Nomogram for prediction of the international study Group of Liver Surgery (ISGLS) grade B/C Posthepatectomy liver failure in HBV-related hepatocellular carcinoma patients: an external validation and prospective application study

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the fourth leading cause of cancer-related death worldwide [1]. Hepatectomy is the most effective treatment for early-stage HCC patients, [2] and selective intermediate-stage and advanced-stage HCC patients with resectable tumors and moderate liver function [3]. Advances surgical techniques and management have greatly improved the safety and postoperative outcomes over the past few decades [4]; however, the International Study Group of Liver Surgery (ISGLS) grade B/C posthepatectomy liver failure (PHLF) remains a serious complication, which is a predominant cause of postoperative mortality [5, 6].

Incidence of PHLF as reported in literature widely ranges from 1.2–32% attributing to diverse etiological and pathogenic liver characteristics and surgical procedures [6, 7]. Independent risk factors of PHLF can be grouped into three categories [5, 8]: 1) Patient-related factors including age, sex, comorbidities such as malnutrition, diabetes mellitus, cardiopulmonary, renal or cerebral dysfunction; 2) liver disease-related factors including hepatitis B/C, steatosis, cholangitis, alcoholic liver disease and cirrhosis; 3) surgery-related factors including future liver remnant volume (FLRV), excessive intraoperative blood loss, prolonged operation time, and ischemia-reperfusion injury resulting from Pringle’s manoeuver manipulation. In particular, as a major cause to promote decompensate liver cirrhosis and dysfunction, chronic hepatitis B is highly prevalent and associated with 70–90% of HCC cases in the Asia-Pacific region [9].

Accurate prediction of PHLF is of primary concern for determining the feasibility of hepatectomy for HCC [5, 8]. Child-Pugh grade, [10] model for end-stage liver disease (MELD), [11] albumin–bilirubin (ALBI), [12, 13] platelet-albumin-bilirubin (PALBI) and aspartate aminotransferase to platelet ratio index (APRI) [14] are commonly conventional scores used for evaluating PHLF, nevertheless their predictive performance remains controversial due to inherent limitations. Child-pugh grade is the most widely used for evaluating compensate liver function and has been incorporated into surgical treatment algorithms [11]. However, subjective and unquantifiable variables usually complicate Child-pugh grade: serum bilirubin level of 55 μmol/L has the same influence on Child-pugh grade as 550 μmol/L due to arbitrary thresholds for continuous variables; there is no clear guideline for distinguishing mild or moderate ascites, and the influence of diuretic therapy on grading ascites remains unclear; sedatives therapy frequently mislead encephalopathy [15]. MELD was developed to evaluate acute liver failure mortality risk and rank candidates for transplantation, [16, 17] which was also good at determining increased PHLF morbidity and mortality risk when a MELD score > 8 on postoperative day 5 [5]. However, MELD has a poor performance at preoperative predicting PHLF [5, 6, 11]. ALBI statistical eliminates subjective observation and assesses liver function and overall survival compared favorably with Child-pugh grade in four geographical and etiological HCC patient groups [18]. A preoperative ALBI score predicting PHLF was more accurately than Child-pugh grade, MELD and indocyanine green retention at 15 min (ICG-15) [12, 13]. However, when patients with hyperbilirubinemia were divide into the ALBI grade 3, patients with obstructive jaundice may have better liver function and prognosis than patients with jaundice caused by decompensate liver dysfunction, which significantly misleading the grading of ALBI [19, 20]. Blood platelet (PLT) counts as a surrogate marker of portal hypertension was added to ALBI to develop the PALBI, which predicting survival in HCC patients across treatment modalities including hepatectomy was better than ALBI and MELD. Nonetheless, further research is necessary as few studies have been done evaluating use of PALBI for predicting PHLF. APRI is noninvasive and reliable for evaluating liver fibrosis and cirrhosis, [21, 22] meanwhile a high preoperative APRI score have a high risk of PHLF in HCC patients [23]. However, APRI only includes two quantitative variables and has no ceiling effect. In general, these conventional scores were primarily designed for assessing liver function or other purposes rather than predicting PHLF. Moreover, when they were used for predicting PHLF none of these scores comprehensively considers patient-related, liver-related, and surgical-related risk factors.

As an evidence-based model, nomogram has been proposed as an alternative tool for therapy risk individualized estimation in clinical application [24, 25]. This study aimed to establish a nomogram to predict grade B/C PHLF risk for HBV-HCC patients.

In this study, after eliminating data redundancy and excessive false positives (Fig. 2), a nomogram was developed by integrating five essential preoperative serum laboratory biochemistries (T-Bil, PLT, PA, AST, PT) and sFLR from different categories with clinical significance comprehensively indicating compensate liver function and the percentage of postoperative remain liver (Table 2). Then a graphical and easy-to-use tool was applied for individualized predicting grade B/C PHLF in HBV-HCC patients (Fig. 3a). This nomogram displayed a good accuracy of prediction for grade B/C PHLF (Fig. 3b) and good agreement between probability and actual observation in training cohort, internal validation cohort and external validation cohort (Fig. 3c-e). Besides, this nomogram had greater predicative performance than conventional scores (Fig. 4a-c, Table 4). Further, calculations of predictive value (95% CIs) of the nomogram revealed that negative predictive values were significantly higher than positive predictive values in training cohort (97.6% vs. 33.0%), internal validation cohort (97.4% vs. 25.9%) and external validation cohort (94.3% vs. 41.1%) (Table 4), respectively, potentially demonstrated that negative predictive values could be precise for predicting grade B/C PHLF. Considering the PHLF can indeed be misdiagnosed, objective evaluation of the diagnostic ability of the nomogram and identification of confidence intervals were conducted. Results from feedback error diagnosis distribution curves revealed that actual distribution of total points for error prediction with 95%CI was concentrated in 175 (158–220), 170 (155–210) and 176 (144–240) in training cohort, internal validation and external validation cohorts, respectively, and were very close to the best cutoff value of 169 (Fig. 4a-c). Such that doctors have more flexibility when using the diagnostic results. Confidence interval is considered to be prediction of low risk of grade B/C PHLF when total points fall below this range and high risk of grade B/C PHLF when total points beyond this range. While total points fall within this range, the prediction results should be carefully considered and further confirmed through other evaluations such as ICG-15 retention or computer residual liver imaging volumetry. In this study, clinical use of the nomogram was evaluated in 120 HBV-related HCC patients who will receive hepatectomy. We found that preoperative application of this nomogram had good predictive performance for acutely judging grade B/C PHLF did not occured in 85 patients; and occurred in 16 patients; misjudged in 19 cases with total points were fall within 165–197, which were all fall within the 95%CI of diagnostic errors between 158 and 220 (Supplemental Table 1). The scoring range of misjudged cases was consistent with the objective evaluation, which supports the scientific nature of this study and guides further flexible application of this nomogram. In addition, this nomogram had a good predictive performance for judging non-occurrence of grade B/C PHLF in clinical practice, which was consistent with negative predictive values analysis.

A growing body of researches confirmed that major hepatectomy and insufficient sFLR was associated with high risk of PHLF [27, 29]. Our result is consistent with previous findings revealed that sFLR in this nomogram is of great importance for predicting grade B/C PHLF and adopted sFLR as an important predictive indicator of grade B/C PHLF in our model [30]. Recently, two radiomics-based nomograms based on portal-phase computed tomography or ultrasound were established to predict PHLF, [31, 32] however, they didn’t considered the influence of sFLR on PHLF and integrated this indicator. Moreover, considering mild-moderate liver dysfunction after liver surgery is very common, these nomograms remains to be further validated for predicting ISGLS grade B/C PHLF, particular in HBV-related HCC patients.

This study remains some limitations. First, all of the study participants were associated with HBV, while in most western countries and Japan, the majority of HCC cases are related to alcoholic liver disease or HCV. Therefore, further validation is required from other etiological populations. Second, the reliability of the nomogram remains to be further confirmed by conducting prospective and multicenter validation studies with expanding study participants. Moreover, advanced imaging scans and ICG-15 retention to estimate PHLF might be taken into further consideration to improve the diagnostic value.

By comprehensively integrating five essential preoperative serum laboratory biochemistries (T-Bil, PLT, PA, AST, PT) and sFLR with different clinical significance comprehensively indicating the compensate liver function and the percentage of remain liver after hepatectomy, a novel nomogram was generated for individualized predicting ISGLS grade B/C PHLF in HBV-HCC patients. The results of internal and external validations demonstrated that this nomogram had good predicative performance. Prospective clinical application of this nomogram proposed an accurate judgment of non-occurrence of ISGLS grade B/C PHLF. It potentially provides an alternative tool for determining HBV-HCC patients with low risk of ISGLS grade B/C PHLF are appropriate candidates for hepatectomy.