liver cirrhosis” published in the recent issue of the World Journal of Hepatology by Corrêa et al[1], who demonstrated an important finding that the 6-minute walk test (6MWT) is simple, safe, and inexpensive and showed excellent reliability for assessing the functional capacity of patients with liver cirrhosis (LC). In this study, the sample size is limited, and statistical analysis on such a small sample may limit the ability to identify important findings.

Therefore, it is possible to improve this study either by using appropriate statistical analysis or by adding some laboratory testing that enhances the determination of functional capacity in LC patients. Absolute reliability was evaluated using standard errors and the Bland-Altman 95% agreement limit; relative reliability was evaluated using the intra-class correlation coefficient (ICC2,1); and validity was evaluated using the correlation test. Therefore, it is not applicable to test the validity by Pearson’s correlation test using 20 patients, as a minimum number for such a test is 60 participants. The authors did not explain the procedure for calculating the inter-class correlation coefficient. In addition, a collinearity diagnostic test and a bootstrap are useful statistical approaches to eliminate the bias that could be present in the study.

The relationship between LC and functional capacity has been studied in different directions. A systematic review and meta-analysis found that moderate physical exercise significantly improved the functional capacity in LC patients assessed by the GRADE tool[2]. In patients with LC subjected to liver transplantation, it has been found that for each 50 m decrease in the 6MWT, the outcome is a 25% increase in the risk of death[3]. One of the main purposes of improving the functional capacity is to improve the clinical outcome of those patients who have undergone liver transplantation[4].

The other important point is that LC patients are at risk of developing secondary sarcopenia. Muscle growth is under the control of exerkines regulation (Table 1). It has been observed that there is an association between functional ability and sarcopenia in pre-frail adults aged > 60 years, which is significantly associated with up-regulation of the growth differentiation factor-15[5]. In addition, elderly cancer patients with secondary sarcopenia showed a significant decrease in the 6MWT compared with non-sarcopenic[6]. Sarcopenia is a feature of liver disease, e.g., LC, that results from increased degradation and/or decreased synthesis of protein and is significantly accompanied by upregulation of expression of myostatin and decorin[7]. The limitation of the functional capacity could be related to sarcopenia, and it is mediated via myokines, e.g., a growth-differentiated factor-15[8].

Table 1 Regulators of muscle growth.

Negative regulators	Positive regulators
Activins	Bone morphogenic proteins
Growth differentiation factor-1	Follistatin
Myostatin	Irisin
Tumor growth factor-β

Moreover, myostatin (a negative regulator of muscle growth) and titin-N (a biomarker of muscle damage) are considered potential biomarkers for the diagnosis of secondary sarcopenia due to LC[9]. Activins are also involved in maintaining the integrity and function of the liver, and dysregulation in the activity of activins A and B is associated with liver fibrosis and hepatocellular carcinoma[10]. Secondary sarcopenia due to LC is associated with negative prediction outcomes[11]. Determination of the plasma levels of exerkines (myokines) was thoroughly investigated and is a useful test of sarcopenia (primary or secondary) (Figure 1). Among exerkines that have been studied in sarcopenia associated with LC are myostatin, follistatin, irisin, and decorin[12]. Follistatin is a glycoprotein that plays roles in cell differentiation, proliferation, and survival and suppresses the inflammatory process in the liver[13]; irisin protects the liver against the pathogenesis of liver fibrosis[14]; and myostatin is implicated in the fibrinogenesis of liver fibrosis[14]. Finally, the relationship between the serum level of exerkines (myokines) and a 6MWT is still controversial and, in patients with LC, has still not been studied. Patients with obstructive pulmonary disease reported a non-significant correlation (r = 0.05) between serum irisin level (a positive regulator) and 6MWT[15], while in LC, this correlation has still not been reported. A prospective clinical trial that displays each myokine’s cutoff value and demonstrates the relationships between these myokines and the 6MWT results while taking LC grading into account is recommended. It is premature to use myokine levels as a predictive marker unless the standardization of myokine levels is optimized. And the confounding variables, inflammatory biomarkers such as C-reactive protein, and the findings of liver function tests need to be adjusted.

Figure 1  Inter-relationship between sarcopenia, myokine, and 6-minute walking distance test in the assessment of functional capacity in liver cirrhosis patients.

CONCLUSION

Determination of the basal levels of exerkines (myokines) is a helpful test for assessing the functional capacity, and an increase in the positive regulator or a decrease in the negative regulator following 6MWT will support the assessment of the functional capacity in LC.