The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma

Abstract

Background/aims: The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival.

Methods: Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017.

Results: The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients.

Conclusion: The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

Keywords: Follistatin; Hepatocellular carcinoma; Interleukin 6; Myostatin; Sarcopenia.

Figure 1.

Relationship between the PMI and serum cytokine levels, (A) serum myostatin levels, (B) serum follistatin levels, (C) serum IL-6 levels. Spearman’s rank correlation was used to find the correlation between the PMI and the level of myostatin, follistatin and IL-6, and the coefficient of the correlation was indicated as Spearman’s rho (ρ). Serum myostatin levels showed a positive and linear correlation with PMI, though the correlation was weak (ρ=0.356, P<0.001). In contrast, the serum IL-6 levels showed a negative association with the PMI, which was also a weak correlation (ρ=-0.174, P=0.009). The serum follistatin levels were not correlated with the PMI. PMI, psoas muscle index; IL-6, interleukin-6.

Figure 2.

Relationship between the serum levels of (A) myostatin, (B) follistatin, and (C) IL-6 and liver function or tumor extent. Compared to the patients with Child Pugh class A, the patients with Child Pugh class B had a significantly increased level of (A) myostatin (P=0.006), (B) follistatin (P=0.002), and (C) IL-6 (P=0.002). The serum levels of both follistatin and IL-6 increased according to the advanced tumor stage by TNM or BCLC stage, especially in TNM stage 4 or BCLC stage C. However, the serum level of myostatin decreased in TNM stage 4 or BCLC stage C, but the trend was not clearly defined. BCLC, Barcelona Clinic Liver Cancer; IL-6, interleukin-6.

Figure 3.

Overall survival rate in regards to the serum levels of (A) myostatin, (B) follistatin, and (C) serum IL-6. In Kaplan-Meier survival analysis, the overall 5-year survival rate was not different between the high (74.8%) and low myostatin (68.0%) group (P=0.062) (A). However, the high follistatin group had a significantly shorter 5-year overall survival rate (78.4%) than that of the low follistatin group (89.6%, P<0.001) (B). Likewise, the high IL-6 group had a significantly shorter 5-year overall survival rate (78.4%) than that of the low IL-6 group (85.8%, P=0.018) (C). IL-6, interleukin-6.

Figure 4.

Overall survival rate in the patients with sarcopenia and non-sarcopenia. In Kaplan-Meier survival analysis, the hepatocellular carcinoma patients with sarcopenia showed a significantly lower survival than the patients with non-sarcopenia.