Hepatocellular carcinoma (HCC) with varying degrees of cirrhosis is one of the most prevalent malignancies worldwide.[1,2] Partial liver resection is widely regarded as the first-line curative treatment modality for HCC patients. Despite advancements in perioperative management, the invasiveness of surgical procedures in addition to coexisting chronic liver diseases still cause an incidence of posthepatectomy liver failure (PHLF). Due to lack of effective treatments, PHLF remains the main cause of postoperative mortality in HCC patients undergoing liver resection. Yet, the magnitude of PHLF events is still huge and there are still lacking accurate predictive markers. To our knowledge, accurate preoperative assessment of liver function and strict patient selection are the main strategies of preventing adverse postoperative outcomes.
Hepatic fibrosis and cirrhosis, which are mostly associated with chronic viral hepatitis or steatosis, often accompany with impaired liver function. Recently, several noninvasive biomarkers of liver fibrosis based on laboratory parameters have been proposed. The fibrosis-4 index (FIB-4)  and aspartate aminotransferase (AST) to platelet count ratio index (ARPI)  are 2 alternative biomarkers which have been shown to be effective in assessing liver fibrosis and cirrhosis.[7–12] However, only a few studies investigated the accuracy of FIB-4 and ARPI indices in predicting short-term outcomes of liver resection in HCC patients.[13–16]
Liver function is a major determinant of postoperative outcomes. As a simple and objective assessment tool of liver function, the ALBI grading system has recently been proven to be a powerful predictor of short-term and long-term outcomes after liver resection.[17–25] However, the ALBI grading system is limited by its inability to account for portal vein pressure (PVP). As a key step in the pathophysiological mechanism of liver cirrhosis, portal hypertension was reported to be correlated with adverse postoperative outcomes.[26–28] Being an indicator of severe portal hypertension, spleen thickness (ST) has been proven to be a reliable predictor of PHLF. On this basis, we proposed an innovative biomarker, the ALBI score to spleen thickness ratio (ALBI/ST), to predict PHLF in HCC patients.
In the present study, we investigated and compared the accuracy of ALBI/ST ratio, FIB-4 index, and APRI in predicting PHLF among HCC patients who underwent liver resection.
2 Patients and methods
A total of 932 patients who were diagnosed with HCC and underwent hepatectomy at the Second Xiangya Hospital were retrospectively enrolled between 2010 and 2017. Eligibility criteria included: Child–Pugh grade A or B liver function, no therapy for neoplasm before hepatectomy, and no cardiopulmonary dysfunction, renal insufficiency or cerebropathy before surgery. Exclusion criteria included: coexisting malignancies, former splenectomy, splenomegaly caused by etiology beyond liver cirrhosis, and obstructive jaundice before surgery. This study complied with the principles of Helsinki Declaration and was approved by the Institutional Ethical Board of Central South University. Informed consent was waived for this retrospective research.
2.2 Diagnosis and definitions
Spleen thickness was routinely measured and reported by ultrasonography, and it was defined as the transversal distance between the splenic hilum and the point of tangency of the opposite convex surface. Operators were experienced in ultrasound and not aware of hemodynamic information of the patients. Classification of the Child–Pugh score was based on prepublished methodology. Clinically significant portal pressure (CSPH) was confirmed as the development of esophageal/gastric varices or low platelet count (< 100 × 109/L) with splenomegaly (major diameter > 12 cm).[31,32] The definition of PHLF was in accordance with the guidelines proposed by International Study Group of Liver Surgery, as a total serum bilirubin > 50 μmol/L and a prothrombin time index < 50% (which corresponds to international normalized ratio >1.7) on or after postoperative day 5.[33,34] Postoperative mortality was defined as death within 30 days of surgery or during the hospital stay if this was longer.
- ALBI score, ALBI/ST, FIB-4 index, and APRI were calculated using the following formulas :[5,6,17]
- ALBI score = −0.085 × (albumin [g/L]) + 0.66 × log10(bilirubin [μmol/L]);
- FIB-4 = age [years] × AST [U/L]/(platelet count [109/L] × ALT [U/L]1/2);
- APRI = ([AST/upper limit of normal (ULN)]/platelet count [109/L]) × 100;
- ALBI/ST ratio = ALBI score/spleen thickness (cm);
- ALBI score was further stratified into 3 classifications: ALBI grade 1 (≤ −2.60), grade 2 (>−2.60 to ≤ −1.39) and grade 3 (> −1.39).
2.3 Surgical technique
The remnant liver volume (RLV) was assessed based on the imaging data, especially for patients who underwent major liver resection. An RLV of 30% was used as the lower limit for patients with normal liver function, whereas a minimum RLV of approximately 40% was used for patients with impaired hepatic function. Conventional open hepatectomy was performed in the majority of patients, with a small number undergoing laparoscopic surgery. Liver transection was conducted using an ultrasonic dissector or clamp crushing method under low central pressure based on the operator's preference. Intermittent Pringle maneuver was used if needed to control intraoperative hemorrhage. Hepatic resection was defined as major if a removal of 3 segments or more was performed and minor if fewer than 3 segments were resected.
2.4 Statistical analysis
Statistical analysis was conducted using SPSS version 17.0 (SPSS, Inc., Chicago, IL) and MedCalc version 15.2.2 (MedCalc Software bvba, Ostend, Belgium). Data were expressed as mean ± SD or absolute values and percentages. P values < .05 were considered significant. Student t-test, Chi-square test, and Fisher exact test were used for univariate analysis where appropriate. Univariate analysis and multivariate logistic regression analysis were applied to determine independent risk factors correlated with PHLF. The discriminative power of different noninvasive methods for the prediction of PHLF was evaluated using the receiver operating characteristic (ROC) curve analysis and expressed as area under the ROC curve (AUC). The cut-off points for the occurrence of PHLF were also determined by ROC curve analysis. Comparison between AUCs was made using Delong test.
3.1 Patient demographics
The clinical characteristics and laboratory data of the 932 patients are summarized in Table 1. This study included 827 males and 105 females, with a mean age of 51.3 years. The main etiology of liver diseases was hepatitis B, present in 799 (85.7%) patients. A total of 247 (26.5%) patients underwent major liver resection. Eighteen deaths occurred during 30 days of operation, with a mortality rate of 1.9%.
3.2 Univariate and multivariate analyses of risk factors for PHLF
PHLF occurred in 69 (7.4%) patients. In univariate analysis, factors associated with PHLF included age, ALT, tumor size, blood loss, major hepatectomy, FIB-4, APRI, ALBI score, ST, Child–Pugh score, and ALBI/ST (Table S1, http://Links.lww.com/MD/C915). Two multivariate analysis models were conducted to exclude collinearity (Table 2). In the APRI model, blood loss, major hepatectomy, APRI, and ALBI/ST were found to be significant predictors of PHLF. In the FIB-4 model, ALT, blood loss, major hepatectomy, FIB-4, and ALBI/ST were identified as independent predictors of PHLF. Interestingly, the ALBI/ST ratio exhibited a strong predictive accuracy of PHLF in both models.
3.3 Predictive power of the indices for PHLF
The ability of ALBI/ST, FIB-4, APRI, ALBI, and ST in predicting PHLF was evaluated by ROC analysis (Fig. 1). The AUC for ALBI/ST ratio (AUC = 0.774, P <.001) was larger than that of FIB-4 (AUC = 0.696, P <.001), APRI (AUC = 0.697, P <.001), ALBI (AUC = 0.701, P <.001), and ST (AUC = 0.710, P <.001). The optimal cut-off values of ALBI/ST ratio, FIB-4, APRI, ALBI, and ST were −0.627, 2.58, 0.93, −2.496, and 3.8, respectively. The cut-off value of ALBI/ST showed a sensitivity of 67.3% and a specificity of 82.6%. We further compared the AUCs of ALBI/ST, FIB-4, and APRI using the Delong test. The difference between the AUCs of ALBI/ST and FIB-4 (P =.022), difference between ALBI/ST and APRI (P =.036) were both significant.
3.4 Predictive power of the indices for PHLF in the subgroups stratified by the extent of hepatectomy
To further investigate the predictive accuracy of the indices, we divided the entire cohort of patients into 2 subgroups according to the extent of liver resection. Multivariate analysis in minor hepatectomy subgroup revealed that age, Child–Pugh score and ALBI/ST were significant predictors of PHLF in the APRI model, while Child–Pugh score, FIB-4, and ALBI/ST were found to be significant risk factors of PHLF in the FIB-4 model (Table 3). In the major hepatectomy subgroup, multivariate analysis revealed that APRI and ALBI/ST were independent predictors of PHLF in the APRI model, while ALT and ALBI/ST were found to be independent risk factors of PHLF in the FIB-4 model (Table 4). The ROC analysis demonstrated that ALBI/ST has a superior or comparable predictive accuracy for PHLF compared with FIB-4, APRI, ALBI, and ST in both major and minor hepatectomy subgroups (Fig. 2, Table 5). The distribution of values of the indices are shown in Figure S1, http://Links.lww.com/MD/C915.
3.5 ALBI/ST and clinicopathological characteristics of patients
Table 6 displays the clinical and laboratory data based on the ALBI/ST values. Comparison between patients with an ABLI/ST ≤ −0.627 and patients with an ALBI/ST > −0.627 revealed statistical differences in etiology of liver diseases, total bilirubin, albumin, AST, prothrombin time, INR, platelet count, blood loss, ST, FIB-4, APRI, ALBI score, Child–Pugh score, CSPH, and PHLF (All P <.05, Table 6).
A majority of HCC patients has a background of liver fibrosis or cirrhosis. Liver fibrosis or cirrhosis accompanied with portal hypertension in HCC patients plays an important role in the occurrence of PHLF. Hence, accurate evaluation of liver fibrosis and cirrhosis before surgical operation is imperative. The APRI and FIB-4 indices have been proposed to be alternative measurements of liver fibrosis to liver biopsy.[11,35,36] The 2 indices are widely used because they are noninvasive and possess high accuracy. The APRI formula consists of AST and PLT, while the FIB-4 formula includes age and ALT besides the 2 parameters above. FIB-4 and APRI are considered to be accurate measurements because they incorporate existing liver injury (as manifested by transaminases level) and sinusoidal injury (which influences platelet count).
To our knowledge, only a few studies have explored the predictive power of FIB-4 and APRI for PHLF.[14,16] Consistent with these studies, our study found that FIB-4 and APRI were significant predictors of PHLF. Multivariate analysis revealed that FIB-4 and APRI were both significant risk factors. The ROC analysis revealed that the AUCs of FIB-4 and APRI for predicting PHLF were 0.696 (P <.001) and 0.697 (P <.001), respectively. These results showed that the 2 indices have a high discriminative power for PHLF.
It was previously reported that the severity of portal hypertension could predict the occurrence of PHLF.[27,28] This is because PVP may increase after surgery due to a smaller liver size hence increased portal flow per tissue unit mass. The resultant acute portal hypertension may cause endothelial damage and suppress liver regeneration, all of which play key roles in the mechanism of PHLF. As a parameter that can be easily measured, spleen thickness (ST) has been confirmed to be an indicator of portal hypertension which associates with PHLF.[11,29,37,38] The newly proposed ALBI score was found to have a higher prognostic value compared with conventional methods such as Child–Pugh score, ICG R15 and MELD score.[21,23,25] Given that, we put forward the ALBI/ST ratio and explored its capability in predicting PHLF.
The results confirmed our hypothesis that ALBI/ST ratio was a significant predictor of PHLF as revealed by multivariate analysis. ROC curves further showed that the AUC value of ALBI in predicting PHLF was 0.701, which is closer to 0.723 reported by Wang et al. In addition, the AUC value for ST in predicting PHLF was 0.710, which is smaller than 0.754 reported by Chen et al. This discrepancy may be due to the composition of patients enrolled; in the study by Chen et al, only HBV-related HCC patients were enrolled while a small number of non-HBV HCC patients were recruited in our study. By combining the ALBI and ST indices, we obtained a larger AUC value of ALBI/ST than ALBI or ST alone, which were confirmed to be good predictors of PHLF in previous studies.[21–23,29] In addition, we compared the predictive ability of ALBI/ST with FIB-4 and APRI, and found that ALBI/ST had a higher diagnostic accuracy for PHLF than FIB-4 and APRI.
In general, the relatively small liver after a major liver resection often increases the risk of developing PHLF. As expected, major hepatectomy was identified as an independent risk factor of PHLF in this study. To rule out the effects caused by the reduction of liver volume, we further conducted a stratification analysis based on the extent of hepatectomy. We observed that ALBI/ST ratio was a significant risk factor of PHLF in all hepatectomy subgroups as revealed by the multivariate analysis, while FIB-4 was only an independent predictor of PHLF in minor hepatectomy subgroup, and APRI only showed significance in major hepatectomy subgroup. Moreover, ROC curve analysis showed that the AUC value of ALBI/ST ratio was higher than that of FIB-4 and APRI, both in the minor and major hepatectomy subgroups, which suggested that ALBI/ST had a higher diagnostic accuracy for PHLF compared with APRI and FIB-4. Being a combination of ALBI and ST, the ALBI/ST ratio not only considers the liver function, but also takes into account portal hypertension indicating that it has higher predictive power for PHLF which can be applied in clinical practice.
The cut-off value of ALBI/ST as determined by ROC analysis was −0.627. Statistical differences were found in the majority of clinical characteristics between patients with ALBI/ST ≤ −0.627 and those with ALBI/ST > −0.627. Interestingly, patients with ALBI/ST > −0.627 had a higher risk of blood loss and occurrence of PHLF, implying that HCC patients with an ALBI/ST > −0.627 should be given more attention during perioperative care.
The current study suffered several limitations. Firstly, majority of patients had a history of HBV infection. Therefore, to improve the findings of this study, the predictive power of the indices for PHLF should be investigated in HCC patients with different etiologies. Secondly, parameters related to splenomegaly such as spleen width, spleen length, or spleen volume were not measured by computed tomography or magnetic resonance imaging in the present research. Lastly, though previous studies reported that ALBI, FIB-4 and APRI had an influence on prognosis of HCC after surgery,[12,39] we did not compare their ability in predicting postoperative long-term outcomes, which remained to be investigated in our future studies.
In conclusion, this study found that a combination of ALBI score with spleen thickness (ALBI/ST ratio) was a significant predictor of PHLF. We also found that APRI and FIB-4 indices, the commonly used noninvasive measurements of liver cirrhosis, had high discriminative power for PHLF. More importantly, the diagnostic accuracy of ALBI/ST ratio for PHLF was superior to that of APRI and FIB-4. Hence, we recommend the clinical application of ALBI/ST as supplement of liver functional reserve assessment before surgery to achieve better postoperative results for HCC patients.
Conceptualization: Zequn Zhang, Jiangjiao Zhou.
Data curation: Bo Yang.
Formal analysis: Zequn Zhang, Heng Zou.
Investigation: Bo Yang.
Methodology: Heng Zou.
Supervision: Jiangjiao Zhou.
Validation: Jiangjiao Zhou.
Visualization: Li Xiong, Xiongying Miao, Yu Wen.
Writing – original draft: Zequn Zhang, Bo Yang, Heng Zou.
Writing – review & editing: Li Xiong, Xiongying Miao, Yu Wen, Jiangjiao Zhou.
Heng Zou orcid: 0000-0002-3683-7916.
. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108.
. Thompson Coon J, Rogers G, Hewson P, et al. Surveillance of cirrhosis for hepatocellular carcinoma
: systematic review and economic analysis. Health Technol Assess 2007;11:1–206.
. de Lope CR, Tremosini S, Forner A, et al. Management of HCC. J Hepatol 2012;56(suppl 1):S75–87.
. van Mierlo KM, Schaap FG, Dejong CH, et al. Liver resection for cancer: new developments in prediction, prevention and management of postresectional liver failure. J Hepatol 2016;65:1217–31.
. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518–26.
. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–25.
. Lackner C, Struber G, Liegl B, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology 2005;41:1376–82.
. Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest. Hepatology 2007;46:32–6.
. Wang H, Xue L, Yan R, et al. Comparison of FIB-4 and APRI in Chinese HBV-infected patients with persistently normal ALT and mildly elevated ALT. J Viral Hepat 2013;20:e3–10.
. Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index
for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology 2015;61:292–302.
. Zhang EL, Zhang ZY, Wang SP, et al. Predicting the severity of liver cirrhosis through clinical parameters. J Surg Res 2016;204:274–81.
. Okamura Y, Ashida R, Yamamoto Y, et al. FIB-4 index is a predictor of background liver fibrosis and long-term outcomes after curative resection of hepatocellular carcinoma
. Ann Surg Oncol 2016;23:467–74.
. Dong J, Xu XH, Ke MY, et al. The FIB-4 score predicts postoperative short-term outcomes of hepatocellular carcinoma
fulfilling the Milan criteria. Eur J Surg Oncol 2016;42:722–7.
. Tanaka S, Iimuro Y, Hirano T, et al. Prediction of postoperative hepatic failure after liver resection for hepatocellular carcinoma
: significance of the aspartate aminotransferase-to-platelet ratio index. Hepatogastroenterology 2014;61:755–61.
. Dong J, Zhang XF, Zhu Y, et al. The value of the combination of fibrosis index based on the four factors and future liver remnant volume ratios as a predictor on posthepatectomy outcomes. J Gastrointest Surg 2015;19:682–91.
. Ratti F, Cipriani F, Catena M, et al. Liver failure in patients treated with chemotherapy for colorectal liver metastases: Role of chronic disease scores in patients undergoing major liver surgery. A case-matched analysis. Eur J Surg Oncol 2014;40:1550–6.
. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma
: a new evidence-based approach-the ALBI grade. J Clin Oncol 2015;33:550–8.
. Hiraoka A, Michitaka K, Kumada T, et al. Validation and potential of albumin-bilirubin grade and prognostication in a nationwide survey of 46,681 hepatocellular carcinoma
patients in Japan: the need for a more detailed evaluation of hepatic function. Liver Cancer 2017;6:325–36.
. Zhang ZQ, Xiong L, Zhou JJ, et al. Ability of the ALBI grade to predict posthepatectomy liver failure
and long-term survival after liver resection for different BCLC stages of HCC. World J Surg Oncol 2018;16:208.
. Zou H, Wen Y, Yuan K, et al. Combining albumin-bilirubin score with future liver remnant predicts post-hepatectomy liver failure in HBV-associated HCC patients. Liver Int 2018;38:494–502.
. Wang YY, Zhong JH, Su ZY, et al. Albumin-bilirubin versus Child–Pugh score as a predictor of outcome after liver resection for hepatocellular carcinoma
. Br J Surg 2016;103:725–34.
. Andreatos N, Amini N, Gani F, et al. Albumin-bilirubin score: predicting short-term outcomes including bile leak and post-hepatectomy liver failure following hepatic resection. J Gastrointest Surg 2017;21:238–48.
. Zou H, Yang X, Li QL, et al. A Comparative study of albumin-bilirubin score with child-pugh score, model for end-stage liver disease score and indocyanine green R15 in predicting posthepatectomy liver failure
for hepatocellular carcinoma
patients. Dig Dis 2018;36:236–43.
. Pinato DJ, Sharma R, Allara E, et al. The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma
. J Hepatol 2017;66:338–46.
. Na SK, Yim SY, Suh SJ, et al. ALBI versus Child–Pugh grading systems for liver function in patients with hepatocellular carcinoma
. J Surg Oncol 2018;117:912–21.
. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma
in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22.
. Chen X, Zhai J, Cai X, et al. Severity of portal hypertension and prediction of postoperative liver failure after liver resection in patients with Child–Pugh grade A cirrhosis. Br J Surg 2012;99:1701–10.
. Allard MA, Adam R, Bucur PO, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg 2013;258:822–9. discussion 29-30.
. Chen X, Zou H, Xiong L, et al. Predictive power of splenic thickness for post-hepatectomy liver failure in HBV-associated hepatocellular carcinoma
patients. World J Surg Oncol 2017;15:216.
. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–9.
. Augustin S, Millan L, Gonzalez A, et al. Detection of early portal hypertension with routine data and liver stiffness in patients with asymptomatic liver disease: a prospective study. J Hepatol 2014;60:561–9.
. Schroeder RA, Marroquin CE, Bute BP, et al. Predictive indices of morbidity and mortality after liver resection. Ann Surg 2006;243:373–9.
. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg 2005;242:824–8. discussion 28-9.
. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure
: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery 2011;149:713–24.
. Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010;52:191–8.
. Xiao G, Zhu F, Wang M, et al. Diagnostic accuracy of APRI and FIB-4 for predicting hepatitis B virus-related liver fibrosis accompanied with hepatocellular carcinoma
. Dig Liver Dis 2016;48:1220–6.
. Berzigotti A, Seijo S, Arena U, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013;144: 102-11e1.
. Berzigotti A, Zappoli P, Magalotti D, et al. Spleen enlargement on follow-up evaluation: a noninvasive predictor of complications of portal hypertension in cirrhosis. Clin Gastroenterol Hepatol 2008;6:1129–34.
. Toyoda H, Kumada T, Tada T, et al. A laboratory marker, FIB-4 index, as a predictor for long-term outcomes of hepatocellular carcinoma
patients after curative hepatic resection. Surgery 2015;157:699–707.
albumin-bilirubin score to spleen thickness ratio; aspartate aminotransferase to platelet count ratio index; fibrosis-4 index; hepatocellular carcinoma; posthepatectomy liver failure
Supplemental Digital Content
Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.