Sarcopenia is a prevalent muscle abnormality in patients with cirrhosis. The presence of sarcopenia is a major predictor of mortality pre- and post-liver transplantation10–13, longer hospital stay14–16, hepatic encephalopathy17. Sarcopenia is also associated with poor survival in patients with HCC18. The pathogenesis of sarcopenia is multifactorial: hyperammonemia19,20, increased autophagy19, proteasomal activity21, myostatin22 and impaired mitochondrial function21 play important roles in sarcopenia with cirrhosis.
Nutritional factors are also main factors in the pathogenesis of sarcopenia. Nutritional deficits, especially BCAAs, are frequent in patients with cirrhosis. Skeletal muscle consumption of BCAAs is accelerated in liver cirrhosis, leading to muscle protein breakdown and resulting in sarcopenia23. Thus, BCAAs are widely known to be important in the progression of sarcopenia, but the association between sarcopenia and FAs in liver diseases is unclear. In the present study, we analyzed the relationship between sarcopenia and blood FAs levels in patients with liver cirrhosis and HCC and found that sarcopenia in patients with cirrhosis and HCC was associated with lower levels of n-3 PUFAs.
We revealed that the FA levels were lower in patients with low liver reserve function (CP score B or C) and, especially, n-3 PUFAs were most negatively correlated with the albumin-bilirubin score (R=-0.33, p < 0.0001). This result is consistent with previous reports showing that patients with liver cirrhosis have a lack of crucial FAs including n-3 PUFAs, which could be explained by a reduced alimentary intake as well as an impaired synthesis in the liver and an increased degradation of PUFAs due to lipid peroxidation24–26. It was expected that the FA levels would decrease with worsening cancer disease due to the worsening nutritional status. However, there was no association between the HCC status and FA levels in the patient background of this study. This might be because the patients in this study were mainly those with good hepatic reserve who could be treated for cancer. Further case studies are needed on the FA composition in patients with HCC with impaired hepatic reserve.
Next, we analyzed the association between the composition of FAs and skeletal muscle mass. The correlation analysis revealed that SMI was significantly correlated only with the n-3 PUFAs level. Because we elucidated the association between hepatic reserve (CP score and ALBI score) and blood FA levels, we also analyzed the correlation only in patients with CP grade A (Fig. 3B). The only FA that showed a significant correlation with muscle mass, even for patients with CP grade A, was n-3 FAs. In the multivariate analysis, the lower level of n-3 PUFAs was associated with an increased risk of sarcopenia among patients with cirrhosis when adjusted for patient backgrounds (etiology, TNM classification, Fib-4 index and plasma BCAA level). Furthermore, we found lower n-3 PUFAs levels in patients with sarcopenia when patient backgrounds were aligned using propensity score matching. These results showed an association between loss of skeletal muscle and lower level of n-3 FAs fraction in patients with cirrhosis and HCC. It has been known that n-3 PUFAs, especially EPA and DHA, play important roles in decreasing inflammatory processes27 and the impact that n-3 PUFAs may have on skeletal muscle systems has recently come to attention. A cross-sectional study of 363 people aged 60 years and above assessed the relationship between dietary fish oil intake and frailty and found that fish oil intake had a positive effect on the frailty status of younger subjects28. Studies have also demonstrated a relationship between n-3 PUFAs and sarcopenia in patients with cancer: the change in muscle mass during chemotherapy was calculated in 41 patients with non-small cell lung cancer receiving chemotherapy, and patients with muscle loss had lower plasma EPA and DHA compared with those who were gaining muscle29. Itoh, et al. showed that low EPA and DHA levels were associated with preoperative sarcopenia in patients with HCC30. The effect of n-3 PUFAs supplementation on sarcopenia is controversial but randomized controlled trials have been conducted to elucidate the impacts of n-3 PUFAs on sarcopenia in older individuals31–33. Although further clinical studies are needed to examine the effects of adding n-3 PUFA, we believe that our large retrospective cohort study identifying the association between n-3 PUFAs and sarcopenia represents a new target for nutritional therapy in patients with HCC and cirrhosis.
There are some limitations in this study. Firstly, this study was a single-center retrospective design. Prospective multicenter studies are needed. As the second limitation, we could not assess such factors as the effects of daily eating and exercise habits and medications of dyslipidemia and diabetes mellitus. The lack of grip strength data is also a limitation. The sarcopenia guidelines of the Japan Society of Hepatology, Asian Working Group for Sarcopenia, and European Working Group on Sarcopenia in Older People includes grip strength criteria34–36. The assessment of grip strength is becoming increasingly important༎ For example, a large multicenter study in Japan showed that reduced grip strength predicts poorer survival in chronic liver diseases37. These factors should be evaluated in future studies.
Despite these limitations, the strength of this study is that it consisted of a large number of recent patients with FAs profiles and detailed analyses were performed such as multivariate analysis and propensity score matching.
In conclusion, this retrospective study elucidated that FA levels, especially n-3 PUFAs were decreased with impaired hepatic reserve, and a low n-3 PUFAs level was associated with sarcopenia in patients with hepatic cirrhosis and HCC. These results showed that n-3 PUFAs may be a target for nutritional therapy or FA supplementation therapy for sarcopenia in patients with HCC and cirrhosis. Further prospective and multi-center studies are needed to elucidate whether intervention with n-3 PUFAs can prevent sarcopenia and improve the prognosis and quality of life in patients with HCC and hepatic cirrhosis.