A retrospective study on the correlation between lipoprotein and occult pancreaticobiliary reflux complicated with gallbladder cholesterolosis

doi:10.21203/rs.3.rs-3224585/v1

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A retrospective study on the correlation between lipoprotein and occult pancreaticobiliary reflux complicated with gallbladder cholesterolosis

https://doi.org/10.21203/rs.3.rs-3224585/v1

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Objective

It is found in clinical practice that many patients with gallbladder stone also have occult pancreaticobiliary reflux (OPBR) and cholesterol deposition on the gallbladder wall. However, there is no study reporting their correlations. The purpose of the present study was to explore the correlation between lipid metabolism and occult pancreaticobiliary reflux (OPBR) with complicated gallbladder cholesterolosis by analyzing lipoproteins in the venous blood.

Methods

According to the inclusion and exclusion criteria, 407 patients who received gallbladder surgery at the Center for Gallbladder Diseases of Shanghai East Hospital between December 2020 and November 2021 were included, of whom 55 patients were consistent with the diagnosis of OPBR. The baseline information and preoperative lipid levels of all patients were collected to analyze the correlation between lipid metabolism and OPBR with complicated gallbladder cholesterolosis.

Results

Serum lipoprotein associated phospholipase (LP-PL)-A2 and low-density lipoprotein cholesterol (LDL-C) in the Study group were significantly higher than those in the Control group ( p = 0.0023; p = 0.0344). LP-PL-A2 showed a moderately strong correlation with OPBR (R = 0.446, p = 0.002), and LDL-C showed a weak correlation (R = 0.277, p = 0.042). Multivariate Logistics regression analysis showed that LP-PL-A2 (OR: 1.014, 95%CI: 1.001 ~ 1.026, p = 0.029) was an independent risk factor. The AUC value of ROC curve for LP-PL-A diagnosis of OPBR with cholesterolosis was 0.7592, with 95%CI: 0.616 ~ 0.902, specificity: 96.15% and sensitivity: 57.14% (p = 0.0025).

Conclusion

LP-PL-A2 is an independent risk factor for OPBR complicated with cholesterolosis, showing a certain clinical value for the diagnosis of OPBR with cholesterolosis. Inhibiting the expression and secretion of LP-PL-A2 by using drugs to inhibit inflammatory cells or reduce the activity of LP-PL-A2 should be a viable option to block the development and progression of cholesterolosis in OPBR patients so as to protect the gallbladder function and slow down the progression of gallbladder diseases.

Health sciences/Gastroenterology/Gastrointestinal diseases/Biliary tract disease/Bile duct disease/Cholestasis

Health sciences/Gastroenterology/Gastrointestinal diseases/Biliary tract disease/Gall bladder disease/Cholelithiasis

occult pancreaticobiliary reflux

gallbladder cholesterolosis

lipoprotein associated phospholipase A2

low-density lipoprotein cholesterol (LDL-C)

Pancreaticobiliary maljunction (PBM) is a congenital anomaly defined as a union of the pancreatic and biliary duct that is located outside the duodenal wall, which is regarded as a high-risk factor for cholangiocarcinoma, especially that with congenital biliary duct dilation ^[1–4]. Research in recent years has revealed that PBR is also present in patients with normal pancreaticobiliary junction, which is defined as occult pancreaticobiliary reflux (OPBR) ^[5–8]. Current research on PBR is mainly focused on the anatomic features of the biliary duct system, believing that PBR is attributed to pancreatin reflux into the biliary system due to the higher hydrostatic pressure in the pancreatic duct than that in the common bile duct; the pancreatin in the pancreatic fluid is activated to produce protease and toxic substances such as phospholipase A2, which hydrolyze lecithin to lysophosphatidylcholine, leading to epithelial hyperplasia, metaplasia and dysplasia of the gallbladder mucosa and other pathophysiological changes ^{[1, 6, 9, 18]}. In addition, the abnormally activated pancreatin also impacts lipid metabolism in the gallbladder bile. Analysis of the lipid composition revealed that free fatty acid (FFA) and triglyceride (TG) were elevated in the gallbladder bile of OPBR patients ^[10–11].

Co-existence of the above two pathological changes in the gallbladder of 0PBR patients breaks the balance between the bile components, and the gallbladder mucosal epithelium undergoing constant hyperplasia and metaplasia would engulf the cholesterol abnormally secreted from the bile, forming cholesterol deposition on the gallbladder wall, which is known as cholesterolosis in clinical practice (Fig. 1). The pathogenesis of cholesterolosis is similar to atherosclerotic plaque formation in coronary heart disease (CHD). In addition, inflammation can also stimulate macrophages to engulf lipids, thus accelerating lipid deposition on the vascular epithelium ^[12–14]. Although cholesterolosis on the gallbladder wall is often observed in clinical practice and many clinicians have also realized that cholesterolosis would change homeostasis of the gallbladder, affecting the gallbladder function, breaking balance of the bile composition and promoting stone formation, it is unclear about the relationship between double injury from OPBR plus gallbladder cholesterolosis and lipid metabolism. Whether serum lipid metabolism parameters can reflect this relationship needs to be clarified.

The aim of the present study was to determine whether there was a correlation between cholesterolosis and abnormal lipid metabolism in OPBR patients by analyzing lipoproteins in the venous blood.

Subjects

According to the inclusion and exclusion criteria, 407 patients who underwent gallbladder surgery at the Center for Gallbladder Diseases (Shanghai, China) between December 2020 and November 2021 were initially enrolled in this study, of whom 55 patients were consistent with the diagnosis of OPBR and included for final analysis. The study protocol was approved by the Medical and Life Science Ethics Committee of the Shanghai East Hospital affiliated to Tongji University (2019tjdx46). Informed consent was obtained from all participants and/or their legal guardians for this study. all experiments were performed in accordance with relevant guidelines and regulations. OPBR was diagnosed in patients whose serum amylase was within the normal range but amylase level in the bile was higher than the serum level ^{[5, 15–18, 25]}. The inclusion criteria were patients 1) who were scheduled to undergo selective gallbladder surgery after admission; 2) who were clinically diagnosed as having gallbladder stone, polyps and adenomyosis whether symptomatic or symptomatic; 3) with a clinical diagnosis of common bile duct stone or cholangitis but whose serum amylase was within the normal range; and 4) whose amylase concentration in the bile extracted during the operation was higher than the serum amylase level. The exclusion criteria were patients 1) whose preoperative amylase was higher than the upper limit of the normal value; 2) who had acute/chronic pancreatitis, hyperamyloemia and hyperthyroidism; and 3) who were suspected as having gallbladder and biliary malignant tumors.

Methods

Clinical data (including sex, age, body mass index (BMI), abdominal pain, diabetes, hypertension, cardiovascular disease, gallbladder stone, gallbladder polyps and adenomyosis) were collected. Laboratory parameters included total cholesterol (TCH), TG, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small and dense low-density lipoprotein cholesterol (sdLDL-C), lipoprotein a (Lp-a), lipoprotein associated phospholipase-A2 (LP-PL-A2), Lp-E, and FFA, in addition to inflammatory indexes such as white blood cell count (WBC), neutrophil count (NC) and lymphocyte count (LC).

5 ml bile was drawn from the gallbladder during operation in each patient, which was detected for the amylase level at the laboratory of our hospital by colorimetry using Roche Cobas c702Biochemical Analyzer and attached reagents. OPBR was diagnosed when the bile amylase level was higher than the serum amylase level. Patients with cholesterol deposition in the gallbladder as confirmed by the surgeon during operation or postoperative pathology were included in the study group, and those without were included in the study group.

Statistical analysis

Data obtained were analyzed by SPSS 25.0. Comparison of measurement data of normal distribution between groups was performed by independent sample t test, and comparison of measurement data of abnormal distribution was performed by Mann-Whitney U test. All data are expressed as the mean ± standard deviation (‾X ± S). Comparison of counting data between groups was performed by Pearson test or Fisher test. Counting data are expressed as [n (%)]. Rank correlation was used for correlation analysis and the results are expressed as Spearman correlation coefficient. Univariate and multivariate analyses were performed on risk factors of complicating gallbladder cholesterolosis in PBR using Logistics regression. Values of p < 0.05 were considered statistically significant.

Basic clinical features of OPBR patients

The mean age of the 55 included patients was 56.76±10.959 years, including 24 patients in the Study group (10 male and 14 female with a mean age of 56.38±12.125 years), and 31 in the Control group (13 male and 18 female with a mean age of 57.06±10.162 years). The incidence of gallbladder adenomyosis in the Study group was lower than that in the Control group (0% vs. 22.6%, p=0.037). There were no significant differences in age, sex, BMI, hypertension history, diabetes history, cardiovascular disease history, and the presence or absence of gallbladder stone and polyps (all p>0.05) (Table 1). In 407 patients, with OPBR patients as the case group and non-OPBR as the control group, there was a statistically significant difference in the incidence of gallbladder cholesterolosis between the two groups (p< 0.0001)(Figure 2).

Table 1: Comparison of clinical baseline features between the Study and Control groups
Item	Study group	Control group	Z/X2/t value	P value
Age (yr,`X ± S)	56.38±12.125	57.06±10.162	-0.178	0.858
Sex (F/M)	14/10	18/13	<0.0001	0.983
BMI (kg/m2,`X ± S)	22.64±5.839	23.29±3.514	-0.322	0.748
Abdominal pain [n (%)]	18(75%)	22(71%)	0.111	0.739
Hypertension [n (%)]	4(16.7%)	10(32.3%)	1.733	0.188
Diabetes [n (%)]	3(12.5%)	3(9.7%)	<0.0001	1
Cardiovascular disease [n (%)]	1(4.2%)	4(12.9%)	0.416	0.519
Gallbladder stone [n (%)]	23(95.8%)	26(83.9%)	0.951	0.329
Polyp [n (%)]	3(12.5%)	6(19.4%)	0.099	0.754
Adenomyosis [n (%)]	0(0%)	7(22.6%)	4.343	0.037

Differences in preoperative serum parameters between the two groups

Differences in preoperative serum parameters were compared between the two groups, showing that serum LP=PL-A2 and LDL-C levels in the Study group were significantly higher than those in the Control group (551.62±128.693 vs. 430.54±127.314, p=0.0023; 3.271±0.795 vs. 2.821±0.724 p=0.0344), while WBC and NC were significantly lower (4.6±0.979 vs. 2.667±0.845, p=0.0033; 2.667±0.845 vs. 3.848±1.34, p=0.0014). There was no significant difference in the other serum parameters (all p>0.05) (Table 2, Figure 3).

Table 2: Comparison of preoperative serum parameters and inflammatory indexes between the Study and Control groups
Item	Study group	Control group	Z/X2/t value	P value
TCHOl (mmol/L,`X ± S)	4.862±0.959	4.524±0.841	-1.377	0.175
TG (mmol/L`,X ± S)	1.533±0.742	1.655±1.121	-0.261	0.794
HDL-C (mmol/L,`X ± S）	1.319±0.379	1.369±0.428	0.451	0.654
LDL-C (mmol/L,`X ± S)	3.271±0.795	2.821±0.724	-2.173	0.034
sdLDL-C (mmol/L ,`X ± S)	0.782±0.381	0.651±0.37	-1.384	0.166
Lp (a) (nmol/L,`X ± S)	54.13±62.089	64.3±77.15	-0.609	0.542
LP-PL-A2 (U/L,`X ± S)	551.62±128.693	430.54±127.314	-3.226	0.002
FFA (mmol/L,`X ± S)	0.573±0.218	0.565±0.317	-0.098	0.922
WBC (10^9/L,`X ± S )	4.6±0.979	5.83±1.542	3.111	0.003
NC (10^9/L,`X ± S )	2.667±0.845	3.848±1.34	3.428	0.001
LC (10^9/L,`X ± S )	1.416±0.469	1.481±0.407	0.499	0.62

Correlation between clinical demographic parameters and gallbladder cholesterolosis

Spearman correlation analysis showed that LP-PL-A2 was moderately correlated with PBR complicated with gallbladder cholesterolosis (R=0.446, p=0.002); LDL-C showed a weak positive correlation (R=0.277, p=0.042); and WBC and NC showed a moderate correlation (R=-0.437, p=0.003 and R=-0.489, p=0.001) (Table 3).

Table 3: Correlation between clinical demographic parameters and gallbladder cholesterolosis
Item	R value	P value
Age	0.024	0.86
Sex (M/F)	-0.003	0.984
BMI	0.046	0.751
Abdominal pain	0.045	0.745
Hypertension	-0.178	0.195
Diabetes	0.045	0.745
Cardiovascular disease	-0.151	0.272
Gallbladder stone	0.19	0.164
Gallbladder polyp	-0.092	0.505
Cholesterolosis	-0.336	0.012
TCHOL (mmol/L)	0.143	0.301
TG (mmol/L)	0.036	0.797
HDL-C (mmol/L)	-0.043	0.757
LDL-C (mmol/L)	0.277	0.042
sdLDL-C (mmol/L)	0.19	0.168
Lp (a) (nmol/L)	-0.084	0.547
LP-PL-A2(U/L)	0.446	0.002
FFA (mmol/L)	0.002	0.986
WBC (10^9/L,`X ± S )	-0.437	0.003
NC (10^9/L,`X ± S )	-0.489	0.001
LC (10^9/L,`X ± S )	-0.021	0.893

Analysis of risk factors related to PBR complicated with cholesterolosis

Univariate Logistics regression analysis showed that LP-PL-A2 (OR: 1.008, 95%CI: 1.002~1.013, p=0.006), LDL-C (OR: 2.225, 95%CI: 1.037~4.772, p=0.04), WBC (OR: 0.457, 95%CI: 0.255~0.819, p=0.008) and NC (OR: 0.337, 95%CI: 0.158~0.716, p=0.005) were risk factors for OPBR complicated with cholesterolosis. Multivariate Logistics regression analysis showed that LP-PL-A2 (OR: 1.014, 95%CI: 1.001~1.026, p=0.029) was the independent risk factor for OPBR complicated with cholesterolosis (Table 4).

Table 4: Univariate and multivariate Logistic regression analyses of OPBR complicated with cholesterolosis
Variate	Univariate analysis		Multivariate analysis
Variate	OR（95%CI）	P value	OR (95%CI)	P value
Age	0.994(0.947-1.044)	0.815	-	-
Sex (M/F)	1.011(0.343-2.979)	0.984	-	-
BMI (kg/m2)	0.97(0.859-1.095)	0.621	-	-
Abdominal pain	1.227(0.367-4.100)	0.739	-	-
Hypertension	0.42(0.113-1.559)	0.195	-	-
Diabetes	1.333(0.244-7.279)	0.74	-	-
Cardiovascular disease	0.293(0.031-2.815)	0.288	-	-
Gallbladder stone	4.423(0.481-40.689)	0.189	-	-
Gallbladder polyp	0.595(0.132-2.674)	0.499	-	-
LDL-C (mmol/L)	2.225(1.037-4.772)	0.04	1.318(0.26-6.675)	0.738
LP-PL-A2 (U/L)	1.008(1.002-1.013)	0.006	1.014(1.001-1.026)	0.029
WBC (10^9/L)	0.457(0.255-0.819)	0.008	1.249(0.163-9.576)	0.83
NC (10^9/L )	0.337(0.158-0.716)	0.005	0.139(0.009-2.072)	0.152
LC (10^9/L)	0.699(0.175-2.791)	0.612	-	-

The capability pf LP-PL-A2 in predicting OPBR complicated with cholesterolosis

The receiver operating characteristic curve (ROC) of the subjects was used to evaluate the diagnostic value of LP-PL-A2 on OPBR complicated with cholesterolosis, showing that the maximum Youden index was 0.5329, the optimal diagnostic threshold was 598.5U/L, the area under the curve (AUC) value was 0.7592 (95%CI：0.616~0.9020), the specificity was 96.15%, and the sensitivity was 57.14% (p=0.0025) (Figure 4), indicating that when serum LP-PL-A2 level was ≧598.5U/L, the risk of OPBR complicated with cholesterolosis increased in a concentration-dependent manner.

To the best of our knowledge, no study has reported the pathological status of OPBR complicated with cholesterolosis. For the first time, we explored the correlation between serum lipid metabolism and cholesterolosis in OPBR patients. The results showed that LP-PL-A2 and Lp A-II in venous blood were to some extent correlated with OPBR complicated with cholesterolosis, of which LP-PL-A2 showed a moderately positive correlation with OPBR complicated with cholesterolosis. Multivariate Logistics regression analysis showed that LP-PL-A2 was an independent risk factor of OPBR complicated with cholesterolosis and had a certain value for the diagnosis of OPBR complicated with cholesterolosis. LP-PL-A2 has become an important early warning index in cardiovascular disease and ischemic stroke. LP-PL-A2, along with LDL-C and Lp (b), is an indicator of lipid metabolism in all these diseases, which has been reported in the literature ^[19–21], and is consistent with the finding in our study. All these findings indicate a correlation between lipid metabolism and OPBR complicated with cholesterolosis.

The impact of OPBR on lipid metabolism of the human body begins from the very beginning of PBR, when the sphincter of Oddi (SO) dysfunction loses its control of bile and pancreatic fluid secretion, inducing the occurrence of PBR ^{[15, 22–23]} and resulting in digestive fluid composition deficits due to outflow impatency of the common passage, which affects the digestion and absorption of exogeneous fat substances and causes damage to the balance of lipid metabolism of the body. In addition, when the refluxed pancreatin is abnormally activated by the bile, the activate amylase such as LP-PL-A2 not only causes damage to the gallbladder mucosal epithelium causing repeated inflammatory reactions but degrades lecithin in the bile mixture thus damaging bile homeostasis, and toxic substances produced during the process is also cytotoxic ^{[22,24,26−27]}. Both damage to the gallbladder mucosal epithelium and that to bile homeostasis would affect lipid metabolism of the body. When OPBR is complicated with cholesterolosis, the movement pattern and composition of the bile undergo further change, which causes repeated occurrences of cholecystitis, and at the same time vessels at the inflammatory sites would gather macrophages continuously, which promotes strong expression of LP-PL-A2 in macrophages. LP-PL-A2 can hydrolyze and oxidize lecithin to generate lysophosphatidylcholine and FFA ^[28–29], forming a positive feedback damage mode, which may promote chemicals to induce cancer transition from a local perspective ^[30–31], and from the holistic perspective may affect lipid metabolism of the body. LP-PL-A2 belongs to the family VII of the phospholipase A2 superfamily, which is mainly secreted by macrophages. When it is released to blood circulation, it participates in lipid metabolism by forming complexes with LDL-C and HDL-C ^[32–33]. The presence of OPBR and cholesterolosis damages the bile homeostasis and induces repeated local inflammatory reactions. Bile functional damage and LP-PL-A2 secreted by inflammatory cells can both damage lipid metabolism of the body.

Many studies have reported the high incidence of OPBR in patients with gallbladder cancer. Immunohistochemical assay of non-cancerous gallbladder mucosal epithelia in gallbladder cancer patients showed Codon 12 of K-ras gene and P53 gene mutations and strong expressions of mucin core protein 1(MUC1) and COX-2 gene, suggesting the potential mechanism of OPBR in causing cancerogenesis ^{[2, 34–36]}. OPBR is a high-risk factor of gallbladder cancer and cholangiocarcinoma. In addition, OPBR is also closely associated with benign diseases of the biliary duct system such as cholecystitis, gallbladder stone, common bile duct stone and cholangitis ^{[5–6, 27, 37, 38]}. Given the above understanding, early cholecystectomy is suggested in OPBR patients. However, there is no standardized therapeutic strategy for patients with OPBR complicated with cholesterolosis, and at present, the principle of treatment of such patients still follows that for OPBR. However, some asymptomatic patients or those in the early stage are often unwilling to undergo cholecystectomy. We strongly recommend that high risk patients who have strong objective consciousness should be intervened early to delay the occurrence and progression of cholesterolosis in OPBR for the sake of reducing the occurrence of gallbladder malignant diseases.

The data obtained in this study showed that the incidence of OPBR was about 13.514%. However, the relatively small sample size is the main limitation of this study. In addition, although our study revealed the correlation between lipid metabolism and gallbladder cholysterolosis in OPBR, more larger-sample and multi-center studies are required to explore the impact of OPBR complicated with cholesterolosis on the development and progression of gallbladder diseases. Finally, we did not detect the change of the lipid composition in the bile, nor did we simultaneously compare changes of lipids in the bile and venous blood, and further explore the correlation of such a change with gallbladder cholesterolosis.

In summary, for the first time we revealed the special pathological status of OPBR complicated with gallbladder cholesterolosis, finding that serum LP-PL-A2 had a positive correlation with this pathological status, which we suppose would affect the lipid metabolism of the human body. It is our recommendation that OPBR complicated with gallbladder cholesterolosis should be detected and treated early. Whether the development and progression of OPBR complicated with gallbladder cholesterolosis could be prevented or delayed by inhibiting LP-PL-A2 secretion or its activity needs to be further explored in future study.

Conflicts of interest

All authors declare no conflicts of interest.

Authors’ contributions: Cai Jingli, Zhang Honglei and Xiang Yukai: collecting the data, writing the manuscript, and reviewing the references; Zhang Honglei, Xiangyukai, Kong Xiangyu and Zhang Cheng: collecting the data and performing the experiments; Da Xuanbo, Qiu Chen and Wang Yubin: performing the experiments; Qiu Chen and Lv Beining: integrating the pictures and making the tables; Yang Yulong, Tian Fuzhou and Huhai: supervising the research and revising the manuscript.

A data availability statement

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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A retrospective study on the correlation between lipoprotein and occult pancreaticobiliary reflux complicated with gallbladder cholesterolosis

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