Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor. The incidence of HCC is being increased over the last decades across the world (1). It was estimated that 782,000 new HCC cases and 745,000 deaths related to HCC occurred worldwide during 2012 (2). HCC is the third leading cause of death from cancer. A major complication of HCC is acute upper gastrointestinal bleeding (AUGIB) due to variceal bleeding or peptic ulcer (3). Both complications are related to the concomitant presence of liver cirrhosis as the major risk factor for HCC (4). The actual incidence of patients with HCC who present with variceal bleeding ranges from 1% to 13% (3,5,6). However, there are no established guidelines for the treatment of AUGIB in patients with HCC. Recently, the AASLD guidance statement suggests that the prevention and treatment of acute variceal bleeding in patients with HCC should follow the same principles as those without HCC (7). Furthermore, the prognosis of HCC patients with AUGIB remains unclear. Traditional prognosis scores for AUGIB have been prospectively evaluated in patients with non-variceal bleeding (8), but do not adequately predict the mortality risk in patients with liver cirrhosis or HCC (9).
Neutrophil to lymphocyte ratio (NLR) is a simple marker of inflammation that has been linked with the prognosis of gastrointestinal malignancy and other cancers such as non-small cell lung cancer (10-14). Recently, our meta-analysis indicated that NLR should be a major prognostic factor for HCC (15). Additionally, albumin-bilirubin (ALBI) score is a convenient model to assess the severity of liver dysfunction in patients with HCC (16) without the need of subjective variables, such as ascites and encephalopathy. Our recent study found that the prognostic performance of ALBI score was comparable with that of Child-Pugh score and model of end-stage liver disease (MELD) score for predicting the in-hospital mortality of AUGIB in liver cirrhosis without HCC (17).
Herein, we conducted a retrospective observational study to evaluate the prognostic performance of NLR and ALBI score in HCC patients with AUGIB.
This retrospective study was approved by the Medical Ethical Committee of the General Hospital of Shenyang Military Area. The approval number was No. k (2016) 18. The patient’s informed written consent was waived because of the retrospective nature. The eligibility criteria were as follows: (I) all patients were consecutively admitted to the General Hospital of Shenyang Military Area between January 2012 and June 2014; (II) patients had a diagnosis of liver cirrhosis and HCC based on the history of chronic liver diseases, clinical manifestations, laboratory tests, and imaging tests (liver histology was required, if uncertain); and (III) patients had a diagnosis of AUGIB based on the occurrence of haematemesis and melena within 5 days before hospital admissions or positive occult blood on the stool at the first routine test after admissions. Source of AUGIB was not restricted, because not all patients underwent endoscopic examinations at their admissions. The endoscopic examination is dependent upon the patients’ conditions, recommendations from physicians, and considerations from patients and their relatives. Some patients did not perform the endoscopic examination due to severe conditions. Some family members refused the endoscopic examinations due to advanced stage of HCC. The primary endpoint was the in-hospital mortality.
Data were reviewed regarding demographic profiles, causes of liver diseases, severity of bleeding, vital signs of hospitalized patients, routine laboratory data, treatment options of AUGIB (endoscopic ligation or sclerotherapy, vasoactive drug, and/or surgery, etc.), previous treatment options of HCC, in-hospital death, and causes of death from the electronic medical charts and calculated NLR, platelet to lymphocyte ratio (PLR), ALBI score, Child-Pugh score, and MELD score. Another investigator checked the data accuracy.
The scores were calculated as follows: NLR = ratio of neutrophil to lymphocyte (18).
ALBI score = [log10 bilirubin (µmol/L) ×0.66] + [albumin (g/L) × (−0.085)] (19).
PLR = ratio of platelet to lymphocyte (20).
Child-Pugh score was calculated based on the severity of hepatic encephalopathy, grade of ascites, total bilirubin, albumin, and INR (21).
MELD score =9.57× ln[creatinine (µmol/L) ×0.01] + 3.78× ln[bilirubin (µmol/L) ×0.05] + 11.2× ln(INR) +0.643 (22).
We performed the statistical analyses in the SPSS software version 17.0 and MedCalc software version 18.104.22.168. Continuous and categorical data were expressed as the mean ± standard deviation (SD) in combination with the median with minimum and maximum and the frequency (percentage), respectively. The discriminative capacities of the NLR, PLR, ALBI score, Child-Pugh score, and MELD score for the in-hospital mortality were calculated by the receiving operator characteristics curve analyses and expressed as the areas under the receiving operator characteristics curves (AUC) with 95% confidence intervals (CIs). A best cut-off value was selected as the sum of sensitivity and specificity was maximal. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), and negative predictive value (NPV) with 95% CIs were also calculated. Subgroup analyses were performed in patients with only hepatitis B virus-related HCC, in those treated with endoscopic therapy for AUGIB, and in those with and without infection. Due to the retrospective nature of our study, infection was arbitrarily identified based on the use of antibiotics. P<0.05 was considered statistically significant.
A total of 191 HCC patients with AUGIB were included. The patient characteristics were shown in Table 1. A majority of patients were male (84.82%) and had hepatitis B virus infection (58.63%). Before admissions for AUGIB, 125 (65.45%) patients were on conservative treatment alone, 54 (28.27%) underwent interventional therapy alone, 8 (4.2%) underwent surgery alone, 2 (1.04%) underwent a combination of interventional therapy and surgery, 1 (0.52%) underwent sorafenib alone, and 1 (0.52%) underwent a combination of interventional therapy and sorafenib for the treatment of HCC. At our admissions, 135 (70.68%) patients were treated with somatostatin or octreotide, 91 (47.64%) received blood transfusion, and 58 (30.37%) underwent endoscopic therapy for the treatment of AUGIB. Additionally, 81 patients received antibiotics during their hospitalizations, who formed a group of infected subjects.
The in-hospital mortality was 10.47% (20/191). The diagnostic performances of the different scores were summarized in Table 2. The AUC of NLR for the in-hospital mortality was not significantly different from that of PLR (P=0.1425), Child-Pugh score (P=0.3810), MELD score (P=0.3230), or ALBI score (P=0.4938). The AUC of ALBI score for the in-hospital mortality was not significantly different from that of Child-Pugh score (P=0.5673) or MELD score (P=0.5520). The AUC of ALBI was superior to that of PLR (P=0.0126).
The in-hospital mortality in patients with only hepatitis B virus related HCC was 11.61% (13/112). The diagnostic performances of the different scores were summarized in Table 2. The AUC of NLR for the in-hospital mortality was not significantly different from that of PLR (P=0.2593), Child-Pugh score (P=0.2502), MELD score (P=0.1053), or ALBI score (P=0.5401). The AUC of ALBI score for the in-hospital mortality was not significantly different from that of PLR (P=0.0706), Child-Pugh score (P=0.2369), or MELD score (P=0.1776).
The in-hospital mortality in patients treated with endoscopic therapy for AUGIB was 3.4% (2/58). The diagnostic performances of the different scores were summarized in Table 2. The AUC of NLR for the in-hospital mortality was not significantly different from that of PLR (P=0.0678), MELD score (P=0.3213), or ALBI score (P=0.2365). The AUC of NLR was superior to that of Child-Pugh score (P=0.0002). The AUC of ALBI score for the in-hospital mortality was not significantly different from that of PLR (P=0.5497), Child-Pugh score (P=0.7791), or MELD score (P=0.3264).
The in-hospital mortality in patients without infection was 7.27% (8/110). The diagnostic performances of the different scores were summarized in Table 2. The AUC of NLR for the in-hospital mortality was not significantly different from that of PLR (P=0.7491), MELD score (P=0.0820), ALBI score (P=0.1238), or Child-Pugh score (P=0.2454). The AUC of ALBI score for the in-hospital mortality was not significantly different from that of PLR (P=0.0685), Child-Pugh score (P=0.9116), or MELD score (P=0.4814).
The in-hospital mortality in patients with infection was 14.81% (12/81). The diagnostic performances of the different scores were summarized in Table 2. The AUC of NLR for the in-hospital mortality was not significantly different from that of PLR (P=0.0876), MELD score (P=0.8082), ALBI score (P=0.4268), or Child-Pugh score (P=0.8738). The AUC of ALBI score for the in-hospital mortality was not significantly different from that of PLR (P=0.1126), Child-Pugh score (P=0.5237), or MELD score (P=0.7013).
Various scoring systems of HCC have been proposed all over the world, such as Okuda stage firstly proposed in 1985 (23), BCLC stage firstly proposed in 1999 (24), the sixth edition of TNM stage that was jointly launched by the AACIF of Anti-Cancer in 2003 (25), and Japan Integrated Staging score (26), etc. However, there is no consensus regarding which system is the most suitable for evaluating the prognosis of HCC patients.
Liver cirrhosis underlies HCC in approximately 80%-90% of cases worldwide (27). AUGIB is one of the most common complications and leading causes of death of liver cirrhosis and HCC. A multi-center case-control study has shown that patients with variceal bleeding and HCC have worse outcomes than those with variceal bleeding without HCC (28). Secondary prophylaxis offers the survival benefit for HCC patients. Therefore, we should pay more attention to the prevention and treatment of HCC patients with esophageal variceal bleeding. However, there is no consensus about the treatment of HCC with esophageal variceal bleeding (7). At the same time, the prognostic scoring system of HCC with AUGIB is still lacking.
Child-Pugh and MELD scores are important prognostic models for the assessment of liver cirrhosis complicating AUGIB. Our previous study found that the discriminative ability was not significantly different between the two scoring systems (29) and that the prognostic performance of the ALBI score was comparable with that of the Child-Pugh and MELD scores for the in-hospital mortality of AUGIB in liver cirrhosis without HCC (17).
In the present study, the target population has the following features: (I) all patients had a diagnosis of liver cirrhosis and HCC; (II) all patients presented with the clinical suspicion of AUGIB; (III) not all patients underwent endoscopic examinations to identify the sources of bleeding, partially because some family members refused the endoscopic examinations due to advanced stage of HCC.
To our knowledge, the present study is the first to explore the prognostic performance of NLR, ALBI, and PLR scores for the assessment of in-hospital mortality of HCC with AUGIB. The prognostic performance of NLR and ALBI score might be comparable to that of classical prognostic models in such patients.
Considering that endoscopic therapy is a mainstay treatment option for AUGIB in HCC patients, we performed a subgroup analysis of patients treated with endoscopic therapy for AUGIB and demonstrated that NLR score had an excellent prognostic performance (AUC =0.959). Certainly, we had to acknowledge only a small sample size and a very low proportion of patients who died during their hospitalizations in this subgroup. Therefore, the subgroup results should be further validated.
White blood cell and neutrophil reflect the underlying infection or stress related leukocytosis. However, since pancytopenia is common in cirrhosis, NLR should be more appropriate to reflect the underlying leukocytosis and possible infection. Thus, we performed two subgroup analyses according to the infection status. We found that NLR could significantly predict the in-hospital death of HCC patients with infection, but not that of HCC patients without infection. Notably, the absolute AUC of NLR is very close to that of Child-Pugh score and larger than that of MELD score in the subgroup analysis of infection alone. By comparison, after excluding infection, the absolute AUC of ALBI score is larger than that of Child-Pugh score, but smaller than that of MELD score. This might be because ALBI score should be more appropriate to reflect the underlying nutritional status and decompensated liver function, but not infection.
Additional limitations included (I) the long-term follow-up outcomes were lacking, (II) a substantial proportion of patients did not undergo the endoscopic examinations to disclose the source of AUGIB, and (III) the definition of infection is arbitrary.
In conclusion, patients with HCC and AUGIB have a high risk of in-hospital mortality, and NLR and ALBI score appear as promising predictive scores for adverse outcomes. Future studies should prospectively evaluate these scores, potentially in conjunction with other biomarkers, to improve the prognostication in clinical practice, because the combination of different scores (e.g., MELD score plus NLR) or the addition of other biomarkers (e.g., lactate) might further improve the predictive power of NLR or ALBI score in this setting (30).
Fundling: This study was partially supported by the grants from the Natural Science Foundation of Liaoning Province (no. 2015020409) and China Postdoctoral Science Foundation (2015M582886) for Dr. X Qi.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: This retrospective study was approved by the Medical Ethical Committee of the General Hospital of Shenyang Military Area. The approval number was No. k (2016) 18. The patient’s informed written consent was waived because of the retrospective nature.
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Cite this article as: Peng Z, He Z, Guo X, Tacke F, Yang SS, Sugawara Y, Han T, Deng H, Wang R, Han D, Song T, Mancuso A, Romeiro FG, Qi X. Neutrophil to lymphocyte ratio and albumin-bilirubin score for predicting the in-hospital mortality of hepatocellular carcinoma with acute upper gastrointestinal bleeding. AME Med J 2017;2:169.