LT has several advantages for treating HCC, such as a relatively low recurrence rate and survival benefit compared to other options. Therefore, it is one of the most useful and important treatment methods, especially in patients with concern about liver dysfunction. However, the recurrence rate of HCC after LT, estimated between 15% and 20%, is still an important clinical issue for LT recipients8, and the 5-year survival was significantly lower in patients with recurrence (22%) than in patients without recurrence (64%)19.

In the present study, the use of statins was significantly associated with a lower HCC recurrence rate in LT recipients (aOR = 0.38, 95% CI = 0.16–0.91). This is consistent with results from previous studies, including a recent large-scale cohort analysis, showing that the use of statins reduced the incidence of HCC13,15,18,20. However, the longer survival period increases the opportunity for exposure to statins. For this reason, bias may occur in studies with a retrospective design. Furthermore, there is controversy about how long a period of statin therapy is required to assume a protective role against tumor recurrence. Therefore, in this study, time-dependent Cox analysis was performed by adjusting the known risk factors related to HCC recurrence. As a result, we could confirm that statins played a role in preventing HCC recurrence, even after adjusting for various risk factors.

Previous studies have shown that the effect of statins on decreasing the risk of HCC is more evident in high-risk patients, such as patients with chronic liver disease (aOR = 0.32, 95% CI = 0.17–0.57)21 or diabetes mellitus (aOR = 0.36, 95% CI = 0.22–0.60)20. Hepatic steatosis and chronic inflammation, which are prominent in conditions such as diabetes22 and liver disease, are also associated with hepatocellular carcinogenesis, and statins have a possible protective role by ameliorating these factors associated with chronic inflammation23,24. A similar degree of risk reduction with statin treatment was obtained in this study (aHR = 0.32, 95% CI = 0.11–0.89). This is probably related to exposure to high-risk conditions for HCC recurrence after LT. In subgroup analysis, patients who started statin early, as well as the high risk group that corresponded to the “Above Milan” criteria, showed more significant effect by statins. However, considering that subgroup analysis showed a decreased statistical power with shorter overall observation period, more patients and observation time will be needed to see more definite results.

The use of statin was also shown to be effective in improving cancer-related mortality; however, bias may have been greater due to the limitations of our study database and design. Therefore, any judgment made against it should be reserved. However, since recurrence of HCC leads to an increase in mortality, statin use may also contribute to decrease of mortality.

It is unclear which mechanism of statins contributes to the prevention of HCC. In a recent review article, the authors suggested some potential anticancer properties of statins. The inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by statins reduces mevalonate pathway metabolites that are essential for cancer cell growth and survival25. In this regard, potential mechanisms of statins, such as antiproliferative effects26, apoptosis induction27, and anti-invasive effects28, have been seen in many cancer types29. Although these studies cannot explain the direct effect of statins on HCC, it is assumed that statins can contribute to HCC prevention, given that the primary target organ of statins is the liver.

Other factors known to increase the recurrence rate after LT have been presented in previous reports. In a meta-analysis of HCC recurrence, patients who did not meet the Milan criteria (patients with solitary HCC of less than 5 cm or with up to three nodules of less than 3 cm)5 had worse overall and disease-free survival and experienced more recurrence after LT for HCC. Total tumor diameter, diameter of the largest tumor, and number of tumors were all associated with higher risk of HCC recurrence30. When evaluating preoperative tumor load, standard imaging methods such as liver CT can underestimate or overestimate the extent of HCC in up to 25% of cases, compared with pathological findings of the explanted liver31. For this reason, in this study, total tumor size, size of the largest tumor, and number of tumors were measured based on the pathologic findings. Moreover, these factors associated with preoperative tumor load were closely related to HCC recurrence in our study, similar to the results of previous studies5,19,30. We found that patients who met “above Milan criteria” were especially closely associated with increased risk of HCC recurrence after adjusting for other risk factors (HR = 2.55, 95% CI = 1.43–4.56).

Vascular invasion32,33 and histological grade32 of HCC also affect prognosis after LT. In our study, we also noted that microvascular invasion, portal vein invasion or thrombosis, and histological grade increased the risk of HCC recurrence. The preoperative AFP concentration was associated with tumor load, and elevated AFP was related to postoperative HCC recurrence in several previous studies34. In this study, high AFP concentration was classified as over 50 ng/mL35, and it was confirmed that high AFP concentration was related to high recurrence rate of HCC (HR = 3.24, 95% CI = 1.86–5.65), consistent with the results of previous studies. Another serum tumor marker, prothrombin induced by vitamin K absence-II, was also measured. Prothrombin induced by vitamin K absence-II has been reported to be associated with microvascular invasion36,37, and it was also associated with HCC recurrence rate, as well as AFP level, in our study (crude HR = 3.76, 95% CI = 2.21–6.41).

In several previous studies, the effect of graft type on tumor recurrence was unclear38,39. We found no difference in risk according to graft type in this study (crude HR = 1.08, 95% CI = 0.61–1.92). Additionally, some studies have found that overexposure to immunosuppressive agents such as tacrolimus is associated with high HCC recurrence risk35; however, there are no randomized controlled trials suggesting that lowering immunosuppressant concentration is related to lower risk of HCC recurrence. The postoperative anti-viral treatment did not show a significant effect on HCC recurrence, unlike the results of previous literature40. In our institution, the presence of chronic hepatitis was monitored regularly after transplantation, and anti-viral therapy was applied immediately after the sign of chronic viral hepatitis. Since anti-viral treatment was performed unconditionally in the patients corresponding to treatment indication, it was impossible to determine whether there was a difference in the occurrence of tumor recurrence according to anti-viral treatment. All of the factors that have been shown to affect recurrence of HCC were included in final multivariate analysis in this study.

The recurrence of HCC after LT has great influence on various vital aspects, such as survival rate and quality of life. However, an effective therapeutic option has not yet been established. Therefore, various efforts are underway for the prevention of HCC recurrence. There has been a wide range of attempts, including administration of adjuvant chemotherapy41, adjuvant oncolytic adenoviral therapy42, the heparinase inhibitor PI-8843, interferon-alpha44, and sorafenib45. Several studies showed survival benefit associated with treatment; however, no treatment has been established as an effective universal method8 in the prevention of HCC recurrence.

Despite concerns about their diabetogenic effect, statins are effective and safe for the prevention of cardiovascular disease in patients with dyslipidemia, and are often used in LT recipients46. Although there is a lack of research regarding statin therapy in LT recipients, statin therapy may be an attractive, low-risk treatment option.

There are several limitations of this study. This was a retrospectively designed study, and thus, the duration of statin maintenance, follow-up period, and statin initiation time were different among the study population. At baseline conditions, the statin group showed lower AFP and higher differentiation level compared to the non-statin group, although it was not statistically significant. In addition, considering the limitation of this study design, clinical trial will be needed for statins to be used as a HCC therapeutic option. Second, in this study, statin effect may be overestimated or underestimated since the number of patients using statin was not large enough (considering follow-up period) and the number of events was relatively small.

However, the strength of this study is that we examined the statin effect after correcting the differences of these limits and conditions through time-dependent Cox analysis. In addition, since the study was performed in a single institution, conditions such as transplantation indication, surgery technique, and follow-up after the operation did not show much difference between patients. This study supports a large-scale observational study of statins’ role in the prevention of HCC development, and shows that use of statins in liver transplant recipients for the reduction of cardiovascular risk may also be helpful in preventing HCC recurrence.

In conclusion, statin use is associated with low HCC recurrence in LT recipients.