Advances in preoperative assessment of liver function

Peng-Lei Ge, Shun-Da Du and Yi-Lei Mao

Beijing, China

Advances in preoperative assessment of liver function

Peng-Lei Ge, Shun-Da Du and Yi-Lei Mao

Beijing, China

BACKGROUND:Postoperative liver failure remains a lifethreatening complication. Preoperative evaluation of liver function is essential in reducing the complications after hepatectomy. However, it is difficult to accurately evaluate liver function before surgery because of the limitations of the liver function tests available. Recent advances in liver function tests improved the ability to assess liver function. The present review was to analyze these methods and their advantages.

DATA SOURCES:MEDLINE was searched using the terms of "liver function test", "liver function evaluation" and "galactosyl serum albumin". Relevant articles published in English and Chinese from 1961 to 2014 were reviewed.

RESULTS:Although serological tests are used frequently in practice, they reflect the degree of total liver damage or function, not the remnant of liver function. Child-Pugh score and model for end-stage liver disease (MELD) score assess whole liver function, and are particularly useful in determining whether patients with hepatocellular carcinoma and cirrhosis are candidates for resection or transplantation, but cannot determine the safe extent or removal. The indocyanine green and other metabolic quantitative liver function tests can evaluate functional hepatocytes, making them more accurate in predicting liver function. Computed tomography (CT) volumetry can provide anatomic information on the remnant liver volume but not on functional volume.99mTc-galactosyl serum albumin scintigraphy, combined with single photon emission computed tomography, CT and three-dimensional reconstruction, may be a better quantitative measure of liver function, especially of remnant liver function.

CONCLUSIONS:Tests used to evaluate liver functional reserve and to predict surgical risk have limitations.99mTc-galactosylserum albumin scintigraphy, which can more accurately evaluate the whole and regional liver function, may be promising in predicting resection margins and risks of liver failure.

(Hepatobiliary Pancreat Dis Int 2014;13:361-370)

liver function test;

hepatectomy;

asialoglycoprotein;

galactosyl serum albumin

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide.[1,2]Surgical resection is an essential component of comprehensive treatment. Improvements in surgical methods and instruments have greatly reduced the perioperative mortality. However, the major cause of mortality after partial hepatectomy is liver failure, which results from an insufficient functional remnant liver mass.[3]Conversely, the erroneous results of liver function tests may mislead the surgeon to make a wrong decision such as precluding some patients with large liver tumors from undergoing surgery, even if surgery is beneficial. Therefore, the accurate evaluation of liver function is very important, particularly in patients with damaged livers who require hepatectomy or liver transplantation.[4]

Among the methods used to evaluate liver function in practice are serological tests which are the earliest and most commonly used and still play important roles in determining whole liver function. Clinical scoring systems, such as Child-Pugh and model for end-stage liver disease (MELD) scores can roughly evaluate the risks of hepatectomy. The indocyanine green (ICG) test is a widely used quantitative test of liver function in patients who scheduled for major hepatectomy. Although these tests can assess whole liver function, they cannot assess remnant liver function. Computed tomography (CT) volumetry can provide anatomic information on remnant liver volume (RLV), but anatomic volume is notequal to functional volume, especially in patients with steatosis and cirrhosis. In recent years,99mTc-galactosyl serum albumin (99mTc-GSA) scintigraphy combined with single photon emission computed tomography (SPECT) and CT with three-dimensional imaging, is relatively accurate in measuring the whole and regional liver function.99mTc-GSA scintigraphy may therefore be a promising method to plan surgical incisions and to predict operative risk (Table 1). This review mainly focuses on the advantages of99mTc-GSA in preoperative assessment of liver function.

Serological indicators

Liver function includes the uptake, metabolism, conjugation and excretion. Strictly speaking, enzymes in blood, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), are indicators of liver damage. In healthy individuals, the blood concentrations of these enzymes are relatively low but high in hepatocytes. These enzymes are released into the bloodstream by hepatocytes in patients with liver disease and those who have undergone hepatectomy and thus, the blood concentrations of the enzymes are increased. These enzymes, however, reflect the degree of liver damage, not of remnant liver function.

Bilirubin, a breakdown product of hemoglobin, is produced by the liver. Bilirubin reflects the uptake, conjugation and excretion function and is therefore a specific marker for serious liver injury and impaired liver function. When red blood cells are degraded, unconjugated bilirubin is released by hemoglobin into the bloodstream, where it combines with serum albumin and is transported to the liver. The bilirubin is taken up by hepatocytes, where it undergoes a series of metabolic steps that convert it to conjugated bilirubin.[5]The conjugated bilirubin is then excreted into the bile across the canalicular membrane.[6]Jaundice may reflect liver function, although nonhepatic factors can also influence bilirubin level, such as the quantity of destroyed red blood cells and bile duct obstruction.[7]Because hemolysis results in the release of additional hemoglobin into the bloodstream, the concentration of unconjugated bilirubin in blood will increase if the amount of bilirubin exceeds the metabolic capacity of the liver. Obstruction of the common bile duct will block bile excretion and greatly increase the concentrations of both conjugated and unconjugated bilirubin. Thus, plasma bilirubin concentration may not be a perfect biomarker of liver function.

Many important proteins are synthesized exclusively by the liver such as albumin and coagulation factors including V, VII, VIII, IX, X, XI and XII. Therefore, the plasma concentrations of these proteins reflect liver synthetic function. Partial damage or resection of the liver reduces hepatic synthesis of these proteins. Plasma albumin concentration, prothrombin time and international normalized ratio (INR) are indicators of liver function. These tests are always used together with dynamic and quantitative tests.

Table 1. Methods for liver function tests

Comprehensive scoring systems Child-Pugh score

The Child-Turcotte scoring system, first proposed in 1964, was originally developed to predict the outcome of cirrhotic patients undergoing surgical therapy for portal hypertension. This scoring system included five simple parameters: presence or absence of encephalopathy and ascites, serum total bilirubin and albumin concentrations, and nutritional status.[8]This system was modified by Pugh et al[9]in 1973, with nutritional status replaced by prothrombin time and the system called the Child-Pugh score (Table 2). Its parameters, based on routine laboratory testing and reflecting different aspects of liver disease, are easy to measure. The Child-Pugh score can be used to assessglobal liver function, which is particularly useful in selecting patients with HCC and cirrhosis for resection or transplantation.[9]Depending on the total score, Child-Pugh score can be divided into classes A, B and C. Generally speaking, surgery is relatively safe in class A patients, not recommended in class C cases, and has various outcomes in class B subjects.

The major disadvantages of the Child-Pugh score are the design flaws. This system evaluates global liver function, and cannot indicate the amount of liver considered safe to remove. In addition, the cutoff points for bilirubin and albumin concentrations and prothrombin time were selected because they were easy to remember, reducing the accuracy of the Child-Pugh score in assessing liver function. Furthermore, since each score is a composite of several parameters, actual liver function may differ in patients with the same score. Moreover, the parameters used to calculate Child-Pugh score are easily affected by external factors. Finally, liver function may be only slightly or moderately impaired in surgical candidates without cirrhosis; thus, in these patients, Child-Pugh score may not predict postoperative liver dysfunction.

Table 2.The Child-Pugh score

Table 3.Formulas for calculating the MELD score and some modified scores

MELD

The limitations of the Child-Pugh score led to the development of MELD. MELD score was originally developed to evaluate the survival rate of patients undergoing transjugular intrahepatic portosystemic shunt procedures, and was thereafter modified to evaluate patients with liver disease undergoing surgery. MELD score is a constellation of serum bilirubin, creatinine concentration, INR and etiology of liver disease, and is calculated using the formula: 11.2× Ln(INR)+9.57×Ln[creatinine(mg/dL)]+3.78×Ln [bilirubin(mg/dL)]+6.43×(etiology: 0 if cholestatic or alcoholic, 1 otherwise), with the score rounded to the nearest integer.[10]

MELD score performs well in predicting death within 3 months in patients awaiting liver transplantation, and is a reliable system to predict the mortality risk in patients with end-stage liver disease. The application of this system to determine organ allocation reduced 15% of the mortality rate in liver transplant candidates.[11]In subsequent clinical applications, outcomes were different in patients with the same score and different serum concentrations of sodium. So in 2006, Biggins et al[12]designed MELD-Na score, which could better predict the mortality within 9 months. This score is calculated using the formula: MELD-Na=MELD+1.59×[135-Na(mmol/L)]. In patients with serum sodium concentrations of 125 to 140 mmol/ L, a 1 mmol/L decrease in sodium would increase the risk of death by 5%.[13]There are also some modified MELD formulas that have been proposed to predict the prognosis of liver disease, such as integrated MELD (iMELD), MELD to sodium (MESO), United Kingdom end-stage liver disease (UKELD), etc (Table 3).[14,15]

MELD can predict the prognosis of patients with end-stage liver disease. However, it cannot accurately predict the actual survival time of patients undergoing hepatectomy. At present, MELD is mainly used to assess the severity and prognosis of chronic liver diseases, and to evaluate the patients awaiting liver transplantation.[16]

ICG clearance test

The ICG clearance test is the most widely used quantitative liver function test in critically ill patients and in those with chronically impaired liver function. ICG is a water-soluble, inert anionic compound. Following intravenous injection, it distributes uniformly in the blood within 2 to 3 minutes, binding to albumin, α1-lipoproteins, and β-lipoproteins.[17]ICG is then selectively taken up by hepatocytes, which are independent of adenosine triphosphate (ATP). All ICG taken up by the liver is excreted unchanged into the bilevia an ATP-dependent transport system.

Blood is drawn from patients early in the morning, followed by the intravenous injection of 25 or 50 mg of ICG and collection of venous blood after 5, 10 and 15 minutes. After ICG injection, its blood level decreases exponentially for about 20 minutes, by which time approximately 97% of the dye has been excreted into the bile.[18]The transition from the distribution phase to the elimination phase lasts approximately 20 to 30 minutes. The ICG clearance test can also be automatically calculated under a dye densito-graph (DDG) analyzer using an optical sensor placed on the finger pulse.[19]The machine expands the application of ICG clearance test in current clinical situation.

Under normal conditions, the uptake of ICG is only limited by blood flow.[20]Since ICG does not undergo enterohepatic recirculation,[21]the ICG excretion rate in bile reflects hepatic excretory function and hepatic energy status. Study in rats found that liver ICG clearance was determined by two processes, sinusoidal uptake and canalicular excretion.[22]In humans, liver sinusoidal transport, mediated primarily by the organic anion transporting polypeptide, plays a major role. Multi-drug resistance associated protein (MRP2) and multi-drug resistance P-glycoprotein (MDR3) may be involved in the canalicular efflux of organic anions.[23]

As expected, the plasma clearance rate of ICG is significantly lower in cirrhotic patients than that in healthy subjects. This is due to decreased ICG uptake by the liver from plasma; in contrast, ICG excretion by the liver into the bile is maintained relatively intact.[24]Therefore, ICG clearance tests reflect several important functional parameters of the liver, including blood flowdependent clearance and cellular uptake and biliary excretion.[25]

The results of ICG tests can be expressed in several ways, including the percent ICG retained in the circulation during the first 15 minutes after bolus injection (ICG-R15), the plasma disappearance rate (ICG-PDR), and the elimination rate constant (ICG-k). Elevated ICG-R15 in cirrhotic patients may be due to decreased ICG transport from the systemic circulation to the liver, and decreased uptake from the sinusoids into hepatocytes.[26]ICG-R15 ＞15% is a high risk factor for serious post-hepatectomy complications,[27]although a cutoff of 14% has been suggested by Lau et al.[28]A high ICG-R15 indicates that the volume of nontumorous liver resected must be minimized. In HCC patients without ascites and with normal bilirubin level, ICG-R15 is the main determinant of resectability. For example, right hepatectomy is considered safe in patients with ICG-R15 ＜10%; whereas left hepatectomy and right paramedian or lateral sectorectomy can be performed in patients with ICG-R15 of 10%-19%. In patients with ICG-R15 of 20%-29%, only approximately one-sixth of the liver parenchyma can be resected as Couinaud's segmentectomy. However, limited resection is indicated for patients with ICG-R15 ＞30%.[24]

ICG-PDR, which ranges from 18% to 25% per minute, is another marker for postoperative recovery and survival. ICG-PDR does not represent liver blood flow but rather ICG uptake by hepatocytes, its excretion into the bile, blood flow dependent liver metabolism, and energy status.[29]Because the ICG-R15 test is inexpensive, easy to perform, and comparable among institutions, it has been widely used to assess hepatic functional reserve.[30]In Japan, the ICG test has become one of methods for testing liver function before hepatectomy. Under certain conditions, however, ICG-R15 is not correlated significantly with liver histology or clinical outcomes.[31]Since ICG-R15 results are largely dependent on hepatic blood flow, the presence of an intrahepaticextrahepatic shunt, which is usually present in patients with portal hypertension, significantly influences ICG results.[32]This test may also be of limited value for cholestatic patients. Furthermore, the results of ICG clearance tests reflect global liver function, not the function of segments preserved after hepatectomy.

Metabolic quantitative liver function tests

Drugs and other foreign substances are metabolized almost exclusively by the liver cytochrome P450 system through sequential oxidative processes; thus, measurements of their major metabolite constitute a marker of liver function.[33]For example, the galactose elimination capacity test measures the rate of galactose elimination from the blood, which depends mainly on the phosphorylation of galactose by galactokinase within the hepatocyte cytoplasm. Galactose elimination is calculated 50 minutes after the intravenous injection of galactose. Galactose concentrations in plasma and urine are assayed spectrophotometrically, based on the reaction of galactose and nicotinamide adenine dinucleotide (NAD) to galactolactone and NAD-hydrogen, and used to calculate the galactose elimination rate.[34]Thus, this test is an indirect determinant of the metabolic capacity of the liver,[34]especially in patients with chronic liver disease, chronic active hepatitis, and primary biliary cirrhosis.[35]A low galactose elimination capacity is indicative of liver failure and other complications.[36]

Similar tests of dynamic quantitative liver function include tests of lidocaine metabolism and aminopyrine breath, which measure the capacity of liver functionand the degree of liver damage. These tests, however, are easily affected by the mass and function of liver cytochrome P450 and by liver blood flow. Thus, in clinical practice, these tests should be combined with other tests in determining liver function. In addition, the tests cannot be used to evaluate the safe extent of hepatectomy.

CT volumetry

Data on liver volume are urgently needed because of the increased number of patients undergoing liver transplantation. Urata et al[37]got a formula for calculating the standard liver volume for Japanese patients, which was 706.2×body surface area (m2)+2.4. These estimates are not accurate for other ethnic groups and therefore, other race or ethnicity should have its own formula.

At present, CT volumetry is the most often used imaging method to determine whether hepatectomy can be performed safely.[38]Following a CT scan, the right liver volume (RLV) is calculated by subtracting the resected liver volume from the total liver volume (TLV) using three-dimensional reconstruction software, and the percentage of remaining liver volume is calculated by dividing RLV by TLV. Hepatectomy is considered safe if the RLV/TLV ratio is greater than 25%-30%.[39]For living donor liver transplantation, the volume of the transplanted donor liver should be greater than 30%-35% of the volume of the recipient liver.[40]Nevertheless, a margin of 40% is taken into account in patients with diseased liver.[41]

However, liver volume is not equal to liver function. CT volumetry is used for preoperative calculations of the volume of resected livers, but does not demonstrate the effects of diseased liver parenchyma on liver function. As CT only shows the anatomic form and the volume of the liver, liver biopsy is required to assess donor liver function before living donor liver transplantation. Moreover, the evaluation of liver function before liver surgery is dependent on the combination of the results of CT volumetry with those of other liver function tests.

99mTc-galactosyl serum albumin scintigraphy

Galactosyl human serum albumin (GSA) is an analogue of asialoglycoprotein, which binds to asialoglycoprotein receptors on hepatocyte membranes, followed by receptor-mediated endocytosis. Receptor density is closely related to hepatocyte function.[42-44]The level of expression of asialoglycoprotein receptor is significantly related to liver function and lower in diseased livers, for example, in patients with chronic hepatitis, cirrhosis and HCC.99mTc-GSA is very stable and only distributes in the blood and liver after intravenous injection.[42]Thus,99mTc-GSA, by monitoring the functional status and distribution of asialoglycoprotein receptor, is an ideal agent for predicting hepatocyte mass and function.

After liver uptake,99mTc-GSA remains trapped in the liver for at least 30 minutes, and there is practically no biliary excretion. Thus, SPECT can assess both liver function and functional volume at the same time.[45]The rates of blood clearance and liver uptake depend on the functional hepatocyte mass. The99mTc-GSA liver uptake ratio (LHL15) and blood clearance ratio (HH15) are quantitative indices frequently used in planar dynamic99mTc-GSA scintigraphy. LHL15 represents the number of hepatocytes. It is defined as 15 minutes after bullet injection of99mTc-GSA and calculated by dividing the radioactivity in regions of interest (ROIs) of the liver by the radioactivity in the liver and heart. HH15 represents the rate of blood clearance, which is calculated by dividing the radioactivity in ROIs of the heart 15 minutes by the radioactivity 3 minutes after injection of99mTc-GSA.[46]These indices can be calculated by manually drawing irregularly shaped ROIs covering the cardiac blood pool and the liver on anterior dynamic images. LHL15 and HH15 are readily calculated from the radioactivity in the heart and liver ROIs. LHL15 reflects functional liver volume and the severity of liver disease.[47]Because LHL15 measures preoperative total liver function, not the function of the remnant liver, postoperative liver failure has been observed in patients with normal LHL15 values.[48]

Compartmental models of kinetics of99mTc-GSA can determine the number of asialoglycoprotein receptors and be used for the quantitative evaluation of liver function. Using multi-compartmental model, Ha-Kawa and colleagues found that the liver blood flow and maximal asialoglycoprotein receptor binding rate (Rmax) assessed by99mTc-GSA are significantly correlated with other quantitative measures of liver function.[49]The maximal removal rate of GSA is related to the severity of liver disease and therefore, can be used to evaluate the functional reserve capacity of the liver[50]and to predict the function of residual liver (GSARL) before partial hepatectomy.[51]These results also suggested that GSA-RL could predict the time interval of postoperative liver function recovery and degree of recovery. A GSA-RL ＞0.15 mg/min was associated with a safe hepatectomy.[52]Use of a two-compartmental model with two parameters, k1and k2, representing the fractional transfer rate constants of GSA from the blood to the liver and from the liver to the blood, respectively, found that k1and k1/k2were significantly correlatedwith the results of ICG-R15, the most reliable indicator of hepatic functional reserve identified to date.[53]There are other complex and perfect compartmental models of99mTc-GSA kinetics for the assessment of liver function.[54,55]

Owing to the complexity of these models, the lack of strict clinical evaluation and the long time required to calculate the parameters, none of them has been widely utilized prior to surgery. Thus, simpler and more convenient methods need to be developed.

99mTc-GSA scintigraphy can also be used to evaluate residual liver function after hepatectomy. The regional liver99mTc-GSA clearance (Ku) for each voxel was estimated using the Patlak plot method, generating functional images of Ku.[56]Total liver99mTc-GSA clearance was defined as the sum of the Ku values of any voxel. Following a simulation of tumor resection on SPECT images, the sum of the Ku values of the residual voxels was estimated to be the residual liver99mTc-GSA clearance. Research on this method has shown great progress in Peking Union Medical College Hospital (Beijing, China). Mao and Du[57]set up a computerized image system, which could provide liver images, assess liver function and predict postoperative remnant liver function. This system generated a two-compartment model, using uptake index (UI). Preliminary results found that the UIs of patients both pre- and postoperatively were consistent with liver function measured by other methods. Moreover, the predicted postoperative UIs of remnant livers before hepatectomy were close to the actual postoperative UIs measured in these patients, especially in those with ascites and abnormal bilirubin. Thus, UI may be an excellent preoperative indicator of hepatic functional reserve after operation (Fig. 1).[57]99mTc-GSA SPECT can specifically assess function in remnant livers.[58]In estimating safe margins for the extent of the resection, the outline extraction method can be used to calculate functional liver volume.[59]As the functions of different regions of the liver differ, static SPECT can be used to visualize regional differences in liver function and functional liver volume.[60]However, the total functional liver volume measured by static SPECT is not necessarily correlated with actual liver function. To solve this shortcoming, dynamic SPECT uses a rapidly rotating multidetector gamma camera to measure uptake in a three-dimensional manner. Moreover, dynamic planar99mTc-GSA SPECT can be used to predict postoperative complications with high accuracy.[58]

Predicting liver function reserve is important before partial hepatectomy to avoid postoperative liver failure. Because the total and functional volumes of the liver are not equal, as in cirrhotic patients, increasing fibrosis is accompanied by a reduction in functional hepatocytes. In patients with liver tumors, the tumor-induced compression of surrounding liver tissues can reduce regional liver function, whereas liver volume is sustained over a long period of time. The functional data from99mTc-GSA SPECT can be combined with the anatomic information from CT scan, enabling three-dimensional measurements of segmental liver function and liver functional volume. The functional remnant liver can be delineated manually on the CT scan and compared with the SPECT images. This novel system can generate fusion images of three-dimensional CT and SPECT and simultaneously show the anatomical dimensions of the entire liver as well as any particular ROIs.[57,61]This system also allows surgeons to determine the planned resection area and to predict remnant liver anatomy and compute its function. Therefore, this system can serve as a platform for the non-invasive preoperative assessment of liver images and functions of patients and can be helpful in the comprehensive planning of resection area and in predicting the postoperative remnant liver anatomy and function (Fig. 2). This novel system is called the "Zhong System" in honor of the pioneering surgeon Zhong Shouxian. In the future, preoperative imitative resection of the tumor can help surgeons develop more reasonable operation plans.[62]

Fig. 1.Plotting with D1 and dD2. The slope of the linear regression is the UI value for the selected liver tissue.A: healthy volunteer;B: patient with liver cirrhosis.

Fig. 2.99mTc-GSA single photon emission computed tomography fusion image and three-dimensional reconstruction image of the liver with tumor in the right lobe.

Discussion

Despite the dramatic reduction in perioperative mortality rate of patients undergoing hepatectomy at most major medical centers, postoperative liver failure remains a life-threatening complication, particularly in patients with steatosis, cirrhosis and HCC. The RLV is closely correlated with liver dysfunction or liver failure after hepatectomy.[63]Thus, accurate measurements of liver reserve and remnant liver function before hepatectomy are crucial for patients with underlying parenchymal disease and require a major resection.

Liver function is quite complex which precludes the use of a single test to assess liver function. Traditional tests, such as serological indicators, Child-Pugh score, MELD score and ICG clearance tests, are important in predicting and reducing the risks of hepatectomy. These tests, however, only provide functional data on the entire liver, not on specific anatomic parts of the liver. In the United States, the American Association for the Study of Liver Diseases recommends that hepatic venous pressure gradient be assessed prior to surgical resection. Portal hypertension is confirmed as a pressure gradient＞10 mmHg, when upper endoscopy shows varices, or when diuretic treatment is needed to control ascites. Most patients with portal hypertension will develop postoperative complication, such as ascites, with a 5-year survival rate below 50%.[64]CT volumetry has become a widely used standard method, providing threedimensional images that can allow surgeons to simulate the excision of tumors, calculate the percent RLV, and determine whether a resection can be performed safely. However, liver volume does not always reflect liver function, especially in patients with steatosis, fibrosis and cirrhosis.[65]

Ideally, assessments of liver function should include both anatomical information and function of the whole and partial liver, providing reliable information for accurate evaluation of surgical risks. This may be accomplished by using hepatobiliary scintigraphy, combined with SPECT, especially when liver function is heterogeneous, such as in patients with steatosis, cirrhosis and HCC.99mTc-GSA scintigraphy was initially developed in Japan and used preoperatively to assess liver function. This method can also be used to assess the increased function of the contralateral liver after portal vein embolization. Some authors also use99mTc-mebrofenin to assess liver function like99mTc-GSA.[66-68]In fact, mebrofenin is an iminodiacetic acid analogue, which is excreted rapidly into the bile without undergoing biotransformation.[25]Thus99mTcmebrofenin scintigraphy is originally used for the diagnosis of biliary diseases. The hepatic excretion of99mTc-mebrofenin is too fast for SPECT acquisition, which may restrict its use in liver function test.[44]In China, the Zhong System provides accurate and clearanatomic information and the function of the whole or parts of the liver. A freehand drawing tool can be used to simulate hepatectomy on the image and to calculate the ratio of residual to whole liver function. In summary,99mTc-GSA scintigraphy may be a promising method for predicting resection margins and the risk of liver failure.[69]

Contributors:GPL wrote the main body of the manuscript. DSD and MYL provided advice and edited the manuscript. All authors have read and approved the final manuscript. MYL is the guarantor.Funding:None.

Ethical approval:Not needed.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received January 16, 2014

Accepted after revision March 10, 2014

AuthorAffiliations:Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing 100730, China (Ge PL, Du SD and Mao YL)

Yi-Lei Mao, MD, PhD, Professor of Surgery, Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, 1# Shuaifuyuan, Wangfujing, Beijing 100730, China (Tel: +86-10-69156042; Fax: +86-10-69156043; Email: yileimao@126.com)

? 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60267-8

Published online June 23, 2014.