The present study focused on the traditional parameters of nutritional status, including albumin and lymphocytes, as risk factors for developing IH after LCRS. Gender, BMI, and operative time became risk factors for IH as previously reported [2, 11, 15–17], but albumin did not. In contrary, a high lymphocyte count was demonstrated as an IH risk factor. Further investigation revealed that in the low albumin group, BMI ≥ 25 kg/m2 became a significant IH risk factor. A high lymphocyte count became an IH risk factor regardless of BMI classification. Finally, we demonstrated that a low albumin and high lymphocyte count can predict IH well in both under and over BMI ≥ 25 kg/m2. To our knowledge, this is the first study evaluating the association of lymphocytes with IH development.
We investigated the incidence and period of developing IH in our cohort, which included many elderly patients. IH incidence after LCRS (10.8%) in the present study was comparable to the previously reported 3.5–21% [2, 3, 11, 17–19]. Furthermore, as in previous reports, almost all cases of IH occurred within 2 years in this study [2, 11].
We first investigated the relationship between IH and albumin, which is the most abundant plasma protein and representative index of nutrition. Decreased albumin represents malnutrition and is known to be associated with a higher postoperative complication rate, longer hospital stay, and worse prognosis in various malignancies [20, 21]. Decreased albumin has also been reported to be an IH risk factor, but the cut-off values vary and several negative reports exist. [10–13]. We thought that the reason why decreased albumin does not become a robust marker for IH development was the offsetting of risk factors. Patients with lower albumin levels often have a low BMI and a low risk of developing IH, while well-nourished patients with higher albumin levels often have a high BMI and a high risk of developing IH [22]. In the present study, albumin was not a risk factor for developing IH despite defining the cut-off value using ROC analysis. We then stratified BMI as under and over 25 kg/m2 and investigated the relationship between albumin level and IH development. In the BMI < 25 kg/m2 group, there was no significant difference in IH incidence between the high and low albumin group. In contrary, in the BMI ≥ 25 kg/m2 group, the low albumin group tended to have higher BMI and a significantly higher IH incidence compared with the high albumin group. A recent study showed that obesity and weight gain were associated with low serum albumin levels [23–24]. Although the exact mechanism by which albumin decreases with weight gain is unclear, chronic inflammation caused by excess adipocytes is thought to alter the albumin synthesis [23]. An ASPEN Position paper mentioned that serum albumin characterizes inflammation rather than describes nutritional status and should not be used as a nutrition marker [25]. In the present study, the tendency of the BMI ≥ 25 kg/m2 group to have higher BMI in the low albumin group may indicate that this group has chronic inflammation because of excess adipocytes. Thus, the reason for a high IH incidence in low albumin cases among obese patients is considered to be the result of impaired wound healing based on chronic inflammation caused by excessive adipocytes. Multifaceted biological studies are required to clarify the effect of decreased albumin levels on IH development.
Next, we investigated the effect of lymphocytes, another traditionally used nutritional marker, on the risk of developing IH. A decreased peripheral lymphocyte count represents malnutrition [26, 27], and is known to be associated with longer hospital stay and unfavorable prognosis for solid tumors [27, 28]. We predicted that a decreased lymphocyte count was associated with IH development, but the result was contrary to our expectation. We further investigated the effect of increased lymphocytes on IH development, focusing on the relationship with BMI, because obesity was reported to increase lymphocyte count [29–31]. Thus, in the BMI < 25 kg/m2 group, the high lymphocyte count group had significantly higher BMI and higher IH incidence compared with the low lymphocyte count group. Interestingly, in the BMI ≥ 25 kg/m2 group, there were no significant differences in BMI between the high and low lymphocyte count groups, but the high lymphocyte count group had a significantly higher risk of developing IH compared with the low lymphocyte count group.
Increased lymphocytes have been reported to be associated with visceral fat accumulation and metabolic syndrome [31, 32], which increases metabolic risk based on systemic inflammation such as in type 2 diabetes, hypertension, stroke, and atherosclerosis [33]. The mechanism of lymphocyte increase remains unclear, but it is suspected to be caused by visceral fat accumulation. Visceral fat accumulation promotes the hematopoietic processes associated with leptin increase [30, 34, 35], causing a chronic inflammatory condition [32] and inflammatory response to molecules released from dead adipocytes [31] and antigens, such as fatty acids. Increased lymphocytes may represent excess adipocyte and impaired wound healing caused by a metabolic disorder [36, 37], which is an IH risk. Recent studies show that both obese and non-obese patients sometimes have excess adipocytes and a metabolic disorder. Such patients are recognized as “metabolically obese” [38, 39]. In the present study, the high IH incidence in the high lymphocyte count group with BMI under 25 kg/m2 suggested that this subgroup represented “metabolically obese.”
Finally, we evaluated the combination of lymphocyte and albumin for predictive value of IH. The group of low albumin and high lymphocyte count was demonstrated as a good predictor of IH in both the under and over BMI 25 kg/m2 with 25.9% and 55.6%, respectively. This result suggested that both parameters of different origins could complementarily predict IH risk. Lymphocyte is a bone marrow or thymus-derived cell that strongly reflects the immune system, while albumin is a liver-synthesized protein that is affected by systemic inflammation.
This study has several limitations. First, the current study is retrospective with a relatively small number of patients at a single center. Second, the cut-off values of continuous variables were limited. The BMI cut-off value of 25 kg/m2 was lower than that of western countries, and those of albumin and lymphocyte were determined by ROC analyses as no standard cut-off values exist. Third, Asians have higher visceral and ectopic fat deposition compared with Caucasians [40]. If excess fat deposition is actually involved in IH prediction in albumin and lymphocytes, IH’s predictive ability in these measurements can be racially different. A large prospective study with strict criteria for participants and surgical procedures is needed to overcome these limitations.