High visceral adipose tissue area is independently associated with early allograft dysfunction in liver transplantation recipients: a propensity score analysis

EAD is a critical complication after LT, which contributes to high mortality. Therefore, a better understanding of the risk factors associated with EAD can help to improve pre-LT patient management and post-LT outcome. In this study, we comprehensively analyzed the impact of adipose tissue distribution on outcomes in patients who underwent LT and determined that VAT area was independently associated with the development of EAD. In addition, we found that recipients with high visceral fat area have worse OS compared with those with relatively low visceral fat area. Therefore, the early identification of those patients who have excess visceral fat may not only prompt a therapeutic intervention, but also warn of an increased risk of poor outcomes.

Limited value of BMI

Our current results indicated that 31.4% of the recipients occurred EAD after LT, which was consistent with the range of 5.2–38.7% reported in previous studies [4,5,6,7,8, 27]. In this study, EAD group tend to have slightly higher BMI value than No EAD group before PSM analysis. At present, the relationship between BMI and prognostic outcome post-transplant needs further verification. Although some studies have revealed an association between pretransplant high BMI value of recipients and poor survival after LT for both adult and pediatric recipients [15, 28, 29], recent studies reported that BMI was not associated with higher risk of post-transplant vascular and biliary complications, graft loss, and death [16, 30,31,32]. The inconsistent results could be attributed to different BMI grouping criteria and the limitations of BMI value in predicting outcomes after LT including the overestimated influence of fluid accumulation or systemic edema and inability to discriminate different components of body composition. Therefore, the application of BMI to reflect obesity and assess prognosis is limited. Body composition measurement based on CT images can provide more accurate information and may be regarded as a useful tool with prognostic value in recipients after LT.

Potential fat distribution indices

Many recent reports have indicated that excessive accumulation of abdominal adipose tissue significantly correlates with postoperative outcomes, including complications and mortality in patients with various cancers [19, 20, 33, 34]. In this study, we observed significant differences between the two groups in the SAT and VAT area before PSM analysis. However, the difference was no longer significant in the SAT area after PSM analysis. The different results between VAT and SAT were on the basis of their differences in anatomical location, cellular, molecular, and metabolic activity [35]. Our results also found that the EAD group have significantly higher IMAT area than No EAD group after PSM analysis and the SMD exhibited significant association with EAD in multivariate analysis after PSM analysis. However, the SMA between two groups was not significantly different before and after PSM analysis. Although many previous studies have reported that low muscle mass was significantly associated with survival in patients who suffered from hepatocellular carcinoma or received LT [36,37,38], recent studies tend to show that muscle quality rather than muscle quantity was identified as a prognostic marker in LT recipients [24, 39]. IMAT is thought to begin to increase when lipids intake exceeds the disposal capacity of adipose tissue and muscle, and the increase represents the decline in muscle strength and quality [40]. The accumulation of IMAT may be associated with a muscle-to-liver cross-talking that the secretion of pro-inflammatory cytokines would increase and concentrations of myokines would decrease, which may in turn lead to systemic inflammation with unfavorable immune response and restricted graft regeneration [41]. In the study of Czigany et al. [24], the researchers have reported that patients with high IMAT accumulation and correspondingly low SMD, rather than reduced muscle mass, had significantly higher post-transplant complication rates and poor perioperative outcomes, which was similar with our results.

Meaningful clinical parameters

In this study, multivariate analysis showed that serum albumin, PLR, VAT area were significantly associated with EAD before PSM analysis. The relationship between serum albumin and post-transplant outcomes remains controversial. Many previous studies have demonstrated that there is no significant correlation between preoperative serum albumin and patient or graft survival [42, 43]. However, in the studies of Hiroi et al. [44] and Bernardi et al. [45], serum albumin can influence short-term outcomes following LT and the albumin administration to patients on wait-listed for LT should be strengthen, which was in line with our results. They hold the view that maintaining high serum albumin level reflects good nutritional status and can reduce the amount of fluid collection in abdominal or thoracic cavity, which could resist the catabolic state induced by surgical stress and inflammatory response in the early postoperative period. As for PLR, our findings stay consistent with several observations of the PLR prognostic role in patients undergoing LT [46, 47]. Pravisani et al. [47] reported that pre-LT and post-LT PLR has shown clear associations with short- or long-term outcomes and HCC recurrence, which can be used as inflammatory and nutritional biomarkers to offer reliable prognostic information after LT. Elevated PLR reflects the more severer liver inflammation and worse nutritional status, and this may be the reason why PLR was significantly associated with EAD [48].

Remarkable performance of VAT

Previous studies have revealed that high VAT area measured by CT is associated with greater risk of post-transplant complications and outcomes. For instance, in the study of Kamo et al. [49], the authors found that incidence of post-transplant bacteremia was significantly higher in patients with high visceral fat area. Terjimanian et al. [50] reported that excessive visceral fat was associated with a shorter one-year and five-year survival after LT. According to Montano-Loza et al. [51], increased visceral fat area was significantly associated with post-transplant tumor recurrence on 78 hepatocellular carcinoma liver transplant recipients. Our results showed that visceral, instead of the subcutaneous adipose deposition, worked as a significant risk factor for the development of EAD. After adjustment for potential confounders with PSM analysis, the independent association between VAT area and EAD still exists. In addition, our study also found that VAT area might also have certain clinical value for predicting the OS of recipients.

Prior researches have shown that VAT compared with SAT contains a larger number of inflammatory and immune cells. The cells will release more pro‐inflammatory cytokines such as tumor necrosis factor (TNF)-ɑ, interleukin (IL)-6, IL-1b and monocyte chemoattractant protein-1 to create a pro‐inflammatory microenvironment that potentially impairs immune function [52]. However, anti-inflammatory cytokines such as adiponectin is more highly secreted form SAT [53]. Thus, patients with high amount of adipose tissue in the visceral region are more easily to be in a state of chronic inflammation status. On the other hand, the pro‐inflammatory cytokines especially TNF-ɑ released by VAT plays an important role in the hepatic ischemia/reperfusion injury (IRI), which is considered to serve as pivotal mechanisms of influencing early and long-term results of the organ transplantation [54, 55]. Therefore, high VAT area can upregulate the release of pro‐inflammatory cytokines that contribute to the IRI, thereby promoting a higher incidence rate of EAD and having a negative impact on the long-term outcomes. In addition, it has been believed that VAT exerts damaging metabolic effects. Excessive accumulation of VAT has high rate of insulin resistance by provoking greater toxic-free fatty acids (FFA) release [56]. FFAs and adipokines secreted from VAT can flow into the liver through the portal vein and directly mediate the metabolic changes and injury of the graft [57]. As reported in previous researches, the accumulation of VAT contributes to increased risk of metabolic syndromes such as cardiovascular events, hyperlipidemia, and diabetes mellitus [15, 58], which may deteriorate the healthy status and indirectly lead to the decline of the OS rate of high VAT group.

This study has several important limitations. First, the number of patients was small in our study, and female patients account for only 18.9% in the cohort; further studies with multi-center larger sample size are needed to confirm the results of this study. Second, this study was retrospective, patients who did not receive an abdominal CT scan within 3 months before LT were not included in the study, and this may have caused selection bias. Although PSM analysis was used to reduce the bias, the results may be affected by unconsidered factors. Third, due to the lack of donor and operation-related data, we are unable to analyze the risk factors of EAD comprehensively. Additionally, the follow-up time is short, and the direct effect of high VAT area on worse OS and graft survival are needed to be testified based on long-term follow-up in the future.

In conclusion, LT recipients with a high amount of visceral fat were more likely to develop EAD. It also seems to have certain clinical value for predicting poor long-term prognosis of patients who underwent LT. More importantly, liver transplant candidates with high VAT area may be targets for timely therapeutic intervention to improve short- and long-term outcomes.

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