Introduction
With considerable improvements in perioperative intensive care and refinements in surgical technique, the rates of death and complications after major liver resection surgery have decreased significantly [
1‐
4]. Nevertheless, because many patients still have liver cirrhosis or other chronic liver disease, death and complications may follow liver resection surgery. Therefore, it is important to investigate the functional liver reserve before liver resection surgery [
5‐
7]. The Child-Pugh scoring system is widely used to determine the hepatic functional status, although its ability to predict mortality after liver resection surgery is inconsistent. Consequently, various laboratory and imaging techniques have been used to complement the Child-Pugh scoring system in order to predict the development of postoperative hepatic insufficiency. For example, the serum hyaluronic acid (HA) level, liver volumetry measured using computed tomographic (CT) scan, hepatic uptake ratio of technetium-99m-diethylene triaminepentaacetic acid galactosyl-human serum albumin at 15 min (LHL 15), indocyanine green retention rate at 15 min (ICG R15), and hepatic venous pressure gradient are usually performed [
8‐
10]. These preoperative tests are important because they allow physicians to decide the extent of liver resection [
11]. Such careful preoperative evaluation of liver function together with the refined operating techniques has significantly reduced the incidence of postoperative hepatic insufficiency [
12‐
14].
Of these preoperative functional tests, hepatic venous pressure gradient is a widely used preoperative test to estimate the degree of hepatic fibrosis and liver reserve in Western countries, whereas ICG R15 is used in Eastern countries including Korea and Japan. However, ICG R15 remains imperfect because of its dependency on both the hepatic flow and the functional capacity of the liver [
15]. Recently, liver stiffness measurement (LSM) using FibroScan
® was reported to reflect the degree of hepatic fibrosis, which is an important factor determining the functional liver reserve [
16]. Therefore, we hypothesized that LSM can predict the hepatic functional reserve.
This prospective study investigated the usefulness of LSM as a predictor of the liver reserve.
Patients and methods
Patients
In this pilot study, 91 consecutive patients who were eligible for curative liver resection surgery for hepatocellular carcinoma between July 2006 and December 2007 at Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, were enrolled prospectively. Patients who underwent surgery because of causes other than hepatocellular carcinoma or had Child-Pugh class C liver function were excluded.
Among all enrolled patients, 19 patients who underwent liver transplantation were also excluded. Written informed consent was obtained from all patients. This study was approved by the Institutional Review Board of Severance Hospital.
The primary end point was the development of postoperative hepatic insufficiency.
Hepatic insufficiency was defined as persistent hyperbilirubinemia (total bilirubin level >5 mg/dl) for more than 5 days after surgery or postoperative death without other causes [
17,
18].
Liver stiffness measurement
On the same day that the ICG R15 test was performed, liver stiffness in the right lobe of the liver was measured, using FibroScan®, through the intercostal spaces with the patient lying in the dorsal decubitus position and with the right arm in maximal abduction. The tip of the transducer probe was covered with coupling gel and placed on the skin between the ribs at the level of the right lobe of the liver. Before performing FibroScan® in all patients, sonographic evaluation was used to target nontumor liver parenchyma. The operator, assisted by real time ultrasound, located a liver portion that was at least 6-cm thick and free of large vascular structures, and then pressed the probe button to commence the measurements. Ten validated measurements were performed on each patient. The success rate was calculated as the number of validated measurements divided by the total number of measurements. The results were expressed in kilopascals (kPa). The median value was considered as representative of the elastic modulus of the liver. Only procedures with ten validated measurements and a success rate of at least 60% were considered reliable.
ICG R15 evaluation
After an overnight fast, 0.5 mg/kg of ICG was administered intravenously. Blood samples were drawn at 5, 10, and 15 min and the plasma ICG concentration was measured spectrophotometrically (710 nm). The plasma retention rate at 15 min (ICG R15, %) and the plasma disappearance rate (ICG-k, min−1) were calculated.
Liver resection surgery
All the patients were examined to confirm the number, size, location, and extent of the tumor and the existence of distant metastases by abdominal ultrasonography, CT scan, magnetic resonance imaging, hepatic angiography, and positron emission tomography. In addition to preoperative routine laboratory examinations and physical examination for determining Child-Pugh classification, ICG R15 was performed to determine the optimal treatment strategy. Anatomical resection was performed according to tumor size, location, and liver reserve function. Indications for hepatic resection and the types of operative procedures were mainly determined on the basis of the criteria of Makuuchi, i.e., the presence or absence of ascites, the serum total bilirubin level, and ICG R15 [
19]. All liver resection surgeries were performed by two surgeons (J.S. Choi and K.S. Kim) and followed the anatomic definitions of segments and lobes of Couinaud [
20]. Patients routinely underwent intraoperative ultrasonography to determine tumor localization and extent and to exclude the presence of additional lesions in the residual liver.
Statistical analysis
Patient characteristics are given as the mean ± SD or median (range). Continuous variables were compared using an independent t-test and categorical variables were compared using χ2-test. A two-sided P-value < 0.05 was considered significant.
Variables associated with the development of postoperative hepatic insufficiency were first assessed using a univariate analysis. Then, the variables that were significant (P < 0.1) were subjected to multivariate logistic regression analysis to identify the independent predictors for the development of postoperative hepatic insufficiency.
The optimal cutoff value for liver stiffness was set as the value maximizing the sum of sensitivity and specificity. The predictive ability of LSM and ICG R15 was assessed by the receiver operating characteristic (ROC) curve and corresponding area under the ROC (AUROC) curve for each. All statistical analyses were performed with SPSS 12.0 (SPSS, Chicago, IL, USA).
Discussion
Liver transplantation, liver resection, and local ablation therapy are curative treatments for hepatocellular carcinoma. Among them, liver transplantation is the best option because it is the only treatment that offers a chance of cure for hepatocellular carcinoma and the underlying cirrhosis by complete extirpation of both. However, the limitation of organ supply remains unresolved. Therefore, liver resection surgery for curative goal is widely performed instead of liver transplantation regardless of restriction of its application to a liver with limited functional reserve and high chance of recurrence in the liver remnant [
21].
Because surgery removes parts of the functioning liver, the volume of the remnant liver determines the risk of postoperative hepatic insufficiency, which is the major cause of mortality and morbidity after liver resection surgery, especially in the cirrhotic liver.
The lack of well-designed, randomized, controlled trials, the use of different staging systems, and the different definitions of postoperative hepatic insufficiency have led to the confusion in the analysis of postoperative outcomes for liver resection surgery [
22]. Careful preoperative evaluation of the functional liver reserve is necessary to minimize the postoperative morbidity and mortality in cirrhotic and noncirrhotic patients [
12,
13]. Several preoperative tests are available for such purposes, including the serum HA assay, liver volumetry using CT scan, LHL 15, ICG R15, and hepatic venous pressure gradient [
8‐
10]. Of these, the ICG R15 is the most reliable and widely available test to determine the extent of liver resection and liver reserve function in Eastern countries [
12]. Although, the ICG R15 has some limitations because it depends on both the hepatic flow and the functional capacity of the liver, there is general agreement concerning the retention value [
15].
Poon et al. [
23] assessed the patient suitability for liver resection surgery by evaluating the Child-Pugh score combined with ICG R15 measurements; in their study, the occurrence of hepatic failure was 1%. Torzilli et al. [
4] reported a preoperative evaluation pattern for liver resection surgery, which included the presence of ascites, serum bilirubin levels, and estimation of the ICG R15, and reported no mortality after liver resection in 107 patients.
Recently, LSM has been shown to reflect the degree of hepatic fibrosis, which is an important determinant of the development of postoperative hepatic insufficiency [
16]. Therefore, we postulated that LSM could be used to predict postoperative hepatic insufficiency before liver resection surgery. In order to test this hypothesis, we compared the abilities of LSM and ICG R15 in predicting the development of hepatic insufficiency after curative liver resection surgery. Although several studies have already reported the correlation between intraoperative liver consistency using specific probes and postoperative outcome [
24‐
26], to the best of our knowledge, no other study has investigated LSM as a preoperative evaluation for predicting the development of postoperative hepatic insufficiency after liver resection surgery, compared with the relationship for ICG R15.
In this study, the cutoff liver stiffness value was set at 25.6 kPa, which gave the best accuracy. Multivariate logistic regression analysis revealed that LSM was the only independent predictor of the development of postoperative hepatic insufficiency. In terms of the AUROC for predicting hepatic insufficiency, the value for LSM was greater than that for the ICG R15. Therefore, in our study population, LSM was better than the ICG R15 in predicting the development of postoperative hepatic insufficiency.
We are aware of several limitations of our study. First, the multivariate logistic regression analysis did not include other variables that can affect the outcome of surgery, such as the serum HA level, which is closely correlated with the functional liver reserve and is a useful predictor of liver regeneration [
27], or the total or resected liver volume measured using CT scan. Second, there were some factors differently represented between who showed hepatic insufficiency and who did not, such as total bilirubin level, bleeding amount, operation time, and the portion of undergoing lobectomy, although there were no statistical differences between the two groups. These points might influence the final results. Finally, because all enrolled patients showed chronic liver disease status, the results of this study are not applicable to patients without chronic liver disease. In order to overcome these limitations, a well-designed, well-controlled, randomized study of a large population is required.
In conclusion, our study showed that preoperative LSM was significantly higher in patients who developed postoperative hepatic insufficiency than in those patients who did not. Therefore, our results suggest that the preoperative liver stiffness is a potentially useful predictor of the development of postoperative hepatic insufficiency in patients with hepatocellular carcinoma undergoing liver resection surgery.