Abstract
Background: We retrospectively investigated factors predictive for ascites after hepatic resection to treat hepatocellular carcinoma (HCC). Patients and Methods: The data of 114 patients with HCC who underwent curative hepatic resection were reviewed. The patients were assigned to two groups according to the presence or not of postoperative ascites. Results: Ascites occurred in 16 patients (14.0%), and refractory ascites in four (3.5%). A MAC2-binding protein glycosylation isomer (M2BPGi) cutoff index of 1.61 [sensitivity=75.0%, specificity 67.9%, area under the curve (AUC)=0.745] and virtual touch tissue quantification (VTQ) of 2.62 (sensitivity=68.8%, specificity=89.8%, AUC=0.827) were the best cut-off values. Patients with ascites had lower serum albumin levels, higher serum creatinine levels, higher albumin-bilirubin (ALBI) grade, higher M2BPGi, higher VTQ, and longer operative time. ALBI grade 2 and both M2BPGi>1.61 and VTQ>2.62 were independent predictors of postoperative ascites. Conclusion: We demonstrated retrospectively that ALBI grade 2 and both high M2BPGi and VTQ were independent predictors of postoperative ascites in patients undergoing hepatic resection for HCC.
Hepatic resection is a high-risk procedure according to many reports because of liver cirrhosis but strict indication criteria and improvements in perioperative management have led to low mortality with this approach in the modern era (1). Perioperative morbidity and mortality rates have decreased during the past 20 years, and low blood loss during hepatic resection has been achieved; however, the relatively high morbidity rate remains problematic in patients with liver cirrohsis who have undergone hepatic resection (2). Ascites is a common postoperative complication among such patients, and although diuretic drugs have improved ascites in some patients, refractory ascites sometimes develop (3). Ascites can also lead to liver failure and prolonged hospital stay and is distressing for patients and medical staff, and leads to higher medical costs. Therefore, predictors of postoperative ascites should be identified. Patients with hepatocellular carcinoma (HCC) usually have liver cirrhosis. In order to evaluate liver function precisely, it is important to prevent postoperative ascites. The Child–Pugh classification is the first systematic and conventional approach used to determine the severity of cirrhosis and select patients who might tolerate hepatic resection (4). However, it is not always a reliable indicator of hepatic reserve and fibrosis. Recently, a new scoring system, the albumin-bilirubin (ALBI) score, was established to evaluate liver function. The ALBI score is a simple liver function assessment score because it requires only two parameters, namely serum albumin and bilirubin. Thus, the prognosis can be predicted at any institute or for any modality such as surgery and radiofrequency ablation (5). Additionally, MAC2-binding protein glycosylation isomer (M2BPGi) is a reliable and non-invasive marker for assessing liver fibrosis (6-8). Furthermore, virtual touch tissue quantification (VTQ) using elastography was reported to show very good accuracy for predicting liver fibrosis (9, 10).
We performed a retrospective study to investigate the predictive factors of ascites after hepatic resection performed to treat HCC.
Patients and Methods
Patient characteristics. We retrospectively collected the data of 114 consecutive patients who had undergone curative hepatic resection at the Department of Hepatobiliary and Pancreatic Surgery, Gunma University for hepatic malignancy from January 2016 to December 2019. This study was approved by the Ethical Committee of Gunma University (approval number: HS2018-226). Perioperative management was standardized by one team during this period. Patients who had undergone hepatic resection with biliary reconstruction or anastomosis of the digestive tract, as well as those without clinical data, were excluded.
Postoperative ascites was defined as a drainage amount >500 ml per day over a period of 3 days (9, 10). Refractory ascites was defined as diuretic-resistant ascites. The clinicopathological and surgical outcomes were analyzed.
VTQ using ultrasonography was performed preoperatively. VTQ was usually performed in the right lobe because VTQ levels in the right lobe are more in diagnosing liver fibrosis. For right hepatectomy, VTQ was performed in the left lobe.
M2BPGi levels in serum were expressed as a cutoff index (COI), which was calculated according to the following formula:
The fibrosis predictor based on four factors (FIB-4) index was calculated using the following formula: FIB-4 index=(age×aspartate aminotransferase)/[platelet count (109/l)×(alanine aminotransferase)1/2] (11). The ALBI score was calculated using the following formula:
Specific cut-offs were then applied to generate the following three prognostic groups: ALBI score ≤−2.60 (ALBI grade 1), >−2.60 to ≤−1.39 (ALBI grade 2), and ALBI score >−1.39 (ALBI grade 3) (5). Postoperative complications were defined as Clavien–Dindo grade III or more complications (those requiring surgical intervention) within 1 month of hepatectomy (12).
Surgical procedures. The details of the surgical techniques and patient selection criteria were reported previously (13). Our criteria for hepatic resection were no ascites detected, the inability to control ascites by diuretics, and a future remnant liver volume >615 ml/m2 after the resection of more than one segment.
Follow-up strategy and recurrence pattern. After discharge, all patients were examined for recurrence by ultrasonography and tumor markers, such as alpha-fetoprotein and 1,3-dichloro-2-propanol (DCP), every month and by computed tomography every 6 months. When recurrence was suspected, additional examinations, such as hepatic angiography, were performed as indicated. Recurrent HCC was treated by repeat hepatectomy, ablation therapy, and lipiodolization according to a strategy described previously (2).
Histological study. Tumor differentiation, microvascular invasion, intrahepatic metastasis, and histological liver cirrhosis were assessed by the pathologist according to the criteria of the Liver Cancer Study Group of Japan (14). Fibrosis staging was scored using METAVIR classification on a scale of 0-4 as follows: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3 numerous septa without cirrhosis; and F4, cirrhosis (15).
Statistical analysis. The associations of continuous and categorical variables with the relevant outcome variables were assessed using Student's t-test and chi-squared test, respectively. A logistic stepwise regression analysis to predict postoperative ascites was performed with variables displaying a p-value of less than 0.05 in univariate analyses. Albumin was excluded from the logistic stepwise regression analysis because this parameter was a confounding factor for the ALBI grade.
All analyses were performed using JMP version 14 software (SAS Institute, Inc., Cary, NC, USA). A p-value of less than 0.05 was considered statistically significant.
Results
The clinical characteristics of all patients who had undergone hepatic resection are shown in Table I. No hospital deaths occurred. The median intraoperative blood loss volume was 181 ml. Postoperative complications Clavien–Dindo greater than grade IIIa occurred in 20 patients (17.5%). Ascites occurred in 16 patients (14.0%), and refractory ascites in four (3.5%).
The best cut-offs of M2BPGi and VTQ were determined for the incidence of ascites or refractory ascites after hepatic resection using a time-dependent receiver operating characteristic curve. According to the area under the curve (AUC), an M2BPGi of 1.61 (sensitivity=75.0%, specificity=67.9%, AUC=0.745) and a VTQ of 2.62 (sensitivity=68.8%, specificity=89.8%, AUC=0.827) were the best cut-off values for predicting postoperative ascites (p<0.01). An M2BPGi of 3.00 (sensitivity=100%, specificity=89.3%, AUC=0.945) and a VTQ of 2.81 (sensitivity=100%, specificity=88.2%, AUC=0.935) were the best cut-off values for refractory ascites (p<0.01). All patients were divided into two groups: Patients with ascites (n=16) and patients without ascites (n=98).
The relevant clinicopathological characteristics of patients with and without ascites are shown in Table II. Among patient-related factors, patients with ascites had significantly lower serum albumin levels, higher serum creatinine levels, higher ALBI grade, higher M2BPGi, and higher VTQ. Among surgical factors, patients with ascites had significantly a longer operative time than those without ascites. Among tumor-related factors, no significant factor was found between the groups. The mean hospital stay was significantly longer in patients with ascites than in those without ascites. The results of logistic regression analysis are shown in Table III. ALBI grade 2 and both M2BPGi>1.61 and VTQ>2.62 were independent predictors of postoperative ascites.
Figure 1A shows the incidence of postoperative ascites according to M2BPGi and VTQ subgroups. In patients without both M2BPGi>1.61 and VTQ>2.62, the incidence of refractory ascites was 3.3%. In patients with both M2BPGi>1.61 and VTQ>2.62, the incidence of ascites was 64.3%. Figure 1B shows the incidence of postoperative refractory ascites according to M2BPGi and VTQ subgroups. In patients without both M2BPGi>3.00 and VTQ>2.81, the incidence of refractory ascites was 0%. In patients with both M2BPGi>3.00 and VTQ>2.81, the incidence of ascites was 80.0%.
Clinical characteristics of patients with hepatic resection (n=114).
Figure 2 shows the relationship between the mean M2BPGi level and fibrosis stage. The M2BPGi level increased according to the progression of fibrosis stage (Figure 2A). In patients without hepatitis C virus (HCV) association, M2BPGi levels also increased according to the progression of fibrosis stage, but in those with HCV, there was no significance between M2BPGi level and fibrosis stage (Figure 2B), nor when patients with HCV were divided into sustained virologic response (SVR) and non-SVR groups (Figure 2C). Figure 3 shows the relationship between VTQ and fibrosis stage. VTQ increased according to the progression of fibrosis regardless of the status of HCV or SVR (Figure 3C).
Discussion
Multivariate analysis in this retrospective study showed that ALBI grade 2 and both M2BPGi>3.0 and VTQ>2.61 were independent predictors of postoperative ascites in patients who had undergone hepatic resection for HCC.
In the modern era, in which 0% mortality and low rates of liver failure have been achieved, the incidence of ascites consistently ranges from 13.5% to 27% (2, 16). In the present study, the incidence of ascites was relatively low at 14.0%. Our indication for hepatic resection was based on the functional liver volume as determined by gadolinium–ethoxybenzyl–diethylenetriaminepenta-acetic acid-enhanced magnetic resonance imaging. This criterion is useful to prevent liver failure in patients who have undergone hepatic resection of more than one segment (13).
Comparison of the clinicopathological factors between the groups classified by postoperative ascites.
Incidence of postoperative (A) and refractory (B) ascites according to the MAC2-binding protein glycosylation isomer (M2BPGi) and virtual touch tissue quantification (VTQ) subgroup. In patients without both M2BPGi>1.61 and VTQ>2.62, the incidence of refractory ascites was 6.3%; in patients with both M2BPGi>1.61 and VTQ>2.62, the incidence of ascites was 64.3%. In patients without both M2BPGi>3.00 and VTQ>2.81, the incidence of refractory ascites was 0%; in patients with both M2BPGi>3.00 and VTQ>2.81, the incidence of ascites was 80.0%.
Logistic regression of significant predictive factors for the occurrence of postoperative ascites.
The relationship between MAC2-binding protein glycosylation isomer (M2BPGi) level and fibrosis stage. A: Considering the whole patient cohort, the M2BPGi level significantly increased according to the progression of fibrosis (p<0.01). B: When considering the association or not of hepatitis C virus (HCV), in patients without HCV, the M2BPGi level also significantly increased according to the progression of fibrosis (p<0.01) but in those with HCV there was no significant association between M2BPGi level and fibrosis stage. C: In patients with a sustained viral response (SVR), there was no significant association between M2BPGi level and fibrosis stage. COI: Cutoff index.
The relationship between virtual touch tissue quantification (VTQ) and fibrosis stage considering the whole patient cohort (A), the association or not of hepatitis C virus (HCV) (B), and a sustained viral response (SVR) (C). VTQ significantly increased according to the progression of fibrosis regardless of the HCV status and SVR.
Evaluating the degree of liver fibrosis before surgery is important. Liver biopsy is not only a very high-risk procedure for diagnosing liver fibrosis but also has a limited indication. Several reports have focused on the relationship between MBP or VTQ and liver fibrosis. VTQ reflects the degree of liver fibrosis (8, 9). Harada et al. reported that VTQ is correlated with METAVIR liver fibrosis and predicts postoperative ascites in multivariate analysis (9). However, this VTQ method has some limitations. Firstly, the diagnostic accuracy of VTQ values in the right and left lobes of the liver is significantly different. Secondly, patients with morbid obesity or with narrow intercostal spaces cannot be successfully evaluated. M2BPGi was reported to predict liver fibrosis precisely compared with markers such as the FIB-1 index, hyaluronic acid, aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen (6, 7). Compared with VTQ, the serum M2BPGi level was almost identical in predicting liver fibrosis F3 and F4, with similar areas under the receiver operating characteristics curves, sensitivity, and specificity (13). We previously reported the M2BPGi level to be the only independent risk factor of postoperative ascites in patients with HCC (10). Although M2BPGi is a useful marker for detecting liver fibrosis and liver failure after hepatic resection (17), the M2BPGi level may differ among patients stratified according to the cause of liver fibrosis. M2BPGi values in HCV-positive patients were significantly higher than those in HCV-negative patients at each stage of liver fibrosis (18). In patients with HCV, the serum M2BPGi values were reportedly more sharply elevated during liver fibrosis and in patients who achieved a SVR significantly decreased (19). Recently, the number of patients with SVR has been increasing because of direct-acting antiviral drugs for HCV achieving a high SVR rate. In this study, the SVR population among patients with HCV were 59% and Figure 3C shows the M2BPGi levels in patients with SVR were relatively lower compared with non-SVR patients. We identified each disadvantage using both M2BPGi and VTQ to predict postoperative ascites more precisely.
The ALBI score was established by a training cohort of 1,313 Japanese patients with HCC. The ALBI score was reported to be superior for distinguishing patients with better hepatic function (5). The ALBI score is a simple liver function assessment score because it requires only two parameters, serum albumin and bilirubin. Thus, the prognosis can be predicted at any institute or for any modality such as surgery, trans-arterial chemoembolization, and radiofrequency ablation. Most patients with HCC who have undergone hepatic resection have Child–Pugh class A liver disease. ALBI can distinguish patients with Child–Pugh A disease into subgroups according to liver function.
This retrospective analysis showed that ALBI grade 2 and both high M2BPGi and VTQ were independent predictors of postoperative ascites in patients who had undergone hepatic resection for HCC. Consideration of the surgical indication is necessary for patients with these high-risk factors.
Footnotes
Authors' Contributions
NH wrote the article. NI, MT, TI, AW and NK performed the surgery and perioperative management of the patient and helped draft the article. RM, KH and KH collected the data. KA and KS participated in revising the article critically. All Authors read and approved the final article.
Conflicts of Interest
All Authors declare no conflicts of interest.
- Received June 2, 2020.
- Revision received June 17, 2020.
- Accepted June 22, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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