- Open Access
Effect of serum triglyceride level on the prognosis of patients with hepatocellular carcinoma in the absence of cirrhosis
© The Author(s). 2018
- Received: 12 August 2018
- Accepted: 23 October 2018
- Published: 6 November 2018
The liver plays an important role in the metabolism of lipid and lipoprotein. Dyslipidemia has been demonstrated to be related with several cancers, but the association between serum lipid and hepatocellular carcinoma (HCC) in the absence of cirrhosis remains unclear.
A total of 2528 patients with HCC at the Beijing Ditan Hospital between February 2008 and December 2017 were retrospectively included in the study. We identified 200 patients with HCC without cirrhosis by histopathology, imaging, endoscopic findings, and laboratory tests. Multivariate regression analysis was performed to determine the independent characteristics associated with HCC without cirrhosis and its prognosis.
In the logistics regression analysis, compared to patients with HCC with cirrhosis, patients with HCC without cirrhosis were more likely to have elevated triglyceride (TG) levels (OR = 2.66; 95% CI, 1.18–6.01; P = 0.019). The Kaplan-Meier analysis revealed that a lower TG level was a risk factor regardless of the presence of cirrhosis. The results of the Cox proportional hazard regression analysis showed that a decreased TG level was significantly related to a worse overall survival (HR = 0.51; 95% CI, 0.29–0.89; P = 0.017).
Serum TG level may be an independent factor to predict the prognosis of patients with HCC in the absence of cirrhosis.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and has the second highest cancer mortality worldwide.[1, 2]. Although most HCCs are usually accompanied by cirrhosis owing to chronic viral infections, a certain number of patients with HCC, ranging widely from 7 to 54%, do not have cirrhosis[3–6]. It is perceived that the liver is one of the most important organs in multiple metabolite pathways, including lipid and lipoprotein. Hepatic cellular necrosis caused by cirrhosis and HCC leads to aberrations in serum lipid and lipoprotein levels[8, 9]. Some studies reported that the triglyceride (TG) level significantly decreased in patients with cirrhosis or HCC[10–12]. However, the alterations in the lipid and lipoprotein levels in patients with HCC without cirrhosis remain unclear.
Recently, abnormal lipid and lipoprotein levels were considered to be related with the incidence and development of several types of cancer[13, 14]. Several researches showed that elevated TG level and suppressed high-density lipoprotein cholesterol (HDLc) level were related to a high risk of occurrence and death in colon, breast, lung, and prostate cancers[15–18]. However, the relationships between blood profile and liver cancer were contradictory due to the complex etiology. Several studies that considered the risk factor of non-alcoholic fatty liver disease (NAFLD) revealed that elevated TG and low HDLc levels attribute to a greater risk of HCC in patients with cirrhosis. In contrast, regarding HBV and HCV infection, TG levels were inverse contributory factors for HCC[20, 21]. Furthermore, the prognostic effect of lipid profiles on HCC remains unclear. Few studies indicated that low cholesterol and HDLc levels could predict the recurrence of HCC in patients after liver resections. However, whether the alterations of lipid profiles are correlated with HCC prognosis is unclear.
In this study, we compared the clinical and laboratory characteristics of patients with HCC with and without cirrhosis and found that high TG levels were independently related to HCC without cirrhosis. Furthermore, by multiple analyses, we identified high TG level to be an independent prognostic factor for better survival.
The statistical analyses were performed using SPSS version 21.0 software. Data were expressed as median and range for non-normal distribution and mean ± standard deviation (SD) for normal distribution. Comparisons of patient characteristics were analyzed using Student’s t-test for normal distribution and Mann-Whitney U test for non-normal distribution. Categorical variables were assessed by Pearson X2 or Fisher’s exact test. One-way ANOVA test followed by Tukey’s multiple comparison test was performed for lipid profiles across the 3 groups (no cirrhosis, compensated cirrhosis, and decompensated cirrhosis). For all analyses, P values of < 0.05 were considered statistically significant.
The univariate and multivariate logistic regression analyses were performed to identify factors that were independently associated with patients with HCC without cirrhosis. We used Kaplan-Meier curves to estimate overall survival (OS) and progression-free survival (PFS) of different groups and compared survival curves using the log-rank test. The Cox proportional hazard regression analysis was used to determine the variables associated with the prognosis in patients with HCC without cirrhosis.
Between 2008 and 2017, we identified 2528 patients with HCC, of whom 2328 (92.1%) had cirrhosis before or at the time of HCC diagnosis and 200 (7.9%) did not have cirrhosis. Figure 1 shows the flowchart used to classify patients into the cirrhosis categories.
Demographic data and clinical characteristics of patients with hepatocellular carcinoma
Non-cirrhosis n = 200 (%)
Cirrhosis n = 2328 (%)
Age(mean ± SD)
53.36 ± 11.94
56.96 ± 10.34
Family history of HCC
Coronary artery disease
HBeAg at baseline
HBV-DNA at baseline
Low(< 500 IU/ml)
High(> 500 IU/ml)
Tumor diameter (cm)
3.5 (2.3, 6.2)
3.1 (2.0, 5.7)
PVTT at baseline
AFP < 400
AFP ≥ 400
Treatment for HCC
Leukocyte counts (109/L)
Totall Bilirubin (umol/L)
40.09 ± 4.80
35.014 ± 6.34
1.009 ± 0.49
0.87 ± 0.45
Prothrombin activity (%)
88.77 ± 14.51
75.06 ± 18.00
Factors associated with HCC without cirrhosis
Factors associated with hepatocellular carcinoma in the absence of cirrhosis
Age > 50 yrs
Family history of HCC
HBV-DNA ≥ 500 IU/ml
PVTT at baseline
Leukocyte counts ≥4*109/L
AST ≥ 40 (U/L)
γ-GGT ≥ 60 (U/L)
TG ≥ 1.71 mmol/L
PTA < 70%
AFP ≥ 400 ng/ml
Risk factors of death in patients with HCC without cirrhosis
Factors associated with overall survival of patients with HCC in the absence of cirrhosis
Age > 50 yrs
Family history of HCC
HBV-DNA ≥ 500 IU/ml
PVTT at baseline
Totall Bilirubin (umol/L)
AFP ≥ 400 ng/ml
Tumor size > 5 cm
Tumor numbers ≥2
Risk of overall survival according to cirrhosis status, age, triglyceride level in patients with hepatocellular carcinoma
Age < 50 yrs
Age ≥ 50 yrs
Age < 50 yrs
Age ≥ 50 yrs
TG < 0.81 mmol/L
7.48 (3.58–15.61) P < 0.0001
3.87 (1.87–8.03) P < 0.0001
5.65 (3.07–10.39) P < 0.0001
5.80 (3.19–10.52) P < 0.0001
TG ≥ 0.81 mmol/L
2.93 (1.51–5.68) P = 0.001
3.55 (1.93–6.54) P < 0.0001
3.76 (2.07–6.82) P < 0.0001
Previous studies suggested that dyslipidemia was a newly identified risk factor in the survival of several cancers such as colorectal, breast, and prostate cancers [15, 16, 18]. Although one study demonstrated that preoperative HDL level was a predictor of HCC recurrence after liver resections ; recently, there were few studies that addressed the association between lipid profiles and the outcome of liver cancer. In our study, we found that a decreased TG level in the baseline was an independent risk factor of OS in patients with HCC without cirrhosis. A reduced serum TG level was related to worse OS and PFS by the optimal cutoff values using the ROC analysis.
Hypertriglyceridemia was previously considered to be closely related to a higher risk of cardiovascular disease . However, some epidemiological researches have addressed the interrelation between serum TG and cancer risk lately. A high TG level has been linked to increased esophageal and colon cancer risks in a large-scale European cohort . Other studies revealed a high TG level was inversely associated with prostate and breast cancer [25, 26]. It is inconsistent with the relationship between serum TG concentration and HCC risk. A large prospective cohort study with a long follow-up period showed that elevated TG level contributed to an increased risk of primary liver cancer in patients who had more than 50% history of alcohol liver disease . Another study indicated that the TG level was strongly associated with reduced risk of HBV-related HCC . The association between TG and HCC remains unclear. To our knowledge, this is the first time to report a negative association between TG levels and HCC death. In this study, we have shown that patients with HCC in the absence of cirrhosis with TG level < 0.81 mmol/L had a worse OS and PFS than patients with TG level ≥ 0.81 mmol/L (P < 0.0001). The normal cutoff values for TG may be interpreted by the fact that the serum TG level decreased by 20–30% in patients with HCC compared to healthy participants [28, 29]. In contrast, the pro-inflammatory cytokines like interleukin-6 (IL-6), IL-1, and tumor necrosis factor alpha (TNF-α) secreted by tumor cells may inhibit TG synthesis [30, 31]. On the contrary, increased adipose TG lipase and hormone-sensitive lipase activity in cancer may promote the complete hydrolysis of TG molecule to free fatty acids (FFA), which can provide substrates for the proliferation of tumor cells [32, 33]. Suppressed synthesis and excessive hydrolysis play an important role in dyslipidemia. Decreased levels of TG have been connected with increased circulating levels of IL-6, TNF-α which are thought to induced the tumor cell proliferation and inhibit apoptosis . In addition, the high death rate linked with decreased TG concentration may be a consequence of cancer-associated cachexia. However, the exact mechanisms require further investigation.
We also found that there were some differences in lipid, lipoproteins, and apolipoproteins in patients with HCC with and without cirrhosis. Patients with HCC without cirrhosis had increased triglyceride, cholesterol, HDL-C, LDL-C, and ApoB levels compared to patients with cirrhosis. More profoundly, the decrease of lipid components was more obvious in patients with HCC with decompensated cirrhosis than those with compensated cirrhosis. These results were consistent with a previous study that lowering of lipoprotein levels was significantly linked to the increasing severity of liver disease [35, 36]. Besides, using multiple logistic regression analysis, portal vein thrombosis and tumor size > 5 cm at HCC diagnosis were associated with poor prognosis, consistent with previous studies in several cancers . We also found that patients with HCC without cirrhosis had elevated serum TG levels (OR = 2.66). The liver plays a key role in the synthesis and metabolism of lipids and lipoprotein. Hepatic FA derive form endogenous lipogenesis and the FFA plasma pool are processed to triacylglycerols and stored or rapidly metabolized in hepatocyte . Liver cirrhosis due to long-term virus infections causes greater hepatocyte necrosis and influences the lipid concentration. Our finding may provide new evidence that patients with cirrhosis developed more serious liver injury and dyslipidemia. The better liver function reflected by a higher TG level may explain the better survival in patients with HCC without cirrhosis than those with cirrhosis.
Our study had some limitations. First, the variables analyzed in our study did not have a treatment strategy, which was an important factor affecting the prognosis. The influence of different clinical interventions on the lipid profiles need to be clarified in future studies. Second, HBV infection is the main risk factor for the incidence of HCC in China. The racial differences in TG levels should be considered, and the cutoff value needs to be redefined when generalizing the results to people with different risk factors for HCC. Finally, the patients in our study were mostly men, and the prognostic effect of TG in women may be limited.
In conclusion, this study revealed that TG levels at the time of HCC diagnosis may be considered as independent prognostic factor for liver cancer. These results indicate that some appropriate treatments may be applied to adjust lipids to normal or high levels.
Availability of data and material
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
This work was supported by the Fund of Special research of TCM in Capital City (17ZY02); the Fund for Beijing Science & Technology Development of TCM (No. JJ2016–14); and Application of Clinical Features of Capital City of Science and Technology Commission (No. Z171100001017082).
ZYY designed the study; XLL collected and analyzed the data and wrote the manuscript; MGL, XHW and ZBD provided patients data; YYJ and XBW were responsible for the interpretation of data and revision. ZYY approved for final revision and approval.
Ethics approval and consent to participate
The study was approved by the ethics committee of Beijing Ditan Hospital, Capital Medical University.
Consent for publication
Written informed consent was obtained from each patient. Information that could identify individual participants during or after data collection was not accessible.
The authors declare that they have no competing interests. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.
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