To our knowledge, this study is the largest to directly evaluate the association of serum TBIL with all-cause mortality in patients with cachexia. The distribution of TBIL concentration was associated with several types of tumors in this cohort. Furthermore, TBIL was an independent prognostic marker in multivariate analysis. We then calculated the TBIL cutoff point for the prediction of mortality in Chinese cancer patients with cachexia. Using this cutoff point, we found that a high TBIL level was strongly associated with all-cause mortality. Further analysis showed that the mortality risk was especially elevated in patients with high TBIL levels who had low BMI values, advanced cancer stages, and digestive system cancers. In the sensitivity analysis, the exclusion of patients with evidence of hepatobiliary disease and hepatobiliary tumors did not change the positive association of TBIL with the risk of all-cause mortality. In general, serum TBIL can serve as an indicator for the daily assessment of the prognosis of patients with cancer cachexia.
Cancer cachexia is a multi-organ syndrome that involves more than just skeletal muscle pathogenesis7,16. Hepatic function can directly or indirectly cause whole-body energy expenditure and increased mortality of patients with cancer cachexia 17,18. BLB (TBIL, DBIL, and IBIL), albumin, ALT, and AST are frequently used as indicators of liver function. Elevated physiological marker levels reflect liver disease and hepatocyte injury. Similar to previous studies19–21, these liver parameters, except DBIL and IBIL, were independent prognostic factors in this population-based cohort study. However, there was no association between serum TBIL and all-cause mortality in the subgroup of patients with hepatocellular carcinoma (HCC) and cachexia (HR, 1.40; 95% CI, 0.68–2.87, P = 0.641, data not shown). It is conceivable that this is attributable to the complexity of pathological changes in the liver, and other mechanisms should be investigated. For example, the different effects of the various forms (alpha- to delta-) of serum TBIL should be explored. Another explanation might be the limited number of HCC participants in our cohort.
To date, a few studies have investigated the associations of BLB with other cancer risks. Moderately elevated serum BLB levels were found to be associated with a markedly reduced prevalence of CRC 22. Meanwhile, two previous studies reported thatserum TBIL was inversely correlated with lung cancer mortality. One study proposed that relatively higher levels of BLB may protect people against lung cancers23. Laura et al also identified an association between elevated levels of serum BLB due to genetic factors and lower rates of lung cancer24. Reports concerning breast cancer are consistent with these findings25,26. Unfortunately, several studies have reported conflicting results regarding the relationship between the BLB concentration and cancer. Two cohort studies confirmed the absence of an association between BLB and CRC27,28. This may be due to the fact that BLB has antioxidant and antineoplastic effects29, and a number of studies have demonstrated that BLB inhibits the activity of cytotoxic T lymphocytes and promotes T regulatory cell (Treg) expansion30,31. Overall, consistent evidence that plasma BLB has a protective effect against cancer is lacking. In our study, in patients with digestive system tumors, there was a significant negative correlation between the TBIL level and overall mortality. We conjecture that BLB signaling to the gut microbiota and its regulation of the liver–gut axis may have led to the above results. This emphasizes the importance of further research to elucidate the current results and confirm whether TBIL can be used to predict survival in patients with cachexia. Further investigation of the genetic factors affecting BLB is also warranted. UDP-glucuronosyltransferase (UGT1A1) is a key enzyme involved in the metabolism of BLB, and its mutations cause BLB metabolism disorders, such as Gilbert’s syndrome32,33. The clinical impacts of UGT1A1 promoter gene variation have been thoroughly studied in CRC patients34. UGT1A1*28 allele carrier status was found to be inversely associated with the development of CRC in males. Nevertheless, the limitation in most analyses was the lack of BLB measurements. In the future study, we will focus on combining genetic analyses with BLB analyses to further elucidate the mechanism.
Patients who are malnourished have a poor response to antitumor therapy and an elevated risk of cachexia-related mortality35.Our interaction analyses established an association between TBIL and BMI, which is a nutrition status indicator. In the subgroup analysis, TBIL was an effective indicator of prognosis in patients with normal BMI values. Patients with high TBIL levels and low BMI values had shorter survival durations, according to the KM analysis. The mechanisms underlying this association are unclear. Interestingly, patients with high BMI tended to have a better prognosis, indicating that obesity might have a protective role against cancer cachexia. Consistent with our study, several meta-analyses reported that women with higher BMI values had a lower lung cancer risk and better prognosis 36,37.
Some limitations of our study need to be considered. Serum TBIL concentrations change dynamically in healthy people, especially depending on the fasting state. The changes in TBIL in patients with cancer cachexia should be taken into consideration. Follow-up studies are warranted to detect the impacts of dynamic changes in TBIL on mortality in patients with cancer cachexia. Another limitation is that some unmeasured indicators, such as alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), which also reflect liver function, or other measured confounding factors may have affected our results.