Introduction

In developed countries, where overweight adults make up a growing proportion of the population, non-alcoholic fatty liver disease (NAFLD) has become increasingly common (Sanyal et al. 2024; Hjelkrem et al. 2008). In China, with the prevalence of excessive eating and sedentary lifestyle, the percentage of obese people has also exponentionally growed. As a consequence, the incidence of NAFLD associated hepatocellular carcinoma (HCC) is increasing throughout the world and is expected to continue growing.

In appropriately selected patients, surgical resection is widely accepted as the first line of treatment for HCC (Raza and Sood 2014). The laparoscopic liver resection (LLR), introduced in 1991, has grown in popularity among liver surgeons as a safe alternative to open resection (Reich et al. 1991; Descottes et al. 2003). It is estimated that approximately 20–70% of patients experience postoperative morbidity following resection for HCC (Farges et al. 1999; Sposito et al. 2016; Takahara et al. 2015). Patients who suffer from postoperative morbidity may experience a longer hospital stay, increased healthcare costs, impaired recovery, and a higher risk of recurrence (Chok et al. 2009; Katz et al. 2009; Kusano et al. 2009). Therefore, it is critical to identify the risk factors associated with postoperative morbidity in order to minimize the incidence of complications and avoid subsequent consequences.

Several clinical and surgical variables have been reported to be associated with postoperative morbidity following liver resection for HCC, such as old age, co-morbidities, cirrhosis, portal hypertension, preoperative liver function, hepatitis virus infection, and extent of liver resection (Choi et al. 2014; Harada et al. 2016a; Hsieh et al. 2006; Sadamori et al. 2010). Since increasing HCC patients with abnormal body weight undergo surgical treatment, it is still controversial whether or not body mass index (BMI) is associated with postoperative morbidity after HCC resection (Cai et al. 2015; Itoh et al. 2012; Okamura et al. 2012; Mathur et al. 2010; Tanaka et al. 2013; Wang et al. 2014; Cucchetti et al. 2011; Mullen et al. 2008; Balzan et al. 2010). In most studies, patients underwent open liver resection (Itoh et al. 2012; Okamura et al. 2012; Mathur et al. 2010; Tanaka et al. 2013) or came from a single center (Cai et al. 2015; Itoh et al. 2012; Okamura et al. 2012; Mathur et al. 2010; Tanaka et al. 2013; Wang et al. 2014; Cucchetti et al. 2011; Mullen et al. 2008), and only one study reported postoperative 30-day morbidity in a standardized manner (Itoh et al. 2012). Additionally, there are a number of studies that focused largely on the effect of high-BMI (Cai et al. 2015; Okamura et al. 2012; Mathur et al. 2010; Wang et al. 2014; Cucchetti et al. 2011; Mullen et al. 2008), but ignored the impact of low-BMI (underweight) on postoperative morbidity, which is common among patients with HCC who have cirrhosis, cancer-related anorexia or cachexia (Anand 2017).

In this study, a large multicenter database was used to determine if there is an association between preoperative BMI and postoperative 30-day morbidity following LLR for HCC. Specifically, the impact of preoperative BMI stratified by low- BMI, normal- BMI, and high-BMI on outcomes following LLR of HCC was examined.

Methods

Patients who underwent curative-intent LLR for HCC between January 2013 to December 2019 at one of the four Chinese hospitals were enrolled into a database (Nantong First People’s Hospital, Nantong Second People’s Hospital, Chinese People’s Liberation Army (PLA) General Hospital, Zhongshan People’s Hospital). During the postoperative pathological examination, the diagnosis of HCC was confirmed. The exclusion criteria included: (i) age less than 18 years old, (ii) underwent open or robotic liver resection, (iii) had received liver resection with concomitant biliary reconstruction, gastrointestinal surgical procedures, splenectomy, portal-azygous disconnection, or portosystemic shunt, (iv) had a palliative liver resection, (v) within one week before LLR, patient’s BMI or liver function tests were incomplete or not available in the preoperative medical record, and (vi) an inaccurate estimate of postoperative 30-day mortality or morbidity (including the type of complications). This study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Ethical approval was obtained from the Institutional Ethics Committee of Nantong First People’s Hospital (approval number: 2024KT260). Written informed consent was obtained from all patients for research purposes before surgery.

Baseline characteristics and operative variables

The baseline characteristics of the patients were retrospectively retrieved. In addition to age, sex, BMI, comorbidities, history of diabetes, and American society of anesthesiologists (ASA) score, other demographic characteristics were also assessed. Hypertension, cardiovascular disease, chronic obstructive pulmonary disease, and renal dysfunction were all recorded as co-morbidities. The laboratory variables, including serum hepatitis B surface antigen (HBsAg), anti-HCV, preoperative platelet count, total bilirubin, albumin, and alanine aminotransferase level (ALT), were collected. Other clinical and pathological characteristics of the patient included cirrhosis and portal hypertension, Child–Pugh grade, maximum tumor size, and number of tumors. Cirrhosis was revealed by histopathological examination. The diagnosis of portal hypertension is based on the presence of either esophageal varices or splenomegaly with a low platelet count (≤ 100 × 109 /L). Also, surgery-related factors, including intraoperative blood loss, intraoperative blood transfusion, operation time, extent of hepatectomy, and type of resection, were collected. A major hepatectomy was defined as resection of more than three Couinaud liver segments, whereas a minor hepatectomy was defined as resection of fewer than three segments. Anatomical and nonanatomical resections were defined according to the Brisbane 2000 Nomenclature of Liver Anatomy and Resections (Strasberg and Phillips 2013).

Patients’ grouping according to their preoperative BMI

According to the World Health Organization (WHO) classification (Consultation, WHO 2000), BMI was formulated by bodyweight [kg]/height2 [m2]. Based on WHO classification, three groups of patients with different preoperative BMI were classified in the current study (Consultation, WHO 2000): low-BMI was defined as BMI ≤ 18.4 kg/m2, normal-BMI as BMI 18.5–24.9 kg/m2, and high-BMI as BMI ≥ 25.0 kg/m2. Patients’ BMI was measured within one week of surgery.

Perioperative evaluation and management

Each hospital generally used the same perioperative evaluation and surgical procedures. Resection criteria were consistent over the study period (Yang et al. 2022). The technical details of the LLR have been described previously in our study (Yang et al. 2022). Generally, patients were placed in the supine or French position and the camera port was placed above or on the right side of the umbilicus under direct version. LLR was performed under CO2 pneumoperitoneum pressure at 12–14 mm Hg and 4- or 5-well method was used. Intraoperative ultrasonography (IOUS) and immunofuorence were used to detect the location of tumors and guide the resection planes, and an ultrasonic knife was utilized to predetermine the resection line. A harmonic scalpel (Ethicon, Somerville, NJ, USA) and LigaSure (ValleyLab, Inc.) were used to transect the liver parenchyma, and endoclips or Hem-o-lok clips were used to secure small hepatic vessels. The resected area was carefully checked for possible bile fistula and bleeding. The resected tumor specimens were placed in a retrieval bag and extracted through an enlarged incision site.

All patients received broad-spectrum antibiotics intravenously before surgery for 3–5 days. If the plasma albumin level was less than 30 g/L, fresh frozen plasma or albumin was given. After resection, blood tests and serologic liver function tests were performed at 1, 3, 5, and 7 days. After resection, all patients were examined by chest X-ray on the third postoperative day (POD) and by ultrasound during the first week after the surgery. Patient whose hemoglobin level was below 7 mg/dl received blood transfusions. Generally, drains are removed when no bleeding, bile leaks, or massive drainage of ascites is observed on the second or third POD.

Postoperative outcomes

Deaths within 30 days of surgery were defined as postoperative mortality, and causes of death were recorded. The definition of postoperative morbidity was any complications within 30 days after surgery based on the Clavien-Dindo grading system (Dindo et al. 2004). The severity of postoperative morbidity was categorized as minor and major morbidities. Minor morbidity was defined as Clavien-Dindo I-II and major morbidity as Clavien-Dindo III-V. The postoperative complications included acute hepatic failure, intra-abdominal hemorrhage, biliary complications, surgical site infection (SSI), pulmonary, renal, cardiovascular, and other vital organ dysfunction. On or after POD 5, postoperative hepatic failure was defined according to the “50–50 criteria” (Paugam-Burtz et al. 2009). The definition of intra-abdominal hemorrhage was a drop of hemoglobin level > 3 g/dL compared to the baseline level after liver resection, as well as any postoperative transfusion of packed red blood cells due to a decreased hemoglobin level or invasive reintervention (Rahbari et al. 2011). According to the Centers for Disease Control and Prevention’s National Nosocomial Infections Surveillance, SSI within 30 days of surgery can be classified as incisional (superficial or deep) or organ/space (A report from the NNIS System 2004). Additionally, diuretics and pleural effusions requiring paracentesis or diuretics were considered as morbidities (Ishizawa et al. 1960). An inflated level of bilirubin in the drainage was defined as a bilirubin concentration that was threefold greater than that in the serum (Koch et al. 2011). Renal dysfunction was defined as a decrease of more than 50% in glomerular filtration rate or a doubling of creatinine levels (Bellomo et al. 2004). Respiratory complications included pneumonia and pleural effusion. Other complications include postoperative acute pancreatitis, acute cholangitis, urinary infection, and cardiocerebrovascular accident, upper gastrointestinal bleeding and delayed gastric emptying. The duration of patients’ postoperative hospital stay was also documented.

Statistical analysis

SPSS version 25.0 (IBM, Armonk, New York, USA) was used for statistical analysis. Normally distributed continuous variables were expressed as mean ± standard deviation or median (range). Number (n) and percentage (%) were used to express categorical variables. For comparisons of continuous variables, Student’s t tests were used when applicable, otherwise, Mann–Whitney U tests were used. Categorical variables were compared using the Chi-square test or the Fisher’s exact test, as appropriate. Among patients with normal-BMI and low-BMI, as well as among those with normal-BMI and high-BMI, the postoperative mortality and morbidity rates, including the incidences of every complication were compared. To identify independent risk factors associated with increased postoperative morbidity following LLR, univariate and multivariate logistic regression analyses were conducted. In both univariate and multivariate analyses, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. It was considered statistically significant if P < 0.05 throughout this study.

Results

Baseline characteristics and operative variables

A total of 269 HCC patients who underwent LLR between 2013 and 2019 at four participating hospitals were initially included. Among them, 43 patients were excluded, because of minors (n = 2), recurrent HCC (n = 11), other unassociated surgery combined (n = 7), important variables missing (n = 23). Finally, 226 patients were enrolled in this study (Fig. 1). There were 122 patients with normal-BMI (54.0%), 20 patients with low-BMI (8.8%) and 84 patients with high-BMI (37.2%). The median preoperative BMI of all the patients was 23.3 kg/m2 (range, 14–29.7 kg/m2). As shown Table 1, baseline clinicopathological characteristics and operative variables are described for patients with normal-BMI, low-BMI, and high-BMI. Compared with the low-BMI group, the normal-BMI group had a significantly higher ALT level (P = 0.010), a numerically lower percentage of portal hypertension (P = 0.032), markedly more minor hepatectomy (P = 0.035), a significantly higher proportion of intraoperative blood transfusion (P = 0.035). Compared with the high-BMI group, the normal-BMI group had a numerically lower percentage of portal hypertension (P = 0.020).

Fig. 1
figure 1

Flowchart of participant population. LLR laparoscopic liver resection, HCC hepatocellular carcinoma, BMI body mass index

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Table 1 Comparisons of baseline characteristics and operative variables in patients with low-BMI, normal-BMI, and high-BMI
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Postoperative outcomes

In Table 2, postoperative short-term outcomes are compared among the three groups. Two patients (0.88%) died after surgery within 30 days, with one in the low-BMI group (acute hepatic failure) and one in the high-BMI group (intra-abdominal hemorrhage). Compared with the normal-BMI group, the postoperative morbidity rates were significantly higher in the low-BMI and high-BMI groups (P = 0.032 and 0.020, respectively). Besides, the major morbidity rate was substantially higher in the low-BMI group than the normal-BMI group (P = 0.035). Regarding the type of complications, surgical site infection (SSI) rate was numerically higher in the low-BMI group than the normal BMI group (P = 0.009), whereas the high-BMI group had a trend of significant higher rate of SSI compared to the normal-BMI group (P = 0.066). As to postoperative hospital stay, the high-BMI group had significantly longer hospitalization than the normal-BMI group (P = 0.004).

Table 2 Comparisons of postoperative outcomes in patients with low-BMI, normal-BMI, and high-BMI
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Univariable and multivariable analyses of postoperative morbidity

In Table 3, univariable and multivariable logistic regression analyses are presented for postoperative 30-day morbidity after LLR for HCC. The results showed that low BMI (P = 0.047), high BMI (P = 0.003), ASA grade > 2 (P = 0.025), comorbidities (P = 0.042), cirrhosis (P = 0.022), portal hypertension (P = 0.001), Child–Pugh class B (P = 0.030), intraoperative blood transfusion (P = 0.041), and major hepatectomy (P = 0.016) were independent risk factors of postoperative morbidity following LLR in HCC patients (Table 3).

Table 3 Univariable and multivariable analyses of risk factors associated with postoperative morbidity after laparoscopic liver resection of hepatocellular carcinoma
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Tables 4 and 5 show the results of a univariable and multivariable logistic regression analysis of minor and major morbidity, respectively. The results showed that high BMI (P = 0.024), ASA grade > 2 (P = 0.030), portal hypertension (P = 0.024), Child–Pugh class B (P = 0.016), and major hepatectomy (P = 0.009) were independent risk factors of postoperative minor morbidity after LLR for HCC (Table 4). On the other hand, low BMI (P = 0.037), cirrhosis (P = 0.017), and portal hypertension (P = 0.019) were independent risk factors of postoperative major morbidity after LLR for HCC (Table 5).

Table 4 Univariable and multivariable analyses of risk factors associated with postoperative minor morbidity after laparoscopic liver resection of hepatocellular carcinoma
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Table 5 Univariable and multivariable analyses of risk factors associated with postoperative major morbidity after laparoscopic liver resection of hepatocellular carcinoma
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Univariable and multivariable analyses of SSI

A pairwise comparison analysis was performed to assess the incidence of postoperative SSI in normal-BMI, low-BMI, and high-BMI patients after LLR for HCC, as well as univariate and multivariate logistic regression analysis. (Table 6). The results demonstrated that low BMI (P = 0.007), high BMI (P = 0.047), and diabetes mellitus (P = 0.047) were independent risk factors of postoperative SSI for HCC patients after LLR (Table 6).

Table 6 Univariable and multivariable analyses of risk factors associated with postoperative surgical site infection after laparoscopic liver resection of hepatocellular carcinoma
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Discussion

Our study examined the impact of preoperative BMI on postoperative morbidity and surgical site infection following LLR for HCC. The results of this study differed from those of previous studies and a meta-analysis (Cai et al. 2015; Mathur et al. 2010; Tanaka et al. 2013; Wang et al. 2014; Cucchetti et al. 2011; Balzan et al. 2010). Our study suggested that preoperative high BMI was an independent predictor of postoperative morbidity. Further, this study demonstrated for the first time that preoperative low BMI was also independently associated with an increased postoperative morbidity following LLR for HCC. As well, preoperative high and low BMI were both significantly associated with a higher incidence of postoperative SSI, which is a common complication following abdominal surgery. To the best of our knowledge, this is the first study that focused on the effect of preoperative BMI on postoperative morbidity in LLR setting.

The prevalence of obesity (Consultation, WHO 2000) and NAFLD-related HCC has increased dramatically (Sanyal et al. 2024; Hjelkrem et al. 2008), and more overweight and obese patients undergo laparoscopic hepatectomy due to the maturity and less invasiveness of this technique. In most previous studies, high BMI is not associated with postoperative morbidity (Cai et al. 2015; Mathur et al. 2010; Tanaka et al. 2013; Wang et al. 2014; Cucchetti et al. 2011). However, Mathur et al. (2010) and Balzan et al. (2010) identified preoperative high BMI as an independent risk factor for postoperative morbidity. In the present study, a close association between preoperative high BMI and postoperative morbidity following LLR was also observed. Diabetes mellitus, steatosis, and non-alcoholic steatohepatitis (NASH) are all diseases that closely relate to high BMI (McCormack et al. 2007). HCC patients with diabetes mellitus, steatosis and/or NASH are more likely to have postoperative morbidity after liver resection (McCormack et al. 2007; Gedaly et al. 2009). Several mechanisms may explain the association between high preoperative BMI and higher postoperative morbidity, including: i) patients with high BMI demonstrate altered cytokine production in their hepatic macrophages (Kupffer cells), which can deplete natural killer cells and compromise their phagocytosis (Kooby et al. 2003; Wang et al. 2004); ii) increased levels of cytokines, leptin, hormones, and insulin-like growth factors lead to disturbed and inbalanced anti-inflammatory ability (Kooby et al. 2003; Wang et al. 2004); iii) immune function is impaired in high-BMI patients (McTiernan 2005). It is also possible that the significant differences in baseline characteristics and operative features among different BMI groups are responsible for differed postoperative morbidity rate, such as portal hypertension, intraoperative blood transfusions, and operation time. It has been reported that these features are linked to postoperative morbidity (Harada et al. 2016b; Bachellier et al. 2011; Sadamori et al. 2013).

In addition, preoperative low BMI was identified as a significant predictive factor for increased postoperative morbidity. A significant differences in baseline and operative characteristics were found between the normal BMI and low BMI groups. Postoperative morbidity is higher after liver resection when these features are present (Harada et al. 2016b; Bachellier et al. 2011; Sadamori et al. 2013). Immunosuppression status combined with a decreased perioperative lymphocyte count was always present in HCC patients with low BMI (Itoh et al. 2012). Furthermore, low BMI is usually related with low albumin levels, which signify malnutrition and impair immunity (Tanaka et al. 2013). Also, patients with low BMI are more likely to suffer from sarcopenia, which impairs their ability to response to stress and starvation during surgery (Anand 2017).

After liver resection, SSI is the most common but prominant complication. Postoperative SSI results in higher morbidity rates, longer hospital stay, and higher healthcare costs. According to this study, both preoperative low and high BMI were independent risk factors for postoperative SSI, which may be attributed to the following reasons. First, adipose tissue usually has a lower blood perfusion and oxygen tension than other tissues, which increases the risk of SSI (Consultation, WHO 2000). In addition, patients with high BMI are usually more difficult in exposing tumor lesions, which causes a larger incision during surgery. Furthermore, immunosuppression is more common in patients with low BMI than patients with normal or high BMI (Itoh et al. 2012), which may contribute to the development of SSI. Last, high-BMI patients are more likely to suffer from metabolism-associated diseases (Gedaly et al. 2009), while low-BMI patients are prone to have poor nutritional status (Anand 2017), which delay the recovery of surgical incisions.

There was a long delay of around 3 months between diagnosis of HCC and surgical treatment (Lim et al. 2017). Although this study found that patients with a delay of 3 months had a higher postoperative morbidity compared with patients who had a delay of less than 3 months (36% vs. 16%) (Lim et al. 2017), preoperative BMI changes did not influence short-term outcomes in patients with HCC undergoing surgery. Therefore, further studies should be conducted on preoperative low-BMI patients who receive nutritional support, as well as on preoperative high-BMI patients who receive diet control and exercise. Studies of such type can distinguish between patients with a recent decline of body weight which indicates tumor-associated cachexia versus those with a consistently low BMI which indicates naturally low body weight.

This study has several limitations. Firstly, this is a retrospective study, which has inherent selection bias. Secondly, although this is a multicenter study, we only enrolled patients from China. It is unclear how preoperative BMI affects postoperative morbidity in other ethnic groups. Thirdly, because the definitive diagnosis of NAFLD relies on invasive pathological test, it is unknown the proportion of HCC patients with high BMI that have NAFLD. Fourthly, this cohort of Chinese patients had a low incidence of obesity (BMI > 30 kg/m2), suggesting that the cohort may not be representative enough.

Based on our findings, preoperative low BMI and high BMI are both independent risk factors associated with postoperative morbidity and surgical site infection in HCC patients undergoing laparoscopic liver resection. The impact of preoperative abnormal BMI on postoperative morbidity following LLR need to be validated using large-scale, prospective studies.