Early postoperative controlling nutritional status (CONUT) score is associated with complication III-V after hepatectomy in hepatocellular carcinoma: A retrospective cohort study of 1,334 patients

Postoperative complication III-V is closely related with hepatectomy-related mortality for hepatocellular carcinoma (HCC) patients. The aim of the study was to investigate the relationship between CONUTS and postoperative complication III-V. 1334 HCC patients who underwent hepatectomy were divided into two groups: high CONUTS group (early postoperative CONUTS ≥ 8, n = 659) and low CONUTS group (early postoperative CONUTS < 8, n = 675). The characteristics and clinical outcomes were compared and analyzed. Risk factors for postoperative complication III-V were evaluated by univariate and multivariate analysis. early postoperative CONUTS showed a good prediction ability for postoperative complication III-V (AUROC = 0.653, P < 0.001), with the cut-off value of 8. The high CONUTS group had higher incidence of postoperative pulmonary complications (12.0% vs 7.9%, P = 0.011), bile leakage (2.6% vs 0.9%, P = 0.018), intra-abdominal hemorrhage (4.9% vs 1.6%, P = 0.001), postoperative liver failure Grade C (3.6% vs 1.0%, P = 0.002), complication III-V (15.6% vs 6.2%, P < 0.001), length of ICU stay > 48 hours (9.4% vs 4.1%, P < 0.001) and mortality in 90 days (2.6% vs 0.4%, P = 0.001), longer period of postoperative hospitalization (10 (8–13) vs 9 (7–11) days, P < 0.001). Multivariable analysis revealed that early postoperative CONUTS ≥ 8 (OR = 2.054, 95%CI = 1.371–3.078, P < 0.001) was independently associated with postoperative complication III-V. Early postoperative CONUTS ≥ 8 was identified as a novel risk factor for postoperative complication III-V, and should be further evaluated as a predictive marker for who are to undergo liver resection.

Several immune-nutritional factors were reported as potential predictor for the outcomes of HCC patients after hepatectomy, such as aspartate aminotransferase to platelet ratio index (APRI) 7 , fibrosis index based on the four factors index (FIB-4) 8 , albumin-bilirubin score (ALBI) 9 , prognostic nutritional index (PNI) 10 . The Controlling Nutritional Status score (CONUTS), first validated and reported by de Ulíbarri J, I. et al. in 2005, as a screening tool for early detection and continuous control of hospital undernutrition 11 . The formula, consists of serum albumin, cholesterol levels, and total lymphocyte count, is shown in Fig. 1A. Previous studies have been reported that preoperative CONUTS could predict the poor prognosis in patients who with colorectal cancer 12 , hepatocellular carcinoma 13 , or esophageal squamous cell carcinoma 14 . However, hemodynamics and blood constituents would be affected, due to intraoperative blood loss and fluid infusion. Hence, we hypothesized that early postoperative CONTS would be superior to preoperative CONUTS in predictive ability. A retrospective cohort study was carried out to investigate the relationship between early postoperative CONUTS and complication III-V after hepatectomy in HCC patients.

Study population. The study included 1334 consecutive HCC patients who underwent treatment at West
China hospital of Sichuan university between January 2011 and December 2013. Hepatocellular carcinoma diagnosis was confirmed based on the current EASL 15 or AASLD 16 HCC management guidelines. The inclusion criteria followed: (1) Pathological diagnosis confirmed hepatocellular carcinoma, (2) received partial hepatectomy by open or laparoscopic hepatectomy, (3) patients >18 years. Exclusion criteria included the following: (1) patients with obstructive jaundice, (2) combined with portal vein tumor thrombus, (3) combined with extrahepatic metastasis, (4) liver function of Child-Pugh grade C, (5) loss to postoperative follow-up within 90 days, (6) poor data integrity. The flowchart was revealed in Fig. 1B. We collected the medical records containing the demographics, preoperative laboratory values, imaging examination data and postoperative clinical outcomes from the clinical liver cancer database of the department of Liver Surgery & Liver Transplantation Center, West China Hospital of Sichuan university.
Perioperative management. Careful history analysis, physical examination and routine preoperative laboratory measurements were performed for all patients. Routine imaging examination to evaluate the tumor and cardiopulmonary function evaluation was carried out before surgery as we previously described 8 . Antiviral drugs were administered to patients with positive HBV-DNA before the operation, and postoperative continuous antiviral therapy follow the current guidelines 17 . Patients were operated under general anesthesia and intraoperative ultrasonography was used routinely. Hepatic vascular inflow occlusion (hemihepatic or total hepatic blocking) or the Pringle maneuver was utilized according to the surgeon's preference in most patients as those previously described 18,19 . Hepatectomy was performed using the clamp crushing or hooking with ligation method, ultrasonic dissector with coagulator. Based on preoperative and intraoperative condition, patients were transferred to the intensive care unit for treatment when necessary.
Parameter definition. Early postoperative CONUTS was calculated from the first postoperative serum albumin level, lymphocytes count and total cholesterol level, the blood samples were obtained within 12 hours after operation. Postoperative CONUTS change was calculated by subtracting the preoperative CONUTS from the early postoperative CONUTS. Clinically relevant portal hypertension (PHT) is defined as the presence of esophageal varices and/or a platelet count of less than 100 × 10 9 /L in association with splenomegaly 20 . The Clavien-Dindo complication classification system 21 was used for postoperative complication grading and grade III-V complications were defined as severe complications. Postoperative liver failure 22 (PLF) and biliary leakage 23 were defined in accordance with the criterion of International Study Group of Liver Surgery. PLF was classified into three categories (grade A, B, and C) 22 . Liver resection with more than three segments was defined as major resection, or as minor resection. Mortality was defined as any death occurring from the time of surgery up to 90 days after hepatectomy. Statistical Analysis. Scientific research secretaries were trained to take the collection and analysis responsibilities. Continuous variables were reported as mean (standard deviation [SD]) or median (interquartile range [IQR]). Student t test for continuous variables with parametric distribution. Mann-Whitney U test or Kruskal-Wallis H test for those with nonparametric distribution. Categorical variables were reported as numbers and percentages, and compared using Pearson χ 2 analyses or Fisher exact test. The predictive ability of potential factors for postoperative complication III-V was assessed by the corresponding area under the receiver operating characteristic (AUROC) curve. Youden index was utilized to choose the optimal cut-off value, which set as the value maximizing the sum of sensitivity and specificity. To identify risk factors for postoperative severe complications, all significant factors in the univariate analysis were used for multivariate analysis by the forward stepwise logistic regression. All statistical analyses were performed using IBM SPSS Statistics software 21.0, and statistical significance was set at P < 0.05, with two-tailed.

Result
1334 consecutive patients were included in this study, including 1136 (85.2%) males and 198 (14.8%) females. 1208 (90.6%) patients with chronic HBV infection. Positive HBV-DNA load was detected in 436 (32.7%) patients. The median age of patients was 50 years old. Total tumor diameter was 7.3 ± 3.2 cm. The preoperative liver function of 1295 (97.1%) patients was classified as Child-Pugh A. 354 (26.5%) patients developed clinically relevant PHT. The other clinical parameters were shown in the Table 1. Several prognostic factors, including APRI, FIB-4, ALBI, PNI, Child score and CONUTS, were compared with ROC curve (Fig. 2A). The area under curves (AUCs), standard error, P-value and 95% Confidence Interval of factors in predicting complication III-V are shown in Fig. 2B. Early postoperative CONUTS (AUC = 0.654, P < 0.001) was selected as an optimal index and 8 was identified as the cut-off value. Then, patients were divided into the two groups: high CONUTS group (early postoperative CONUTS ≥ 8) with 659 patients and low CONUTS group (early postoperative CONUTS < 8) with 675 patients. There is no significant differences in HBV infection, HBV-DNA load, Child-Pugh grade, incidence of CSPH, platelet, tumor number, total tumor diameter, ASA grade, microvascular invasion, tumor differentiation and R-0 resection were observed between the two groups. Patients with early postoperative high CONUTS had more intraoperative blood loss (P < 0.001), transfusion rate (P < 0.001), occupancy rate of ICU (P < 0.001), longer hospitalization time (P < 0.001) and mortality in 90 days (P = 0.001). The details were shown in the Table 1.

Discussion
Severe postoperative complications would prolong the length of hospital stay, increase the morbidity and worsen the prognosis. The main complications after hepatectomy include pulmonary complication, neurological compilation, intractable ascites, bile leakage, intra-abdominal hemorrhage and liver failure. Nutritional intervention could improve the tolerance of patients for chemotherapy and surgery, decrease postoperative complications, and improve the prognosis 4,24,25 . Recently there's increasing study [8][9][10]26,27 focus on the nutritional status of patients and found that complication III-V after hepatectomy was not only associated with liver function reserve, but also with nutritional status.
The CONUT score is composed of serum albumin, cholesterol level and the lymphocyte count, which were associated with immune response, infection, inflammation, tissue repair and regeneration 26 . Hypoalbuminemia and hypocholesterolemia could predict postoperative complications and poor prognosis 9,28 . Lymphocyte is associated with immune response and tumor progression [29][30][31] . Previous studies 13,32 indicated that HCC patients with preoperative high CONUTS had significantly lower recurrence-free survival (P = 0.011) and overall survival (P = 0.006) rates, however further analysis of severe postoperative complications were not carried out. Surgical trauma, blood loss and organic consumption may be closely correlated with postoperative hemodynamics and abnormal blood constituents, which may affect the predictive ability of preoperative CONUTS for postoperative    are ongoing. One study 33 , from the University of Heidelberg, has reported that none of the nutritional assessment scores before operation defined malnutrition relevant to complications after pancreatic surgery. Therefore, we hypothesized that early postoperative CONUTS may become a more meaningful risk factor for postoperative complication III-V than preoperative index. In order to investigate the relationship between the early postoperative CONUTS and complications, we conducted a comparison of multiple ROC curves included Child score, APRI, FIB-4, ALBI and PNI. The results confirmed what we supposed, early postoperative CONUTS, not preoperative or postoperative change CONUTS, was chosen as an optimal index. The postoperative high CONUTS group had more intraoperative blood loss, transfusion, postoperative morbidity, mortality and longer hospital stay after operation. Univariate and multivariate analysis suggested that early postoperative CONUTS ≥ 8 (OR = 2.054, 95%CI = 1.371-3.078, P < 0.001) was identified as an independent risk factor for complication III-V. Once early postoperative high CONUTS appears, attention should be paid and took required measure.

P-value
Transfusion was identified as another independently risk factor for complication III-V in the study. Operative trauma, blood composition consumption and coagulation derangements are important factors, which were associated with transfusion. HCC patients with cirrhosis who usually had lower tolerance to general anesthesia   Table 2. postoperative complications between patients with high-and low early postoperative CONUTS.   Table 3. Clinical parameters between patients with and without complication III-V after liver resection. In addition, previous guidelines 36 recommended that liver resection as an indication of albumin supplementation. Whether preventive albumin supplement could reduce postoperative complications remains controversial. However, it is recognized that component transfusion is beneficial to correct postoperative hypoalbuminemia, severe coagulation disorder and relieve refractory ascites. The present study has some limitations. First, the single-center study could not reduce information bias and selection bias. Second, a retrospective study lacked the validation set and had the poor strength of argument. Third, influence of chemoembolization or anticancer drugs on peripheral lymphocyte count before liver resection cannot be ignored. At last, multi-center prospective studies are required to to evaluate the role of early postoperative CONUTS.
In conclusion, early postoperative CONUTS is a useful tool in assessing the postoperative nutritional status in HCC patients who underwent liver resection. Postoperative high CONUTS did not only influence postoperative complication III-V, but also increase the mortality. The predictive value should be further evaluated.

Ethical review. This study was approved by the Clinical Research Ethics Committee of the West China
Hospital, Sichuan University. Written informed consent was obtained from all patients according to the policies of the committee. All the methods used in this study were carried out according to the approved guidelines.  Table 4. Multivariate analysis of independent risk factors for patient with complication III-V after liver resection.