Neutrophil-lymphocyte ratio, albumin-alkaline phosphatase ratio, and bilirubin predict outcomes in hepatectomy hepatolithiasis patients

Abstract

BACKGROUND

Hepatolithiasis is a common disease whose key treatment modality is hepatectomy. However, postoperative complications are common and can adversely affect the therapeutic outcomes. The analysis of clinical data is essential to prevent a poor prognosis following hepatectomy.

AIM

To determine the prognostic value of the neutrophil-to-lymphocyte ratio (NLR), albumin/alkaline phosphatase ratio (ALB/ALP), and total bilirubin (TBIL) levels in hepatolithiasis hepatectomy.

METHODS

We retrospectively studied 135 patients with hepatolithiasis who underwent hepatectomy between March 2021 and August 2023. The patients were stratified into good and poor prognosis groups. We compared the general data and peripheral blood levels of NLR, ALB/ALP, and TBIL. Multivariate logistic regression was used to identify factors influencing poor prognosis, and the predictive value of these biomarkers was assessed using receiver operating characteristic (ROC) curve analysis.

RESULTS

Of 135 patients, 41 had poor prognosis. Comparative analysis revealed this group had significantly higher proportions of patients with an American Society of Anesthesiologists (ASA) score ≥ grade II, intraoperative blood transfusion, and a history of hepatobiliary surgery. These patients also had a lower anatomical hepatectomy rate and significantly greater intraoperative blood loss (P < 0.05). Biochemically, the poor prognosis group exhibited an elevated NLR and TBIL levels, along with a significantly reduced ALB/ALP (P < 0.05). Multivariate analysis confirmed ASA ≥ II, anatomical hepatectomy, blood loss, transfusion, and surgical history as independent factors for poor prognosis. Furthermore, ROC curve analysis established that NLR, ALB/ALP, and TBIL levels were valuable predictive biomarkers for post-hepatectomy prognosis in patients with hepatolithiasis, demonstrating high efficacy when combined.

CONCLUSION

The independent risk factors for poor post-hepatectomy prognosis were identified as ASA ≥ II, non-anatomical resection, high blood loss, transfusion, and prior surgery; NLR, ALB/ALP, and TBIL also held predictive value.

Key Words: Hepatolithiasis; Neutrophils; Albumin; Total bilirubin; Poor prognosis

Core Tip: This study primarily compared the clinical data of patients with hepatolithiasis with good and poor prognoses following hepatectomy, analyzed the factors influencing poor prognosis, and identified scientific and reasonable indicators of poor prognosis. The novelty of this study lies in evaluating the peripheral blood levels of neutrophil-to-lymphocyte ratio (NLR), albumin/alkaline phosphatase ratio (ALB/ALP), and total bilirubin (TBIL) levels after hepatectomy and analyzing their individual and combined predictive values for poor prognosis. Notably, the NLR, ALB/ALP, and TBIL levels demonstrated predictive value for poor prognosis following hepatectomy, with high combined predictive efficiency.

INTRODUCTION

Intrahepatic bile duct stones are highly prevalent biliary diseases in East Asia, particularly in China, Japan, and South Korea. Their occurrence is related to multiple factors, including environmental factors, dietary habits, and genetic background[1]. The main feature of this disease is the formation of stones in the intrahepatic bile ducts caused by abnormal bile components (e.g., cholesterol supersaturation and calcium bilirubin precipitation), biliary tract infection, bile stasis, and abnormal biliary anatomy. These lead to changes in the physical and chemical properties of bile and eventually contribute to the formation of stones. Stones can cause biliary obstruction, secondary cholangitis, liver abscess, biliary cirrhosis, and even serious complications, such as cholangiocarcinoma[2]. The resection of a diseased bile duct can significantly reduce the possibility of stone recurrence, prevent bile duct stenosis and infection, and reduce the risk of bile duct carcinogenesis. However, post-hepatectomy complications, including bile leakage, bleeding, and infection, must be closely monitored and treated in a timely manner[3]. Timely intervention and treatment can improve the patient’s prognosis and quality of life. Therefore, it is crucial to explore the factors that influence the poor prognosis following hepatectomy in patients with hepatolithiasis. The neutrophil-to-lymphocyte ratio (NLR) is an important systemic inflammatory marker derived from routine blood examination. It was calculated by dividing the absolute value of neutrophils by the absolute value of lymphocytes. The albumin/alkaline phosphatase ratio (ALB/ALP) is an interesting prognostic predictor in the study of liver diseases. It is calculated by dividing the serum albumin level by alkaline phosphatase (ALP) level, where total bilirubin (TBIL) is the sum of all forms of bilirubin in the blood, including indirect bilirubin (IBIL) (unconjugated bilirubin) and direct bilirubin (conjugated bilirubin). It is the core index to evaluate the function of the hepatobiliary system and hemolytic status. The NLR, ALB/ALP, and TBIL levels are associated with the inflammatory response, liver function, and prognosis in patients undergoing hepatectomy[4,5]. Therefore, this study aimed to investigate the prognostic value of the NLR, ALB/ALP, and TBIL levels in patients admitted to our hospital with hepatolithiasis following hepatectomy to provide a basis for postoperative prognosis assessment.

MATERIALS AND METHODS

Study subjects

We retrospectively analyzed data from 135 patients with hepatolithiasis who underwent hepatectomy between March 2021 and August 2023. Patients were classified into good and poor prognosis groups according to their postoperative prognosis. The inclusion criteria were as follows: (1) Meeting the diagnostic criteria for intrahepatic bile duct stones[6]; (2) Successful completion of open hepatectomy; (3) Absence of preoperative infectious diseases; and (4) Availability of complete clinical data. The exclusion criteria were as follows: (1) Presence of other malignant tumors, such as cholangiocarcinoma; (2) Preoperative infectious diseases or abnormal coagulation function; (3) Mental disorders or communication disorders; and (4) Autoimmune diseases. This study was approved by the Hospital’s Medical Ethics Committee.

Clinical data

The clinical data of all patients were collected, including sex, age, body mass index (BMI), disease course, American Society of Anesthesiologists (ASA) score, hepatectomy status, hepatectomy location, intraoperative blood loss, intraoperative blood transfusion, history of hepatobiliary surgery, and complications. Fasting venous blood (5 mL) was collected within 24 hours of surgery and centrifuged at 3000 rpm for 15 minutes, from which the supernatant was collected. Biochemical parameters including serum albumin (ALB), ALP, TBIL, IBIL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were analyzed using an automatic biochemical analyzer. The absolute values of neutrophils and lymphocytes were determined using a Mindray BC-5390 fully automatic blood analyzer, and the NLR was calculated.

Surgical treatment

Combined intravenous and inhalational anesthesia was administered. The patients were placed in the supine position, disinfected, and draped. A reverse L-shaped incision was made in the right upper abdomen to explore the adhesions between the liver and the diaphragm. Under ultrasonic guidance, a precut line was drawn using an electric knife. The perihepatic tough band was separated using the clamp method, the liver parenchyma was cut off, and the catheter was clamped. The bile duct stones were removed using forceps. The bile duct was examined by choledochoscopy, sutured, and closed. The common bile duct was exposed, the sphincter of Oddi was explored, and the common bile duct was sutured. A drainage tube was placed and the abdomen was closed.

Prognostic effect evaluation criteria

The curative effect was evaluated as follows[7]: The outcomes were considered markedly effective if clinical symptoms disappeared and imaging confirmed that most of the calculi were removed, effective if the clinical symptoms improved and imaging showed a reduction in calculi, and ineffective if no significant changes were observed in the clinical symptoms or imaging findings. Patients with markedly effective or effective outcomes were classified into the good treatment group (n = 94), whereas those with ineffective outcomes were classified into the poor treatment group (n = 41).

Statistical analysis

Statistical analyses were performed using SPSS v.20.0. Continuous variables were expressed as the mean ± SD and compared using t-tests, whereas categorical data were presented as n (%) and analyzed using the χ² test. Multivariate logistic regression was used to identify predictors of poor prognosis after hepatectomy, and receiver operating characteristic (ROC) curves were used to evaluate the predictive value of the preoperative NLR, ALB/ALP, and TBIL levels. Statistical significance was set at P < 0.05.

RESULTS

A summary of the data in each group is provided in Table 1. No significant differences were observed in terms of sex, age, BMI, disease duration, proportion of partial liver resection, liver resection site, or comorbidities (hypertension, hyperlipidemia, and diabetes) between the two groups (P > 0.05). Compared to the good prognosis group, the poor prognosis group had a higher proportion of patients with an ASA score ≥ grade II, intraoperative blood transfusion, and a history of hepatobiliary surgery, as well as a lower proportion of patients with anatomical hepatectomy. The amount of bleeding was significantly greater in the poor prognosis group than in the good prognosis group (P < 0.001).

Table 1 Comparison of general data between the groups, n (%).

Items	Good prognosis group (n = 94)	Poor prognosis group (n = 41)	t/χ2	P value
Sex			0.027	0.870
Male	45 (47.87)	19 (46.34)
Female	49 (52.13)	22 (53.66)
Age (years), mean ± SD	44.53 ± 5.27	44.83 ± 5.45	0.298	0.766
BMI (kg/m2), mean ± SD	21.46 ± 2.22	21.74 ± 2.16	0.678	0.499
Course of disease (years), mean ± SD	2.45 ± 0.50	2.39 ± 0.49	0.607	0.545
ASA score grade II	4 (4.26)	7 (17.07)	6.267	0.012
Partial hepatectomy	48 (51.06)	20 (48.78)	0.060	0.807
Anatomical hepatectomy	56 (59.57)	17 (41.46)	3.771	0.005
Location of hepatectomy			0.279	0.870
Bilateral hepatic lobectomy	29 (30.85)	13 (31.71)
Left hepatic lobectomy	31 (32.98)	15 (36.59)
Right hepatic lobectomy	34 (36.17)	13 (31.71)
Intraoperative blood loss (mL), mean ± SD	297.66 ± 26.74	386.93 ± 38.72	15.467	< 0.001
Intraoperative blood infusion	10 (10.64)	13 (31.71)	8.966	0.003
Hepatobiliary surgery history			4.844	0.028
Yes	38 (40.43)	25 (60.98)
No	56 (59.57)	16 (39.02)
Comorbidity
Hypertension	18 (19.15)	9 (21.95)	0.140	0.708
Hyperlipidemia	15 (15.96)	7 (17.07)	0.026	0.872
Diabetes	13 (13.83)	6 (14.63)	0.015	0.902

BMI: Body mass index; ASA: American Society of Anesthesiologists.

The unconditional logistic regression analysis of the factors influencing poor prognosis is summarized in Table 2. Multivariate unconditional logistic regression analysis was conducted using the incidence of poor prognosis after hepatectomy as the dependent variable and ASA score ≥ grade II, anatomical hepatectomy, intraoperative blood loss, intraoperative blood transfusion, and history of hepatobiliary surgery as independent variables. Notably, an ASA score ≥ grade II, anatomical hepatectomy, intraoperative blood loss, intraoperative blood transfusion, and history of hepatobiliary surgery were all identified as factors influencing poor prognosis following hepatectomy.

Table 2 Unconditional logistic regression analysis of factors influencing poor prognosis following hepatectomy.

Items	β	SE	Wald	Sig	Exp (β)
ASA score grade II	1.585	0.740	4.580	0.032	4.877 (1.143-20.816)
Anatomical hepatectomy	1.295	0.459	7.967	0.005	3.651 (1.486-8.974)
Intraoperative blood loss	0.095	0.019	24.067	< 0.001	1.099 (1.158-1.142)
Intraoperative blood infusion	2.135	0.588	13.189	< 0.001	8.458 (2.672-26.774)
Hepatobiliary surgery history	1.313	0.458	8.227	0.004	3.717 (1.515-9.115)

ASA: American Society of Anesthesiologists; SE: Standard error.

A comparison of the biochemical indices of the hepatobiliary function is provided in Table 3. The NLR and TBIL levels were significantly higher in the poor prognosis group than those in the good prognosis group, whereas ALB/ALP was significantly lower (P < 0.001). No significant differences were observed in the serum IBIL, AST, or ALT levels between the two groups (P > 0.05).

Table 3 Comparison of biochemical indices of hepatobiliary function between the groups.

Groups	NLR	ALB/ALP	TBIL (μmol/L)	IBIL (μmol/L)	AST (U/L)	ALT (U/L)
Good prognosis group (n = 94)	3.45 ± 0.83	0.35 ± 0.07	10.25 ± 2.33	19.84 ± 5.49	10.37 ± 2.46	21.65 ± 5.82
Poor prognosis group (n = 41)	4.65 ± 0.94	0.26 ± 0.05	12.85 ± 2.77	19.33 ± 5.30	9.64 ± 3.27	20.86 ± 5.52
t	7.412	7.504	5.623	0.501	1.428	0.736
P value	< 0.001	< 0.001	< 0.001	0.617	0.156	0.463

NLR: Neutrophil-to-lymphocyte ratio; ALB: Albumin; ALP: Alkaline phosphatase; TBIL: Total bilirubin; IBIL: Indirect bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

The ROC curve analysis results are summarized in Table 4 and Figure 1. The area under the curve (AUC) values for NLR, ALB/ALP, and TBIL levels in predicting poor prognosis of patients following hepatectomy were 0.834, 0.855, and 0.769, respectively. The combined diagnostic AUC value of the three variables was 0.939, with a sensitivity of 80.54% and a specificity of 93.58%.

Figure 1 Receiver operating characteristic curves of peripheral blood neutrophil-to-lymphocyte ratio, albumin/alkaline phosphatase, and total bilirubin levels for evaluating poor prognosis following hepatectomy. NLR: Neutrophil-to-lymphocyte ratio; ALB: Albumin; ALP: Alkaline phosphatase; TBIL: Total bilirubin.

Table 4 Predictive value of peripheral blood neutrophil-to-lymphocyte ratio, albumin/alkaline phosphatase ratio, and total bilirubin levels for poor prognosis following hepatectomy.

Indicator	Cut-off value	AUC	95%CI	P value	Sensitivity (%)	Specificity (%)
NLR	4.10	0.834	0.756-0.912	< 0.001	75.62	79.81
ALB/ALP	0.31	0.855	0.792-0.918	< 0.001	82.86	76.59
TBIL	12.33	0.769	0.680-0.858	< 0.001	61.00	84.00
Combined detection	-	0.939	0.893-0.985	< 0.001	80.54	93.58

NLR: Neutrophil-to-lymphocyte ratio; ALB: Albumin; ALP: Alkaline phosphatase; TBIL: Total bilirubin; AUC: Area under the curve.

DISCUSSION

Hepatolithiasis is a common condition that occurs after hepatobiliary surgery and is characterized by the formation of stones in the intrahepatic bile ducts. Its incidence is affected by several factors[8]. Hepatolithiasis is primarily managed using non-resection approaches; however, these methods often fail to achieve complete stone removal, resulting in high recurrence rates[9,10]. Hepatectomy enables the complete removal of stones by excising the affected liver segments or lobes, as well as the diseased bile duct tissue. However, hepatectomy is a relatively major surgical procedure with certain risks, including considerable trauma, slow postoperative recovery, and a higher risk of postoperative complications, all of which may contribute to poor prognosis and affect therapeutic outcomes[11,12]. Among the 135 patients with hepatolithiasis in this study, 41 (30.37%) had poor postoperative prognosis, indicating a substantial risk. Therefore, early risk assessment following hepatectomy and corresponding intervention measures are essential.

In this study, the poor prognosis group exhibited a higher proportion of patients with an ASA score ≥ grade II. The ASA score is used to evaluate the general condition of patients before anesthesia, predict the risk of surgery, and guide anesthesia management. A score of ASA ≥ grade II indicates systemic disease. Surgery and anesthesia may also affect patient health. An ASA score ≥ grade II was identified as a risk factor for poor prognosis following hepatectomy in our study. However, some studies have suggested that the ASA score is not absolute, and patient conditions may improve with treatment and time[13]. Patients with a history of hepatobiliary surgery were overrepresented in the poor prognosis group, suggesting that this factor increases the risk of adverse outcomes. This may be because abdominal adhesions are more likely to occur after hepatobiliary surgery, resulting in increased anatomical difficulty during reoperation. Distinguishing the normal anatomical layers during reoperation is difficult, increasing the risk of injury to the surrounding organs and blood vessels. Patients with a history of hepatobiliary surgery are more likely to present with multiple complex stones[14]. In this study, patients in the poor prognosis group experienced significantly greater intraoperative blood loss and had a higher rate of intraoperative blood transfusion, indicating that substantial bleeding not only compromises intraoperative hemodynamic stability, but may also contribute to postoperative anemia, delayed recovery, and increased risk of poor prognosis. Furthermore, the proportion of patients who underwent anatomical hepatectomy was lower in the poor prognosis group, indicating that anatomical hepatectomy may be a protective factor against poor prognosis. Resection following the anatomical structure of the liver allows for a more precise removal of diseased tissue while preserving normal liver tissue, reducing intraoperative bleeding, and minimizing surgical risk[15,16].

Neutrophils are primary phagocytes in the immune system. An elevated NLR typically indicates a relative increase in neutrophils and a relative decrease in lymphocytes, potentially due to an enhanced inflammatory response or immunosuppressive state[17]. In tumors and cardiovascular diseases, an elevated NLR is associated with intensified inflammation and closely linked to poor prognosis[18]. Simultaneously, a decrease in lymphocyte levels may indicate impaired immune system function, which reduces the body’s ability to control inflammation and tumor progression. Therefore, a high NLR may indicate an increased risk of disease progression, specifically in patients with cancer, and high NLR values may be associated with poor survival and disease progression[19]. In this study, peripheral blood NLR was significantly higher in the poor prognosis group than in the good prognosis group, which is consistent with the results of previous studies. This implied a more pronounced inflammatory response and an elevated risk of complications in the poor prognosis group.

ALB is the most abundant plasma protein synthesized by the liver, which maintains plasma osmotic pressure and transports various substances, including hormones, drugs, and nutrients. Reduced serum ALB levels typically indicate impaired liver synthesis, likely due to liver or other systemic diseases[20].

ALP is expressed in the liver, bone, intestine, and other tissues, and plays a role in phosphate metabolism, particularly in the biliary system. In conditions such as gallstones or other biliary obstructive diseases, the ALP levels are typically elevated owing to impaired bile excretion, resulting in increased enzyme activity[21]. ALB/ALP is commonly used to assess liver function and disease status. In this study, a lower ALB/ALP was observed in patients with poor prognosis, likely due to decreased ALB levels and increased ALP levels, indicating impaired liver synthesis and biliary obstruction. In this study, no significant difference was observed in the classic enzymatic indicators, ALT and AST, which reflect hepatocyte injury, between the two groups. This suggests that in patients with intrahepatic bile duct stones, the degree of hepatocyte injury alone is not the key to differentiating the postoperative prognosis. In contrast, the NLR serves as a marker of systemic inflammatory responses. ALB/ALP comprehensively reflects the liver’s synthetic function and the state of biliary obstruction, whereas TBIL directly reflects the liver’s excretory and metabolic capabilities. These three indicators comprehensively capture the complex pathophysiological states that affect postoperative recovery, including systemic inflammation, nutritional status, biliary pressure, and liver function reserves. Therefore, they showed a stronger prognostic predictive value than traditional liver enzymes.

The liver is the main metabolic and detoxification organ of the body. Elevated TBIL levels are an important clinical indicator of hepatolithiasis and reflect the decreased ability of the liver to process bilirubin. Elevated TBIL levels in the peripheral blood of patients with hepatolithiasis indicate impaired liver function, decreased metabolic and detoxification functions, and inhibition of protein synthesis, including coagulation factors and other important plasma proteins, leading to postoperative coagulation dysfunction and an increased risk of intraoperative bleeding and thrombosis[22]. Systemic inflammatory responses and bile duct infection following hepatectomy in patients with hepatolithiasis increase the risk of postoperative infection, including surgical site and systemic infections. A sustained inflammatory state may lead to postoperative liver failure and affect other organ systems, including the cardiovascular, respiratory, and renal systems, thereby increasing the overall risk of postoperative complications[23,24]. In our study, the TBIL levels were significantly higher in the poor prognosis group than in the good prognosis group, indicating that elevated TBIL levels are a contributing factor to poor outcomes following hepatectomy. Moreover, the liver and metabolic functions of patients are seriously affected after hepatectomy. ROC analysis showed that the peripheral blood levels of NLR, ALB/ALP, and TBIL exhibited a certain predictive value for poor prognosis, with a higher combined prediction efficiency. Despite being a single-center retrospective study with a limited sample size, these findings suggest that the postoperative measurement of peripheral blood NLR, ALB/ALP, and TBIL levels may be useful for predicting poor prognosis in patients with hepatolithiasis following hepatectomy. In particular, the number of cases in the poor prognosis group was relatively small, which may have affected the stability of the multivariate analysis and prediction model. In the future, multicenter prospective studies with larger sample sizes are needed to verify these findings.

CONCLUSION

Taken together, ASA ≥ II, anatomical hepatectomy, intraoperative blood loss, intraoperative blood transfusion, and history of hepatobiliary surgery were identified as factors associated with poor prognosis following hepatectomy. Furthermore, peripheral blood NLR, ALB/ALP, and TBIL levels demonstrated a predictive value for poor prognosis following hepatectomy. Nevertheless, this study has some limitations. The relatively small sample size may have introduced a statistical bias, and the findings may not be directly generalizable to clinical practice. Moreover, we did not analyze patients with different pathological types or surgical procedures, limiting our ability to assess the factors influencing postoperative infections across these subgroups.