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Association of Omega-3 Polyunsaturated Fatty Acids with Sarcopenia in Liver Cirrhosis Patients with Hepatocellular Carcinoma

  • Akitoshi Sano1,
  • Jun Inoue1,* ,
  • Eiji Kakazu1,2,
  • Masashi Ninomiya1,
  • Mio Tsuruoka1,
  • Kosuke Sato1,
  • Masazumi Onuki1,
  • Satoko Sawahashi1,
  • Keishi Ouchi1 and
  • Atsushi Masamune1
 Author information
Journal of Clinical and Translational Hepatology 2024;12(7):613-624

DOI: 10.14218/JCTH.2024.00036

Abstract

Background and Aims

Sarcopenia is associated with the prognosis of patients with liver cirrhosis and hepatocellular carcinoma (HCC). Given their diverse physiological activities, we hypothesized that plasma fatty acids might influence the progression of sarcopenia. This study aimed to clarify the association between fatty acids and sarcopenia in cirrhotic patients with HCC.

Methods

In this single-center retrospective study, we registered 516 cases and analyzed 414 cases of liver cirrhosis and HCC. The skeletal muscle mass index was measured using a transverse computed tomography scan image at the third lumbar vertebra. The cutoff value for sarcopenia followed the criteria set by the Japan Society of Hepatology. Fatty acid concentrations were measured by gas chromatography.

Results

Fatty acid levels, particularly omega-3 (n-3) polyunsaturated fatty acid (PUFA), were lower in patients with poor liver function (Child-Pugh grade B/C) and were negatively correlated with the albumin-bilirubin score (p<0.0001). The prognosis of HCC patients with low PUFA levels was significantly worse. Among the different fatty acid fractions, only n-3 PUFAs significantly correlated with skeletal muscle mass index (p=0.0026). In the multivariate analysis, the n-3 PUFA level was an independent variable associated with sarcopenia (p=0.0006).

Conclusions

A low level of n-3 PUFAs was associated with sarcopenia in patients with liver cirrhosis and HCC.

Keywords

Liver cirrhosis, Hepatocellular carcinoma, Sarcopenia, Skeletal Muscle, Fatty Acids, Omega-3 polyunsaturated fatty acids

Introduction

Morbidity and mortality due to liver cirrhosis are increasing worldwide. Liver cirrhosis is the most potent risk factor for the development of hepatocellular carcinoma (HCC), the 6th most common cancer globally.1 Cirrhosis is a significant predisposing condition for malnutrition, frailty, and sarcopenia.2 Sarcopenia is defined by the European Working Group on Sarcopenia as “a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes, including falls, fractures, disability, and mortality”.3 Pathophysiological factors contributing to sarcopenia include hepatocellular necrosis with cytokine release, host biomolecules such as danger-associated and pathogen-associated molecular patterns, portosystemic shunting resulting in hyperammonemia and endotoxemia, and the underlying etiology of liver disease (ethanol, cholestasis, insulin resistance, etc.).2 Sarcopenia is associated with shorter survival and higher recurrence rates of HCC in patients with cirrhosis and HCC.4 Exercise and nutritional therapy are vital treatments for sarcopenia. Several studies have reported that exercise therapy, rehabilitation, and branched-chain amino acids (BCAAs) have contributed to improved frailty and prolonged prognosis in sarcopenia patients with HCC.5

Fatty acids (FAs) are essential components of lipids and play important roles in cell and tissue metabolism and function. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are a class of long-chain fatty acids with many beneficial biological effects. It has been shown that n-3 PUFAs suppress muscle protein degradation, enhance the rate of muscle protein synthesis in response to anabolic stimuli, oxidative stress, and inflammation, and improve insulin sensitivity and lipid profiles.6,7 Although the impact of FAs on skeletal muscle systems has recently come to attention, few studies have been reported on the composition of plasma FAs in cirrhosis with sarcopenia. We hypothesized that plasma FAs influence sarcopenia in patients with cirrhosis and HCC. To verify this hypothesis, we retrospectively examined the status of sarcopenia and plasma FA profiles using our institution’s database of patients with liver cirrhosis and HCC.

Methods

Study design

This is a single-center, retrospective observational study. We retrospectively enrolled 516 patients with FA data who were admitted to Tohoku University Hospital for the treatment of liver diseases from December 2017 to June 2021. Cases without skeletal muscle volume data, liver cirrhosis, or HCC were excluded (Supplementary Fig. 1). The diagnosis of HCC was performed by combining computed tomography (CT) and tumor markers (alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin). The Barcelona Clinic Liver Cancer (BCLC) staging system was used to evaluate tumor progression.8 The diagnosis of liver cirrhosis was based on histological findings (F4) or imaging findings (presence of varices, liver deformity, splenomegaly, etc.) and serological findings.

Blood examination and plasma fatty acids measurement

Blood samples were obtained in the early morning after overnight fasting. The plasma specimens were separated, and FA concentrations were measured by gas chromatography at a central laboratory (SRL, Inc., Tokyo, Japan) according to the method described elsewhere.9 Briefly, total lipids in plasma were extracted following Folch’s procedure, followed by hydrolysis to free FAs. Free FAs were esterified with potassium methoxide/methanol and boron trifluoride–methanol. The methylated FAs were analyzed using a GC-17A gas chromatograph (Shimadzu Corporation, Kyoto, Japan) with an omegawax-250 capillary column (SUPELCO, Sigma–Aldrich Japan, Tokyo, Japan). The Child-Pugh (CP) grade, albumin-bilirubin (ALBI) score, and model for end-stage liver disease (MELD)-Na score were calculated to assess the severity of liver dysfunction.10,11 The fibrosis-4 (FIB-4) index was derived from aspartate aminotransferase, alanine aminotransferase, platelet count, and age to predict advanced fibrosis.12

Measurement of skeletal muscle volume for evaluating sarcopenia

CT scans were used to measure skeletal muscle mass. A transverse CT image at the level of the third lumbar spine was assessed from each scan. Skeletal muscle was identified, and the cross-sectional areas (cm2) were quantified using Hounsfield unit (HU) thresholds of −29 to +150 with image analysis software (WeVIEW Z-edition, HITACHI, Japan) after calibration with air, water, and bone (air, water, and bone are defined as −1,000 HU, 0 HU, and 1,000 HU, respectively).13 Multiple muscles, including the psoas, erector spinae, quadratus lumborum, abdominal obliques, and rectus abdominis, were quantified by manually tracing the CT images. The cross-sectional areas were then normalized for height (cm2/m2) for the skeletal muscle mass index (SMI),14 Sarcopenia was defined as a third lumbar spine SMI value <42 cm2/m2 for males and <38 cm2/m2 for females according to the Japan Society of Hepatology guidelines for secondary sarcopenia in liver disease.15

Statistical analysis

A comparison of variables between the two groups was made using the unpaired t-test. For comparisons involving more than three groups, Dunnett’s test was used. Pearson’s chi-square test was used to compare gender, etiology, CP grade, and BCLC staging. Data are expressed as mean±standard deviation. The linear association between FAs and other variables was quantified using Pearson’s correlation coefficient. The cumulative overall survival rate was calculated using the Kaplan-Meier method, and differences between the curves were evaluated using the log-rank test. Differences were considered significant at p<0.05. Factors influencing prognosis were analyzed using the Cox proportional hazards model. We examined the association between sarcopenia and FAs by univariate and multivariate analysis using logistic regression analysis. Priori variables were selected based on previous literature and included age, etiology, cirrhosis status (CP grade, ALBI score, MELD-Na score), BCAA levels, liver fibrosis, and tumor progression.16,17 The FIB-4 index and BCLC staging were used as hepatic fibrosis and tumor condition variables, respectively. The final multivariable model included variables with a p-value of <0.10 in the subsequent analysis stage. Propensity score-matching analysis was performed with the add-in package in JMP® Pro 17 software (SAS Institute, NC) using the 1:1 nearest available matching method. The covariates included age, gender, etiology, BCLC staging, CP grade, ALBI score, FIB-4 index, MELD-Na score, and BCAAs. Participants with missing data were excluded from the analysis. A p-value of <0.05 was considered statistically significant in all analyses. All statistical analyses were performed with JMP® Pro 17.

Results

Clinical characteristics of enrolled patients

Data from 516 cases were included in the analysis; the following cases were excluded: acute hepatitis (N=2), acute on chronic liver failure (N=1), and missing data (N=48) (Supplementary Fig. 1). Due to the small sample sizes of patients without HCC (N=24) and patients without liver cirrhosis (N=27), we included only patients with both HCC and liver cirrhosis (N=414) in our primary analysis. The baseline characteristics are shown in Table 1. The average age of patients with liver cirrhosis and HCC was 71.5 years, with males predominant (81%). Regarding liver disease etiology, patients with HCC due to viral hepatitis were in the majority (46%), followed by alcohol-associated liver disease (26%). Most cases were in BCLC stage A (47%) or B (42%). The high FIB-4 index and ALBI score in this group suggested the progression of hepatic fibrosis and decreased liver reserve capacity. Sarcopenia was observed in 247 patients (60%). Liver cirrhosis patients without HCC were younger and had a higher FIB-4 index than the HCC group. Additionally, patients in the chronic hepatitis group were younger than the HCC group and had lower FIB-4 indexes and ALBI scores, indicating less fibrosis and deterioration of liver reserve function. In the chronic hepatitis group, sarcopenia cases were fewer than in the HCC group, but this was not significant (p=0.12).

Table 1

Characteristics of the analyzed patients in this study

Mean±S.D.Cirrhosis with HCC
Cirrhosis without HCC
Chronic hepatitis without HCC
N=414N=24p-valueN=27p-value
Age, years71.5±11.259.4±10.6<0.0001*54.3±19.1<0.0001*
Gender, N79/33511/130.0041*14/130.0003*
  F/M (%)(19/81)(46/54)(52/48)
Etiology, N137/53/107/68/4912/1/1/6/40.0442*8/2/0/10/70.0002*
  HCV/HBV/alcohol/MASLD/others (%)(33/13/26/16/12)(46/4/4/31/15)(34/3/3/34/26)
BCLC staging, N194/172/48NANA
  A/B/C (%)(47/42/11)
Child-Pugh grade, N365/46/319/5/00.3564NA
  A/B/C (%)(88/11/1)(79/21/0)
HCC treatment, N153/155/66/40NANA
  TACE/RFA/chemotherapy/others (%)(37/37/16/10)
T-Bil, mg/dL1.1±0.51.5±0.50.0002*0.8±0.30.0481*
AST, U/L37.6±25.488.6±102.8<0.0001*49.0±32.50.1783
ALT, U/L28.4±20.178.8±83.4<0.0001*63.3±51.5<0.0001*
Albumin, g/dL3.6±0.53.5±0.60.30933.9±0.50.0264*
PT-INR1.0±0.11.1±0.10.41241.0±0.10.178
PLT, ×103/µL143.7±66.396.5±37.50.0012214.6±82.7<0.0001*
Sodium, mEq/L140.4±2.7140.4±3.40.9974140.6±2.10.9
Creatinine, mg/dL1.1±1.20.7±0.30.38060.8±0.20.4495
α-fetoprotein, ng/mL10,332.4±67,525.511.6±14.1<0.0001*3.3±2.4<0.0001*
DCP, mAU/mL12,612.0±58,071.5NANA
ALBI score−2.3±0.4−2.1±0.60.0409*−2.6±0.40.0049*
FIB-4 index4.3±2.87.5±7.0<0.0001*2.1±1.90.0010*
MELD-Na8.7±3.69.0±3.70.82027.1±1.00.0424*
BCAA, nmol/mL481.4±102.4463.0±177.70.6462462.8±119.00.6064
Triglyceride, mg/dL107.6±65.8100.7±48.50.8471106.9±46.70.9985
Total Cholesterol, mg/dL170.9±54.5156.9±46.10.3683181.5±46.70.5546
Total FAs, µg/mL2,827.9±568.72,993.4±727.80.32162,987.7±568.70.308
  SFAs, µg/mL915.0±191.51,007.0±250.30.0505945.8±163.40.6766
  Relative amount, %32.3±1.533.6±1.80.0001*31.7±1.60.0481
  MUFAs, µg/mL675.9±182.2793.9±199.20.0043*708.5±128.80.6034
  Relative amount, %23.7±3.126.6±1.9<0.0001*23.9±3.30.9790
  n-3 PUFAs, µg/mL231.9±83202.2±87.00.1851257.0±111.70.2689
  Relative amount, %8.2±2.46.9±2.30.0184*8.6±3.10.6806
  n-6 PUFAs, µg/mL967.9±200990.4±270.80.85051,076.3±226.40.0184*
  Relative amount, %34.4±3.732.9±3.40.137935.9±4.00.0833
CRP, mg/dL0.4±0.70.3±0.60.72640.3±0.40.6941
SMI, cm2/m240.8±8.135.4±10.60.0039*40.8±7.11.0000
Presence of Sarcopenia247/16717/70.267912/150.1231
  sarcopenia/non-sarcopenia (%)(60/40)(71/29)(44/56)

Plasma fatty acids were correlated with liver dysfunction in subjects with liver cirrhosis

We analyzed the relationship between plasma FA composition and liver function. Saturated fatty acids (SFAs), n-3 PUFAs, and n-6 PUFAs were lower in patients with severe cirrhosis (CP grade B and C) compared to those with CP grade A (Fig. 1, Table 2). There was no significant difference in monounsaturated fatty acid (MUFA) levels. Focusing on the relative amount of each FA fraction, only n-3 PUFAs were significantly lower in Child-Pugh grade B/C patients. Evaluating ALBI scores as another index of liver function, Pearson correlation analysis revealed negative correlations between each FA fraction and ALBI score, especially n-3 PUFAs (R=−0.33, p<0.0001) (Supplementary Fig. 2). Using propensity score matching for patient backgrounds (age, gender, etiology, BCLC staging), decreases in n-3 PUFAs (p=0.007) and n-6 PUFAs (p=0.0305) were observed in the CP B/C group (Supplementary Table 1). Additionally, comparing liver cirrhosis without HCC and chronic hepatitis without HCC using propensity score matching, n-3 PUFAs were decreased in the cirrhosis group (p=0.0441), with a significant relative amount decrease (p=0.0289) (Supplementary Table 2).

Comparison of plasma fatty acid profiles in liver cirrhosis and hepatocellular carcinoma patients according to Child-Pugh grade.
Fig. 1  Comparison of plasma fatty acid profiles in liver cirrhosis and hepatocellular carcinoma patients according to Child-Pugh grade.

n.s., not significant.

Table 2

Comparison of clinical characteristics and fatty acid levels of liver cirrhosis and hepatocellular carcinoma patients with Child-Pugh grade A and B/C

Mean±S.D.Child-Pugh grade A
Child-Pugh grade B/C
p-value
N=365N=49
Age, years72.2±10.966.3±12.30.0005*
Gender, N67/29812/370.4577
  F/M (%)(18/82)(24/76)
Etiology, N121/48/91/64/4116/5/16/4/80.2485
  HCV/HBV/alcohol/MASLD/others (%)(33/13/25/18/11)(33/10/32/8/17)
BCLC staging, N172/152/4121/20/70.7834
  A/B/C (%)(47/42/11)(43/41/16)
HCC treatment, N133/147/56/2920/8/10/110.1018
  TACE/RFA/chemotherapy/others (%)(36/40/15/9)(41/16/20/23)
T-Bil, mg/dL1.0±0.41.7±0.9<0.0001*
AST, U/L35.2±23.958.6±28.4<0.0001*
ALT, U/L27.5±19.435.8±23.70.0148*
Albumin, g/dL3.7±0.43.0±0.4<0.0001*
PT-INR1.0±0.071.1±0.1<0.0001*
PLT, ×103/µL145.4±61.2129.8±99.60.2359
Sodium, mEq/L140.6±2.5139.1±3.80.0005*
Creatinine, mg/dL1.0±1.01.2±2.50.3374
α-fetoprotein, ng/mL8,698.2±60,161.524,663.7±113,245.60.1476
DCP, mAU/mL11,658.7±56,563.720,935.5±70,143.50.3332
ALBI score−2.4±0.4−1.6±0.5<0.0001*
FIB-4 index4.0±2.57.0±3.9<0.0001*
MELD-Na8.3±3.210.8±4.6<0.0001*
BCAA, nmol/mL489.6±98.7412.8±108.4<0.0001*
Triglyceride, mg/dL107.9±48.5104.3±152.60.7131
Total Cholesterol, mg/dL169.7±35.6182.5±136.80.0941
Total FAs, µg/mL2,858.4±566.42,568.1±527.30.0043*
  SFAs, µg/mL923.2±192.7845.6±168.40.023*
  Relative amount, %32.3±1.533.0±1.30.0086*
  MUFAs, µg/mL680.3±183.3638.3±170.90.2199
  Relative amount, %23.6±3.224.7±3.20.0558*
  n-3 PUFAs, µg/mL238.0±81.7180.7±77.8<0.0001*
  Relative amount, %8.3±2.37.0±2.60.0013*
  n-6 PUFAs, µg/mL980.1±197864.4±198.30.0011*
  Relative amount, %34.4±3.733.8±3.70.3052
CRP, mg/dL0.4±0.70.8±1.20.0005*
SMI, cm2/m240.9±8.040.0±9.20.4808
Presence of Sarcopenia, N216/14930/180.6581
  sarcopenia/non-sarcopenia (%)(59/41)(61/39)

Plasma fatty acids were not associated with the progression of hepatocellular carcinoma

To evaluate whether HCC progression affects plasma FA levels, we examined the association between FA levels and HCC status using BCLC staging, number of liver tumors, and maximum tumor diameter. Each FA fraction showed no differences with BCLC staging or number of tumors (Supplementary Fig. 3A, B). Similarly, no correlations were found between FA levels and tumor diameter (Supplementary Fig. 3C). In addition, we compared liver cirrhosis patients with and without HCC by using propensity score matching to account for patient backgrounds (age, gender, etiology, CP grade, ALBI score, FIB-4 index, MELD-Na score) (Supplementary Table 3). While the relative amount of MUFAs showed a significant difference, the levels of each fatty acid fraction were not different between those groups.

Comparison of patients according to the presence of sarcopenia and outcome

The clinical characteristics of HCC patients with and without sarcopenia are shown in Table 3. Patients with sarcopenia had a higher proportion of females, aspartate aminotransferase, alanine aminotransferase, AFP, and FIB-4 index, and a lower number of BCLC staging A cases. Nutritionally, total BCAAs were significantly lower in subjects with sarcopenia, as previously described.18 Notably, total FAs were significantly lower in patients with sarcopenia than those without. The absolute amounts of SFAs, MUFAs, and n-3 PUFAs were significantly lower in patients with sarcopenia. Focusing on relative amounts of FAs, there was no significant difference between SFAs and MUFAs, but the relative amount of n-3 PUFAs was significantly lower in subjects with sarcopenia. The relative amount of n-6 PUFAs was higher in patients with sarcopenia.

Table 3

Comparison of clinical characteristics of patients with and without sarcopenia

Mean±S.D.Sarcopenia (-)
Sarcopenia (+)
p-value
N=167N=247
Age, years71.7±9.071.4±12.50.8010
Gender, N20/14759/1880.0019*
  F/M (%)(12/88)(24/76)
Etiology, N49/17/45/36/2088/36/62/32/290.0705
  HCV/HBV/alcohol/MASLD/others (%)(29/10/27/22/12)(36/14/25/13/12)
BCLC staging, N93/65/9101/107/390.0005*
  A/B/C (%)(56/39/5)(41/43/16)
Child-Pugh grade, N149/17/1216/29/20.8527
  A/B/C (%)(89/10/1)(87/12/1)
HCC treatment, N58/76/17/1695/79/49/240.2033
  TACE/RFA/chemotherapy/others (%)(35/45/10/10)(38/32/20/10)
T-Bil, mg/dL1.2±0.61.0±0.40.4833
AST, U/L34.2±17.839.9±29.30.0248*
ALT, U/L29.3±15.927.7±22.50.4381*
Albumin, g/dL3.7±0.43.6±0.50.0882
PT-INR1.0±0.091.0±0.080.7076
PLT, ×103/µL140.4±57.3146.0±71.80.5113
Sodium, mEq/L140.7±2.2140.3±3.00.1476
Creatinine, mg/dL1.1±1.01.0±1.40.9343
α-fetoprotein, ng/mL1,958.8±11,318.716,030.6±86,648.40.0394*
DCP, mAU/mL5,294.0±38,196.817,540.8±67,909.60.0380
ALBI score−2.3±0.4−2.3±0.50.4728
FIB-4 index3.9±2.54.5±3.00.0416*
MELD-Na8.8±3.58.6±3.70.5311
BCAA, nmol/mL505.1±101.5465.3±100.10.0002*
Triglyceride, mg/dL118.9±56.299.9±70.70.0054*
Total Cholesterol, mg/dL170.1±33.9171.5±64.90.7983
Total FAs, µg/mL2,938.9±590.32,749.2±540.70.0020*
  SFAs, µg/mL954.6±202887.0±1790.0010*
  Relative amount, %32.5±1.732.3±1.30.1949
  MUFAs, µg/mL709.7±189.8651.9±173.20.0033*
  Relative amount, %24.0±3.023.6±3.40.2345
  n-3 PUFAs, µg/mL254.0±92.7216.3±71.6<0.0001*
  Relative amount, %8.6±2.57.9±2.30.0093*
  n-6 PUFAs, µg/mL984.7±193.7956.1±2040.9070
  Relative amount, %33.7±3.734.8±3.60.0051*
CRP, mg/dL0.3±0.50.5±0.80.0068*
SMI, cm2/m248.5±5.835.5±4.4<0.0001*

We analyzed the presence of sarcopenia and FA fractions in relation to the prognosis of HCC. The Kaplan-Meier curves in Figure 2 show that patients with sarcopenia had significantly worse overall survival rates than those without sarcopenia. To evaluate the relationship between FA levels and mortality, patients with low levels of each FA were defined as those with FA levels lower than the quartile. Although low relative amounts of SFAs and MUFAs were associated with better overall survival rates, worse survivals were observed in subjects with low relative amounts of n-3 and n-6 PUFAs (Log-rank: p=0.011, p=0.030, respectively). Using the Cox proportional hazards model, an analysis of variables related to prognosis was conducted (Supplementary Table 4). The levels of n-3 PUFAs and the relative amount of n-6 PUFAs were found to be independent variables related to the prognosis of HCC in the multivariate analysis.

Kaplan-Meier survival curves for the length of time until death.
Fig. 2  Kaplan-Meier survival curves for the length of time until death.

(A) Analysis for patients with and without sarcopenia. (B-E) Analysis for patients with and without low levels of each fatty acid fraction. SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; +, with; -, without.

The level of n-3 polyunsaturated fatty acids was correlated with skeletal muscle mass index in liver cirrhosis patients with hepatocellular carcinoma

We analyzed the correlation between SMI values and each FA fraction in liver cirrhosis patients with hepatocellular carcinoma. Although SFAs, MUFAs, and n-6 PUFAs did not show significant correlations, only n-3 PUFAs were positively correlated with SMI (R=0.15, p=0.0026) (Fig. 3A). Focusing on the relative amount of each FA fraction, n-3 PUFAs were positively correlated (R=0.19, p=0.0003), and n-6 PUFAs were negatively correlated (R=−0.14, p=0.011) with SMI (Fig. 3B). This result was similar to the analysis of all patients, including cirrhosis patients without HCC and chronic hepatitis patients (Supplementary Fig. 4). Calculating the n-6/n-3 ratio also showed a negative correlation with SMI (R=−0.15, p=0.0041) (Supplementary Fig. 5).

The correlation between various fatty acid fraction levels and skeletal muscle mass index.
Fig. 3  The correlation between various fatty acid fraction levels and skeletal muscle mass index.

(A) Analysis of absolute amounts of fatty acids. (B) Analysis of relative amounts of fatty acids. n.s., not significant.

Since we found a significant association between liver function and FA levels, as shown in Figures 1 and 2, we performed the same analysis only in the CP grade A cohort (Supplementary Fig. 6). Even in the CP grade A population, only n-3 PUFAs were positively correlated with SMI (R=0.20, p=0.0003).

Logistic regression analysis revealed that the level of n-3 PUFAs was the independent variable related to sarcopenia

Given the significant correlation between n-3 PUFAs and skeletal muscle mass, we analyzed the association between the level of n-3 PUFAs and the risk of sarcopenia using logistic regression analysis. Table 4 shows the odds ratio for the presence of sarcopenia in patients with liver cirrhosis for each variable. In the univariate analysis, gender, metabolic dysfunction-associated steatotic liver disease (MASLD), BCLC staging, FIB-4 index, BCAA level, and n-3 PUFA level were associated with the presence of sarcopenia. Multivariate analysis showed that the n-3 PUFA fraction was associated with the presence of sarcopenia. In addition to n-3 PUFAs, gender, etiology (MASLD), and BCLC staging B and C were identified as factors associated with sarcopenia. In the univariate analysis, every n-3 PUFA except C20:3 (eicosatrienoic acid) was a significant variable: C18:3 (alpha-linolenic acid), C20:5 (eicosapentaenoic acid (EPA)), C22:5 (docosapentaenoic acid) and C22:6 (docosahexaenoic acid (DHA)) (Supplementary Table 5).

Table 4

Logistic regression analysis for variates associated with sarcopenia in patients with liver cirrhosis

Univariate analysis
Multivariate analysis
Odds ratio (95% CI)p-valueOdds ratio (95% CI)p-value
Age0.9977 (0.9803–1.0155)0.8002
Gender
  women1 (Reference)1 (Reference)
  men0.4335 (0.2498–0.7523)0.0019*0.3323 (0.1585–0.6964)0.0035*
Etiology
  virus1 (Reference)1 (Reference)
  alcohol0.7333 (0.4509–1.1926)0.21130.7258 (0.3936–1.3383)0.3046
  MASLD0.4731 (0.2697–0.8300)0.0091*0.3432 (0.1751–0.6723)0.0018*
  others0.7718 (0.4056–1.4684)0.37280.4330 (0.1848–1.0149)0.0541
BCLC staging
  A1 (Reference)1 (Reference)
  B1.5309 (1.0079–2.3253)0.0458*1.8315 (1.1070–3.0300)0.0185*
  C4.0300 (1.8514–8.7724)0.0004*4.3626 (1.5686–12.1327)0.0048*
Child-Pugh grade
  A1 (Reference)
  B-C1.1880 (0.6409–2.2022)0.6595
ALBI score1.1777 (0.7542–1.8392)0.5914
FIB-4 index1.0821 (1.0018–1.1687)0.0365*1.0581 (0.9624–1.1633)0.2303
MELD-NA score0.9752 (0.9223–1.0311)0.3773
BCAA0.9961 (0.9934–0.9982)0.0002*0.9993 (0.9966–1.0021)0.631
n-3 PUFAs0.9944 (0.9917–0.9971)<0.0001*0.9947 (0.9915–0.9978)0.0006*

The comparison of n-3 polyunsaturated fatty acids with and without sarcopenia in matched patients with liver cirrhosis

Finally, the n-3 PUFAs level was compared between patients with sarcopenia and those without, using propensity score matching to align their backgrounds. The covariates included age, gender, etiology, BCLC staging, CP grade, ALBI score, FIB-4 index, MELD-Na score, and BCAA. It was confirmed that there were no significant differences in each factor among the two groups (Supplementary Table 6). The total levels of n-3 PUFAs were significantly lower in the group of patients with sarcopenia, even among patients with matched backgrounds (Fig. 4A). Additionally, among the n-3 PUFA fractions, the levels of alpha-linolenic acid, EPA, docosapentaenoic acid, and DHA were significantly lower in patients with sarcopenia than in those without (Fig. 4B). We also analyzed only the CP grade A patients, with the same results as above (Supplementary Table 6, Supplementary Fig. 7).

The comparison of n-3 polyunsaturated fatty acids with and without sarcopenia in matched patients with liver cirrhosis.
Fig. 4  The comparison of n-3 polyunsaturated fatty acids with and without sarcopenia in matched patients with liver cirrhosis.

(A) The level of n-3 polyunsaturated fatty acids is shown. (B) The levels of each fatty acid in n-3 polyunsaturated fatty acids are shown. n.s., not significant; +, with; -, without.

Discussion

In this single-center retrospective study, we analyzed factors related to sarcopenia in patients with HCC and liver cirrhosis, with a particular focus on various FA levels. Our findings indicated that various FA fractions decreased with declining liver reserve capacity. Among these FAs, the level of n-3 PUFAs showed a correlation with skeletal muscle mass and remained an independent variable associated with sarcopenia, even after adjusting for various confounding factors. Therefore, the level of n-3 PUFAs is considered a factor involved in sarcopenia in patients with liver cirrhosis and HCC.

Sarcopenia is a prevalent muscle abnormality in patients with cirrhosis. The presence of sarcopenia is a major predictor of mortality pre- and post-liver transplantation,19,20 longer hospital stays,21 and hepatic encephalopathy.22 Sarcopenia is also associated with poor survival in patients with HCC.23 The pathogenesis of sarcopenia is multifactorial, involving factors such as hyperammonemia,24,25 increased autophagy,24 proteasomal activity,26 myostatin,27 and impaired mitochondrial function.26

Nutritional factors are also critical in the pathogenesis of sarcopenia. Nutritional deficits, especially BCAAs, are common in patients with liver cirrhosis. Accelerated skeletal muscle consumption of BCAAs in liver cirrhosis leads to muscle protein breakdown, resulting in sarcopenia.28 While BCAAs are widely known to be important in the progression of sarcopenia, the association between sarcopenia and FAs in liver diseases is unclear. In the present study, we analyzed the relationship between sarcopenia and plasma FA levels in patients with liver cirrhosis and HCC and found that lower levels of n-3 PUFAs were associated with sarcopenia.

This study revealed that FA levels were lower in patients with reduced liver reserve function (CP grade B/C). Notably, only the level of n-3 PUFAs was lower in relative amounts in CP grade B/C patients and was most negatively correlated with the ALBI score. This result is consistent with previous reports showing that patients with liver cirrhosis lack crucial FAs, including n-3 PUFAs, which could be explained by reduced dietary intake, impaired liver synthesis, and increased degradation of PUFAs due to lipid peroxidation.29–31 It was expected that FA levels would decrease with worsening cancer due to deteriorating nutritional status. However, there was no association between HCC status and FA levels in this study. This might be because the patients in this study mainly had good hepatic reserve and could be treated for cancer. Further case studies are needed on the FA composition in patients with HCC and impaired hepatic reserve.

In this study, patients with sarcopenia had a significantly worse prognosis, which is consistent with previous studies.17 Past studies have reported that PUFA intake improves mortality in diabetes32 and cancer.33 We found that although a low relative amount of SFAs and MUFAs was associated with a better overall survival rate, significantly worse survival rates were observed in subjects with low relative amounts of n-3 and n-6 PUFAs. In the Cox proportional hazards model, the following independent variables were associated with prognosis: etiology, BCLC staging, tumor marker (des-γ-carboxy prothrombin), the presence of sarcopenia, and PUFA levels. Although HCC treatment was a significant variable in univariate analysis, it became non-significant in multivariate analysis, likely due to confounding between HCC treatment and other variables. These results suggested that there may be a relationship between FA levels and mortality in HCC patients.

When the association between the composition of FAs and skeletal muscle mass was analyzed, it was revealed that SMI was significantly correlated only with the n-3 PUFA level. Because we elucidated the association between hepatic reserve (CP score and ALBI score) and plasma FA levels, it was essential to address the confounding relationship between FA composition and hepatic reserve in our analysis of skeletal muscle mass and FA composition. Hence, we also analyzed the correlation only in patients with CP grade A and conducted a multivariate analysis. The only FA that showed a significant correlation with muscle mass, even in patients with CP grade A, was n-3 PUFAs. In the multivariate analysis, a lower level of n-3 PUFAs was associated with an increased risk of sarcopenia among patients with liver cirrhosis, adjusted for patient backgrounds (gender, etiology, BCLC staging, FIB-4 index, and plasma BCAA level). Furthermore, we found lower n-3 PUFA 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 levels of the n-3 FA 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 processes34 and the impact on skeletal muscle systems has recently come to attention. The nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) is a transcription factor that induces a pro-inflammatory response. The nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha (IκBα), is a vital inhibitor of NF-κB. In C2C12 mouse skeletal myoblast cells, DHA and EPA were effective in inhibiting protein degradation, and DHA was able to increase the total protein IκBα level, which reduced NF-κB DNA-binding activity.35,36 In addition, in mouse myoblasts, EPA was able to preserve cell viability by inhibiting mitogen-activated protein kinase apoptosis and stimulating MyoD, potentially reducing catabolic activity and increasing anabolic activity in skeletal muscle.37 Further studies in C2C12 myoblasts indicate that EPA was able to restore insulin signaling when cells were co-incubated with lipopolysaccharide. This study demonstrated that EPA might help preserve the phosphorylation of mammalian targets of rapamycin, a pathway important for the activation of translation and muscle protein synthesis when cells face LPS exposure.38 In this study, NF-κB was inhibited by EPA, providing a potential mechanism whereby mammalian targets of rapamycin phosphorylation could persist even during LPS exposure.38 In addition, n-3 PUFAs were reported to improve intestinal function with altered intestinal microbiome.39 Since a leaky gut may cause sarcopenia in patients with liver cirrhosis,40 n-3 PUFA supplementation may be effective in preventing and treating sarcopenia in patients with HCC.

There are several clinical reports on the relationship between PUFAs and sarcopenia. 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 subjects.41 Studies have also demonstrated a relationship between n-3 PUFAs and sarcopenia in patients with cancer. For example, 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 to those who were gaining muscle.42 Itoh et al. showed that low EPA and DHA levels were associated with preoperative sarcopenia in patients with HCC.43 Furthermore, Kitagawa et al. reported that the n-6/n-3 ratio and arachidonic acid (AA)/EPA ratio were associated with skeletal muscle depletion in cachexic patients with advanced gastrointestinal cancers.44 In our study, we also found a negative correlation between the n-6/n-3 ratio and AA/EPA ratio and skeletal muscle mass. The effect of n-3 PUFA supplementation on sarcopenia is controversial, but randomized controlled trials have been conducted to elucidate the impacts of n-3 PUFAs on sarcopenia in older individuals.45,46 Although the association between FAs and skeletal muscle mass has been reported in various diseases, the present study is novel as there have been no reports focusing on liver cirrhosis.

There are some limitations in this study. Firstly, this study was a single-center retrospective design. Prospective multicenter studies are needed. Additionally, the subjects of this study were patients aiming for liver cancer treatment, and almost all cases had relatively good liver reserve function. Decreased liver reserve function is a significant risk factor for sarcopenia,17 but this study did not demonstrate any association between CP score, MELD score, and sarcopenia. The absence of cases with poor liver reserve function is also a limitation of this study. Similarly, the small sample size of patients without HCC and those without cirrhosis is a limitation. Although correlations between the various FA fractions and SMI were similar for patients overall (Supplementary Fig. 4) and for patients with HCC and cirrhosis (Fig. 3), the sample sizes of patients without HCC and cirrhosis were too small to adequately reflect these patient groups. Therefore, in the present study, we limited our analysis to the group of patients with cirrhosis and HCC. A further collection of cases is necessary for thorough examination. Furthermore, we could not assess factors such as daily eating and exercise habits and medications for dyslipidemia and diabetes mellitus. Since these factors, especially daily diet may influence plasma lipid concentrations, a database including these data should be established in the future. The lack of grip strength data is also a limitation. The sarcopenia guidelines of the Japan Society of Hepatology, the Asian Working Group for Sarcopenia, and the European Working Group on Sarcopenia in Older People include grip strength criteria.15,47,48 These factors should be evaluated in future studies. This study evaluated FAs in total plasma and not solely free FAs, which is a limitation since it is not clear to what extent these FAs are unbound and possess signaling capacity. However, another publication showed that the total plasma FA profile was comparable to the free FA profile,49 and it is assumed that the overall plasma FA profile may also account for the physiological activity potential.

Despite these limitations, the strength of this study is that it included a large number of patients with FA profiles and performed detailed analyses such as multivariate analysis and Propensity Score matching. We believe that the present study provides a basis for future prospective studies to determine the effects of adding n-3 PUFAs for clinical application in the nutritional therapy of sarcopenia in patients with liver cirrhosis and HCC.

Conclusion

This retrospective study elucidated that FA levels, especially n-3 PUFAs, were decreased with impaired hepatic reserve, and a low n-3 PUFA level was associated with sarcopenia in patients with liver cirrhosis and HCC. Further prospective and multicenter 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 cirrhosis.

Supporting information

Supplementary Fig. 1

The flowchart describing recruited patients in this single-center retrospective study.

(DOCX)

Supplementary Fig. 2

The correlation between each fatty acid fraction and albumin-bilirubin score.

(DOCX)

Supplementary Fig. 3

The levels of blood fatty acids at each hepatocellular carcinoma stage.

(A) The levels of fatty acids in each BCLC stage. (B) The levels of fatty acids in each tumor count in the liver. C. The correlation between free fatty acids and maximum tumor diameter. n.s., not significant; BCLC, Barcelona Clinical Liver Cancer.

(DOCX)

Supplementary Fig. 4

Correlation between skeletal muscle mass index and plasma fatty acid levels in all analyzed patients including groups of cirrhosis patients with HCC, cirrhosis patients without HCC, and chronic hepatitis.

(A) The correlation between skeletal muscle mass index and absolute amounts of fatty acids. B. The correlation between skeletal muscle mass index and relative amounts of fatty acids. HCC, hepatocellular carcinoma; n.s., not significant.

(DOCX)

Supplementary Fig. 5

Correlation between skeletal muscle mass index and n-6/n-3 polyunsaturated fatty acids ratio and arachidonic acid/eicosapentaenoic acid ratio.

AA, arachidonic acid; EPA, eicosapentaenoic acid.

(DOCX)

Supplementary Fig. 6

Correlation between skeletal muscle mass index and plasma fatty acid levels in HCC patients with Child-Pugh grade A.

(A) The correlation between skeletal muscle mass index and absolute amounts of fatty acids. B. The correlation between skeletal muscle mass index and relative amounts of fatty acids. n.s., not significant.

(DOCX)

Supplementary Fig. 7

The comparison of n-3 polyunsaturated fatty acids with and without sarcopenia in matched patients with Child-Pugh grade A.

(A) The level of n-3 polyunsaturated fatty acids is shown. (B) The levels of each fatty acid in n-3 polyunsaturated fatty acids are shown. +, with; −, without.

(DOCX)

Supplementary Table 1

Characteristics of liver cirrhosis and hepatocellular carcinoma patients with Child-Pugh grade A and B/C using Propensity Score matching.

(DOCX)

Supplementary Table 2

Characteristics of matched patients with liver cirrhosis and chronic hepatitis without hepatocellular carcinoma.

(DOCX)

Supplementary Table 3

Characteristics of matched liver cirrhosis patients with and without hepatocellular carcinoma.

(DOCX)

Supplementary Table 4

The analysis for variables related to survival of patients with HCC using the Cox proportional hazards regression.

(DOCX)

Supplementary Table 5

Logistic regression analysis for blood fatty acids associated with sarcopenia in patients with liver cirrhosis and hepatocellular carcinoma.

(DOCX)

Supplementary Table 6

Comparison of liver cirrhosis and hepatocellular patients with and without sarcopenia matching backgrounds using the Propensity Score.

(DOCX)

Declarations

Ethical statement

The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Ethics Committee of Tohoku University Graduate School of Medicine (APPROVAL NUMBER: 2018-1-049, 2021-1-207, 2021-1-540). Informed consent was obtained in the form of an opt-out method.

Data sharing statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author (jinoue@med.tohoku.ac.jp).

Funding

This research was supported by AMED under Grant Number JP22fk0210114 and JSPS KAKENHI Grant Number JP21K20915.

Conflict of interest

The authors have no conflict of interest related to this publication.

Authors’ contributions

Study design (AS), analysis and interpretation of data (AS, JI), acquisition of data (AS, MN, MT, KS, MO, SS, KO), manuscript writing (AS, JI), critical revision (JI, AM), statistical analysis (AS, JI, EK), critical funding (AS, EK), and study supervision (AM). All authors have made significant contributions to this study and have approved the final manuscript.

References

  1. Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet 2021;398(10308):1359-1376 View Article PubMed/NCBI
  2. Tandon P, Montano-Loza AJ, Lai JC, Dasarathy S, Merli M. Sarcopenia and frailty in decompensated cirrhosis. J Hepatol 2021;75(Suppl 1):S147-S162 View Article PubMed/NCBI
  3. Lai JC, Tandon P, Bernal W, Tapper EB, Ekong U, Dasarathy S, et al. Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021;74(3):1611-1644 View Article PubMed/NCBI
  4. Kamachi S, Mizuta T, Otsuka T, Nakashita S, Ide Y, Miyoshi A, et al. Sarcopenia is a risk factor for the recurrence of hepatocellular carcinoma after curative treatment. Hepatol Res 2016;46(2):201-208 View Article PubMed/NCBI
  5. Koya S, Kawaguchi T, Hashida R, Hirota K, Bekki M, Goto E, et al. Effects of in-hospital exercise on sarcopenia in hepatoma patients who underwent transcatheter arterial chemoembolization. J Gastroenterol Hepatol 2019;34(3):580-588 View Article PubMed/NCBI
  6. Buoite Stella A, Gortan Cappellari G, Barazzoni R, Zanetti M. Update on the Impact of Omega 3 Fatty Acids on Inflammation, Insulin Resistance and Sarcopenia: A Review. Int J Mol Sci 2018;19(1):218 View Article PubMed/NCBI
  7. Ganapathy A, Nieves JW. Nutrition and Sarcopenia-What Do We Know?. Nutrients 2020;12(6):1755 View Article PubMed/NCBI
  8. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76(3):681-693 View Article PubMed/NCBI
  9. Ninomiya T, Nagata M, Hata J, Hirakawa Y, Ozawa M, Yoshida D, et al. Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: the Hisayama Study. Atherosclerosis 2013;231(2):261-267 View Article PubMed/NCBI
  10. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60(8):646-649 View Article PubMed/NCBI
  11. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 2015;33(6):550-558 View Article PubMed/NCBI
  12. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43(6):1317-1325 View Article PubMed/NCBI
  13. Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol (1985) 1998;85(1):115-122 View Article PubMed/NCBI
  14. Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab 2008;33(5):997-1006 View Article PubMed/NCBI
  15. Nishikawa H, Shiraki M, Hiramatsu A, Moriya K, Hino K, Nishiguchi S. Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): Recommendation from the working group for creation of sarcopenia assessment criteria. Hepatol Res 2016;46(10):951-963 View Article PubMed/NCBI
  16. Ebadi M, Bhanji RA, Mazurak VC, Montano-Loza AJ. Sarcopenia in cirrhosis: from pathogenesis to interventions. J Gastroenterol 2019;54(10):845-859 View Article PubMed/NCBI
  17. Tantai X, Liu Y, Yeo YH, Praktiknjo M, Mauro E, Hamaguchi Y, et al. Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis. J Hepatol 2022;76(3):588-599 View Article PubMed/NCBI
  18. Sano A, Tsuge S, Kakazu E, Iwata T, Ninomiya M, Tsuruoka M, et al. Plasma free amino acids are associated with sarcopenia in the course of hepatocellular carcinoma recurrence. Nutrition 2021;84:111007 View Article PubMed/NCBI
  19. DiMartini A, Cruz RJ, Dew MA, Myaskovsky L, Goodpaster B, Fox K, et al. Muscle mass predicts outcomes following liver transplantation. Liver Transpl 2013;19(11):1172-1180 View Article PubMed/NCBI
  20. Durand F, Buyse S, Francoz C, Laouénan C, Bruno O, Belghiti J, et al. Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography. J Hepatol 2014;60(6):1151-1157 View Article PubMed/NCBI
  21. Montano-Loza AJ, Meza-Junco J, Baracos VE, Prado CM, Ma M, Meeberg G, et al. Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation. Liver Transpl 2014;20(6):640-648 View Article PubMed/NCBI
  22. Bhanji RA, Moctezuma-Velazquez C, Duarte-Rojo A, Ebadi M, Ghosh S, Rose C, et al. Myosteatosis and sarcopenia are associated with hepatic encephalopathy in patients with cirrhosis. Hepatol Int 2018;12(4):377-386 View Article PubMed/NCBI
  23. Ha Y, Kim D, Han S, Chon YE, Lee YB, Kim MN, et al. Sarcopenia Predicts Prognosis in Patients with Newly Diagnosed Hepatocellular Carcinoma, Independent of Tumor Stage and Liver Function. Cancer Res Treat 2018;50(3):843-851 View Article PubMed/NCBI
  24. Qiu J, Thapaliya S, Runkana A, Yang Y, Tsien C, Mohan ML, et al. Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB-mediated mechanism. Proc Natl Acad Sci U S A 2013;110(45):18162-18167 View Article PubMed/NCBI
  25. Davuluri G, Allawy A, Thapaliya S, Rennison JH, Singh D, Kumar A, et al. Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J Physiol 2016;594(24):7341-7360 View Article PubMed/NCBI
  26. Peth A, Uchiki T, Goldberg AL. ATP-dependent steps in the binding of ubiquitin conjugates to the 26S proteasome that commit to degradation. Mol Cell 2010;40(4):671-681 View Article PubMed/NCBI
  27. Dasarathy S, McCullough AJ, Muc S, Schneyer A, Bennett CD, Dodig M, et al. Sarcopenia associated with portosystemic shunting is reversed by follistatin. J Hepatol 2011;54(5):915-921 View Article PubMed/NCBI
  28. Periyalwar P, Dasarathy S. Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses. Clin Liver Dis 2012;16(1):95-131 View Article PubMed/NCBI
  29. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343(8911):1454-1459 View Article PubMed/NCBI
  30. Ristić-Medić D, Takić M, Vučić V, Kandić D, Kostić N, Glibetić M. Abnormalities in the serum phospholipids fatty acid profile in patients with alcoholic liver cirrhosis - a pilot study. J Clin Biochem Nutr 2013;53(1):49-54 View Article PubMed/NCBI
  31. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother 2002;56(8):365-379 View Article PubMed/NCBI
  32. Jiao J, Liu G, Shin HJ, Hu FB, Rimm EB, Rexrode KM, et al. Dietary fats and mortality among patients with type 2 diabetes: analysis in two population based cohort studies. BMJ 2019;366:l4009 View Article PubMed/NCBI
  33. Bell GA, Kantor ED, Lampe JW, Kristal AR, Heckbert SR, White E. Intake of long-chain ω-3 fatty acids from diet and supplements in relation to mortality. Am J Epidemiol 2014;179(6):710-720 View Article PubMed/NCBI
  34. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta 2015;1851(4):469-484 View Article PubMed/NCBI
  35. Wang Y, Lin QW, Zheng PP, Zhang JS, Huang FR. DHA inhibits protein degradation more efficiently than EPA by regulating the PPARγ/NFκB pathway in C2C12 myotubes. Biomed Res Int 2013;2013:318981 View Article PubMed/NCBI
  36. Huang F, Wei H, Luo H, Jiang S, Peng J. EPA inhibits the inhibitor of κBα (IκBα)/NF-κB/muscle RING finger 1 pathway in C2C12 myotubes in a PPARγ-dependent manner. Br J Nutr 2011;105(3):348-356 View Article PubMed/NCBI
  37. Saini A, Sharples AP, Al-Shanti N, Stewart CE. Omega-3 fatty acid EPA improves regenerative capacity of mouse skeletal muscle cells exposed to saturated fat and inflammation. Biogerontology 2017;18(1):109-129 View Article PubMed/NCBI
  38. Wei HK, Deng Z, Jiang SZ, Song TX, Zhou YF, Peng J, et al. Eicosapentaenoic acid abolishes inhibition of insulin-induced mTOR phosphorylation by LPS via PTP1B downregulation in skeletal muscle. Mol Cell Endocrinol 2017;439:116-125 View Article PubMed/NCBI
  39. Che L, Zhou Q, Liu Y, Hu L, Peng X, Wu C, et al. Flaxseed oil supplementation improves intestinal function and immunity, associated with altered intestinal microbiome and fatty acid profile in pigs with intrauterine growth retardation. Food Funct 2019;10(12):8149-8160 View Article PubMed/NCBI
  40. Kawaguchi T, Torimura T. Leaky gut-derived tumor necrosis factor-α causes sarcopenia in patients with liver cirrhosis. Clin Mol Hepatol 2022;28(2):177-180 View Article PubMed/NCBI
  41. Del Brutto OH, Mera RM, Ha JE, Gillman J, Zambrano M, Sedler MJ. Dietary Oily Fish Intake and Frailty. A Population-Based Study in Frequent Fish Consumers Living in Rural Coastal Ecuador (the Atahualpa Project). J Nutr Gerontol Geriatr 2020;39(1):88-97 View Article PubMed/NCBI
  42. Murphy RA, Mourtzakis M, Chu QS, Reiman T, Mazurak VC. Skeletal muscle depletion is associated with reduced plasma (n-3) fatty acids in non-small cell lung cancer patients. J Nutr 2010;140(9):1602-1606 View Article PubMed/NCBI
  43. Itoh S, Nagao Y, Morita K, Kurihara T, Tomino T, Kosai-Fujimoto Y, et al. Association between Sarcopenia and Omega-3 Polyunsaturated Fatty Acid in Patients with Hepatocellular Carcinoma. JMA J 2022;5(2):169-176 View Article PubMed/NCBI
  44. Kitagawa M, Haji S, Amagai T. Elevated Serum AA/EPA Ratio as a Predictor of Skeletal Muscle Depletion in Cachexic Patients with Advanced Gastro-intestinal Cancers. In Vivo 2017;31(5):1003-1009 View Article PubMed/NCBI
  45. Smith GI, Julliand S, Reeds DN, Sinacore DR, Klein S, Mittendorfer B. Fish oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older adults. Am J Clin Nutr 2015;102(1):115-122 View Article PubMed/NCBI
  46. Lalia AZ, Dasari S, Robinson MM, Abid H, Morse DM, Klaus KA, et al. Influence of omega-3 fatty acids on skeletal muscle protein metabolism and mitochondrial bioenergetics in older adults. Aging (Albany NY) 2017;9(4):1096-1129 View Article PubMed/NCBI
  47. Chen LK, Woo J, Assantachai P, Auyeung TW, Chou MY, Iijima K, et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J Am Med Dir Assoc 2020;21(3):300-307.e2 View Article PubMed/NCBI
  48. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019;48(1):16-31 View Article PubMed/NCBI
  49. Hodson L, Skeaff CM, Fielding BA. Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res 2008;47(5):348-380 View Article PubMed/NCBI
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