Hepatolithiasis Group Research Articles

Evaluating prognostic value of biliary stone in intrahepatic cholangiocarcinoma by propensity score matching analysis.

Background: To explore biliary tract stone (BTS) as prognostic factors of intrahepatic cholangiocarcinoma (ICC). Methods: Clinical data of 985 ICC patients were classified into no BTS group and BTS group-subgrouped into hepatolithiasis (HL) and non-hepatolithiasis (NHL) group. Propensity score matching was utilized to mitigate baseline characteristics. Preoperative peripheral inflammation parameters (PPIP) were further investigated. Immunostaining of CD3, CD4, CD8, CD68, PD1 and PD-L1 were conducted. Results: Overall survival (OS) of patients without BTS surpassed BTS group (P = 0.040) while no difference of time to recurrence (TTR) was observed (P = 0.146). HL group had shorter OS and TTR than HL-matched group (P < 0.001 and P = 0.017, respectively) and survival time of NHL group differed not with NHL-matched group (P > 0.05). PPIP like neutrophils to lymphocytes ratio (NLR), platelet to lymphocyte ratio (PLR) and systemic immune inflammation (SII) of HL group exceeded no BTS group or NHL group (all P < 0.05). Associations of PPIP and tumorous immunocytes differed vastly among HL group, NHL group and no BTS group. Tumorous CD4+/CD3+ ratio and PD1+/CD3+ ratio of HL group surpassed those in no BTS group (P = 0.036 and P < 0.001, respectively) and NHL group (P = 0.015 and 0.002, respectively). Para-tumorous CD68+ macrophages exceeded that in tumor samples of HL group (P < 0.001). No difference of CD8+/CD3+ lymphocyte ratio and PD-L1 rank were detected. Conclusions: Hepatolithiasis, rather than extra-hepatic biliary stone, is a poor prognostic indicator of ICC. Immunotherapy is promising in treating HL-related ICC.

A210 HEPATOLITHIASIS IS A FREQUENT AND PROGNOSTIC FINDING IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS

AimsIntrahepatic biliary stones (hepatolithiasis) are not well characterised in patients with primary sclerosing cholangitis (PSC).MethodsChart reviews were conducted on 302 patients with a histologic or radiographic diagnosis of PSC followed at the Toronto Centre for Liver Disease. Radiographic data were collected for patients between the years 2008–2018. Depending on frequency of testing, magnetic resonance imaging (MRI) and ultrasound (US) data was reviewed every 3–5 years. We assessed factors associated with hepatolithiasis based on sex, race, age and phenotype of PSC and inflammatory bowel disease (IBD). Qualitative radiographic findings on image report review, episodes of cholangitis, endoscopic retrograde cholangiopancreatography (ERCP) and occurrence of cholangiocarcinoma (CCA), death and transplant were documented. Data are reported with median and IQR and analysed using χ 2 and Mann-Whitney U tests.Results302 patients were reviewed. The median time to follow-up, defined as from date of diagnosis to last clinic visit or to transplantation date, was 98 months (IQR = 87). The mean age at diagnosis was 38 (SD = 15.1) years; 54% of patients were male. A total of 224 patients had IBD (74%). Of the 302 patients, 80 patients (26%) had evidence of hepatolithiasis on US or MRI. Patients with hepatolithiasis were more likely to be younger (37.4 vs 39.1, p = 0.025), male (65% vs. 50%, p = 0.021), and have large duct disease (99% vs. 88%, p = 0.004). Imaging report review revealed patients with hepatolithiasis were more likely to have intrahepatic biliary thickening (76% vs. 45%, p < 0.001), extrahepatic biliary thickening (69% vs. 50%, p = 0.003), focal biliary dilation (96% vs. 78%, p < 0.001) and disease characterised by more reported strictures on qualitative imaging report review (89% vs 69%, p < 0.001). Concomitant presence of cholelithiasis was greater in the hepatolithiasis vs. the non-hepatolithiasis group (45% vs. 19%, p < 0.001). There was no significant difference in the prevalence of hepatic or portal venous thrombosis in both groups. Patients with hepatolithiasis more likely have experienced acute ascending cholangitis (50% vs. 20%, p < 0.001) and need for ERCP (50% vs. 35%, p = 0.020). CCA was numerically higher in the hepatolithiasis group (8.75% vs. 4%, p = 0.1). Patients with hepatolithiasis received transplant more frequently (26.3% vs 12.2%, p < 0.001) with no significant difference in mortality.ConclusionsHepatolithiasis is common in PSC and associated with an increased clinical and radiologic disease burden. Funding AgenciesNone

The imbalance of biliary microflora in hepatolithiasis

BackgroundThe imbalance of microbial flora is thought to be associated with many diseases. However, the characteristics of the biliary microflora and its relation to in hepatolithiasis are unknown. MethodsThis study included 40 patients with hepatolithiasis and 10 control patients. Bile samples were taken during hepatectomy surgeries and 16S rRNA sequencing was performed. The sequencing results were analyzed by operational taxonomic unit (OTU) clustering, species annotation and abundance analyses, sample complexity analyses, diversity analyses, and environmental factor correlation analyses. ResultsThere were significant differences in bile microflora between the hepatolithiasis group and the control group. We found that the abundance of microflora in the bile of patients with hepatolithiasis was relatively high (52.4% versus 40.2% and 42.1% versus 29.6%). The diversity of microflora in the bile of patients with hepatolithiasis decreased significantly (Shannon (P = 0.004), Observed species (P = 0.001), PD-whole-tree (P = 0.001)). These differences are mainly associated with Enterococcus(P＜0.001), Enterobacter(P = 0.003). In addition, we found that there were intra-group differences in hepatolithiasis, but the differences in the hepatolithiasis group were generally smaller than the differences in the non-hepatolithiasis group. ConclusionThere is an imbalance of microflora in the bile duct of patients with hepatolithiasis. The imbalance of biliary flora may be associated with hepatolithiasis pathogenesis.

Relationship between Pst-I polymorphism of mucin 4 gene and primary hepatolithiasis

Objective To investigate the relationship between Pst-I polymorphism of mucin 4 gene and primary hepatolithiasis in the Chinese population. Methods Venous blood of 96 healthy controls and 56 patients with hepatolithiasis were collected, and DNA was extracted. Polymerase chain reaction combined with restriction enzyme (PCR-RFLP) digestion was used to detect Pst-I polymorphism of mucin 4 gene in the two groups. The genotype and gene frequency between the two groups were then compared. Results The genotype frequencies of GC, GT, TT in the control and the hepatolithiasis groups were 21.3%, 12.7%, 55.6% and 53.2%, 41.2%, 19.8%, respectively. The alleles C and T gene frequencies in the control and the hepatolithiasis groups were 21.5%, 72.7% and 66.3%, 30.2%, respectively. There were significant differences in Pst-I polymorphism of mucin 4 genotype frequency and gene frequency between the two groups. Conclusion The data showed Pst-I polymorphism of mucin 4 gene was associated with primary hepatolithiasis in Chinese patients. Key words: Mucin 4; Pst-I polymorphism; Hepatolithiasis

Expression and Clinical Pathological Significance of miR-200a in Concurrent Cholangiocarcinoma Associated with Hepatolithiasis.

BackgroundApproximately 2–10% of the patients with hepatolithiasis may develop cholangiocarcinoma (CCA). Despite recent advances in the treatment of cancers, the 5-year survival rate for CCA patients currently remains poor, primarily due to early local invasion and distant metastasis of the cancer. This study aimed to investigate miR-200a expression in combined hepatolithiasis and CCA as well as its correlation with the clinical features of CCA.Material/MethodsmiR-200a expression in combined hepatolithiasis and CCA was detected by real-time reverse transcription PCR (qRT-PCR). Its correlation with the clinicopathology of CCA was analyzed by t-tests. The effect of miR-200a on the proliferation CCA cells was determined by MTT assay. The effect of miR-200a on the invasive ability of CCA cells was assessed by Boyden chamber test.ResultsThe expression level of MiR-200a in patients with combined hepatolithiasis and CCA was significantly decreased compared with patients with only hepatolithiasis (P<0.01). Furthermore, miR-200a expression in hepatic duct cancer RBE cells was substantially reduced compared with hepatolithiasis group (P<0.01). Correlation analysis showed that abnormal expression of miR-200a was only associated with the differentiation degree and metastasis of CCA. MiR-200a transfection significantly inhibited the proliferation and invasion of REB cells (P<0.01).ConclusionsMiR-200a may suppress the proliferative and invasive ability of REB cells. The reduced miR-200a expression might be correlated with the development and progression of CCA.

Expression and Significance of COX-2 and Ki-67 in Hepatolithiasis with Bile Duct Carcinoma.

BackgroundAs an induced enzyme, COX-2 expression is elevated under stimuli from inflammatory mediator or growth factor product. Ki-67, a cell cycle-related proliferative antigen, reflects the tissue proliferative activity. This study analyzed the expressional profile of cyclooxygenase-2 (COX-2) and Ki-67 in hepatolithiasis and bile duct carcinoma tissues, in an attempt to provide evidence for diagnosis and prognosis prediction of disease.Material/MethodsA cohort of tissue samples from hepatolithiasis with bile duct carcinoma (N=47) patients were analyzed using immunohistochemical (IHC) staining method for the expression of COX-2 and Ki-67, in parallel with hepatolithiasis (N=44) and normal bile duct tissues (N=30). The relationship between expression pattern of COX-2 and Ki-67 and pathological conditions was also analyzed, in addition to the correlation with positive expression in hepatolithiasis samples.ResultsThe positive expression rate of COX-2 and Ki-67 in bile duct carcinoma was 76.6% and 80.9%, respectively, and was significantly higher than those in the hepatolithiasis group, which was also higher than the control group. Expression of both COX-2 and Ki-67 is closely related to TNM staging, lymph node metastasis, and differentiation stage. They were also correlated with the mortality rate of patients.ConclusionsBoth COX-2 and Ki-67 are abundantly expressed in hepatolithiasis and bile duct carcinoma tissues and may play an important role in the disease occurrence, progression, and metastasis.

Hepatolithiasis-associated cholangiocarcinoma

Few papers focused on association between hepatolithiasis (HL) and cholangiocarcinoma (CCC) in Western countries. The aims of this paper are to describe the clinical presentation, treatment, and postoperative outcomes of CCC with HL in a cohort of Western patients and to compare the surgical outcomes of these patients with patients with CCC without HL. Among 161 patients with HL from five Italian tertiary hepato-biliary centers, 23 (14.3%) patients with concomitant CCC were analyzed. The results of surgery in these patients were compared with patients with CCC without HL. The 60.9% of patients with HL received the diagnosis of CCC intra- or postoperatively, with a resectability rate of 91.3%. The postoperative morbidity was 61.6%. The 1- and 3-year survival rates were 78.6% and 21.0%, respectively. The recurrence rate was 44.4% and the 3-year disease-free survival rates were 18.8%. The comparison with patients with CCC without HL showed a higher resectability rate (p = 0.02) and a higher frequency of earlier stage (p = 0.04) in CCC with HL. Biliary leakage was more frequent in CCC with HL group (p = 0.01) compared to CCC without HL group. We found no differences in overall and disease-free survival between the two groups. Patients with HL and CCC showed a high resectability rate but a higher morbidity. Nevertheless, overall and disease-free survival of patients with CCC and HL showed no differences compared to those of patients with CCC without HL. Also in Western countries, HL needs a careful management for the possible presence of CCC.

Osteopontin Expression in Patients with Hepatolith.

To investigate the role of osteopontin (OPN) in the formation of hepatolith, we have immunohistochemically studied the involvement of OPN in hepatolithiasis in the intrahepatic bile ducts and the intramural and extramural glands, and in stones. In our hospital, 17 hepatic resections for hepatolithiasis were carried out from June 2006 to October 2009. Immunohistochemistry was performed on 17 liver specimens with hepatolith and on 24 control liver specimens without hepatolith. We compared the osetopontin expression in the epithelia of the intrahepatic bile ducts and peribiliary glands or periglandular macrophages. Staining for OPN was positive in the cytoplasm of the epithelial cells of stone-containing intrahepatic bile ducts and the intramural and extramural glands, and in stones. But there were no significant differences between the hepatolithiasis group and the control group for the OPN immunoreactivity of the luminal surface of the epithelial cells of the intrahepatic bile ducts and intramural and extramural glands. The stone-containing intrahepatic bile ducts were infiltrated by macrophages that showed intense staining for OPN. The core and matrix of the stones showed OPN immunoreactivity. The degree of OPN from the cytoplasm of the epithelia of the intrahepatic bile ducts and peribiliary glands or periglandular macrophages was different between hepatolithiasis and control groups. Our result suggests that the OPN from the intrahepatic bile ducts and peribiliary glands plays a role in the formation of intrahepatic stone.

Biliary manometry in patients with cholelithiasis

Objective To explore the relationship between cholelithiasis and the function of sphincter of Oddi （SO）. Methods To identify the existence of calculi, choledochoscopy was performed in patients 6 weeks after exploration of the common bile duct （CBD） and T tube drainage, in which 71 were patients with stones in gall bladder, CBD or intra-hepatic bile duct, and 9 with trauma of pancreas or liver. Biliary manometry was performed after choledochoscopy, and an additional manometry was applied after calculus removal if calculi were detected. The indices measured included SO basal pressure （ SOBP）, amplitude of SO contractions （ SOCA）, frequency of SO contractions （SOF） and CBD pressure （CBDP）. The patients with cholelithiasis were classified into cholecystolithiasis group, choledocholithiasis group, and hepatolithiasis group according to the position of calculi. Patients with trauma were assigned as the control group. Results All variables in 50 patients with choledocholithiasis were similar before and after the procedure. The variables in patients with cholecystolithiasis and choledocholithiasis had no difference from those of the control （ P 〉 0.05）. The SOBP and SOCA of patients in hepatolithiasis group were lower than those of the control group （ P 〈 0. 05）, while no difference in SOF was detected （ P 〉 0. 05 ）. Conclusion The function of SO in patients with hepatolithiasis is abnormal （decrease in SOBP and SOCA）. Biliary manometry cannot be the reliable evidence for the existence of calculi in bile duct. Key words: Biliary calculi; Sphincter of Oddi; Manometry

Treatment of Non-Endemic Hepatolithiasis in a Western Country. The Role of Hepatic Resection

The aim of this study was to assess the safety and the efficacy of hepatic resective surgery in the treatment of single lobe hepatolithiasis. Retrospective analysis and comparison between hepatic resections in patients with hepatolithiasis (hepatolithiasis group [HG]) and liver masses (control group [CG]). Seventeen consecutive Caucasian patients with single lobe hepatolithiasis (HG) and 30 patients with liver masses without chronic liver disease and previous chemotherapy (CG), were operated during the 5-year period 2000-2005, inclusive. Major hepatic resections including 4 right hepatectomies, 10 left hepatectomies, and 3 left lateral sectionectomy in HG, and 12 right hepatectomies, 3 extended right hepatectomy, 5 left hepatectomies, 4 left lateral sectionectomy, 5 bisegmentectomy, and 1 mesohepatectomy in CG. The main outcome measures were: type and length of surgical procedures, intra- and postoperative blood losses and transfusions (packed red blood cells [PRBC] and fresh frozen plasma [FFP]), intra- and postoperative course and complications (within 30 days of the operation), length of hospitalisation, histopathology, and recurrence of hepatolithiasis. Mean operation time was 6.21 +/- 2.38 h in HG versus 7.10 +/- 2.21 h in CG (P = 0.33). Mean intra-operative blood loss in CG was higher than in HG (1010 +/- 550 ml versus 560 +/- 459 ml; P = 0.035). The other variables considered in the two groups were not statistically different. Intra-operative transfusion were 0.50 +/- 0.85 units in HG versus 1.35 +/- 2.25 units of PRBC in CG (P = 0.06), and 0.66 +/- 1.34 units in HG versus 0.68 +/- 1.20 units of FFP in CG (P = 0.44), respectively. No cases of death were registered. Postoperative complications occurred in 12 patients (25.5%) - 5 cases (10.6%) in HG and 7 cases (14.8%) in CG (P = 0.18). Mean postoperative transfusions were 0.47 +/- 1.24 units in HG versus 1.10 +/- 1.18 units of PRBC in CG (P = 0.35), and 0.65 +/- 1.40 units in HG versus 0.46 +/- 0.82 units of FFP in CG (P = 0.25), respectively. Difference in median hospitalisation was not statistically significant (14 +/- 10 days versus 12 +/- 9 days; P = 0.28). Histopathology showed cholangiocarcinoma in 2 cases (11.7%). During the follow-up period (range, 5-127 months; mean, 50.4 +/- 41.9 months), 1 patient had lithiasis recurrence and 1 patient died for the co-existing cholangiocarcinoma. Hepatic resection is the treatment of choice in patients with single lobe hepatolithiasis. An early indication for surgery may reduce the mortality/morbidity rates of hepatic resection for hepatolithiasis.

Progesterone receptor in patients with hepatolithiasis.

Altered gallbladder motility by progesterone has been recognized as an important factor in the development of gallstones. There are two types of hepatolithiasis, that occurs de novo in the intrahepatic ducts with an intact gallbladder (primary hepatolithiasis) and that which originates in the gallbladder and the stones migrate into the intrahepatic duct (secondary hepatolithiasis). This study was designed to evaluate the possible role of the progesterone receptor of gallbladder in the pathogenesis of hepatolithiasis. Eighty-four patients with hepatolithiasis (34 patients had primary hepatolithiasis and the other 50 patients secondary hepatolithiasis) were included. Paraffin-embedded specimens of gallbladder were processed to have an immunohistochemical staining for progesterone receptor. Positivity for progesterone receptor of gallbladder specimens was noted in eight patients (23.5%) with primary hepatolithiasis and in 23 patients (46%) with secondary hepatolithiasis. There is significant difference (P = 0.031) in positive rate for progesterone receptor between the primary hepatolithiasis and secondary hepatolithiasis groups. In conclusion, many more patients (46%) with secondary hepatolithiasis show positivity for progesterone receptor of gallbladder specimens than patients with primary hepatolithiasis (23.5%) (P = 0.031). This phenomenon is intriguing and should be of further evaluation and elucidated.

Impact of concomitant hepatolithiasis on patients with peripheral cholangiocarcinoma.

The association of hepatolithiasis (HL) and peripheral cholangiocarcinoma (PCC) has been well recognized. However, information concerning the impact of hepatolithiasis on patients with peripheral cholangiocarcinoma is sparse and therefore difficult to assess. A total of 162 consecutive patients with histologically proven peripheral cholangiocarcinoma were treated surgically at Chang-Gung Memorial Hospital between 1977 and 1994. Among them, 106 patients (65.4%) had associated hepatolithiasis (PCC + HL group), and the remaining 56 patients (34.6%) did not (the PCC - HL group). The differences in demographics, symptomatology, laboratory data, tumor staging, histological pattern, resectability rates, and long-term survival of these two groups were compared. The male to female ratio was 0.7 in the PCC + HL group and 1.3 in the PCC - HL group (P < 0.05). Two thirds of the PCC + HL group presented with acute cholangitis, whereas two thirds of the PCC - HL group presented with hepatomegaly (P < 0.01). Those patients in the PCC + HL group were in earlier stages than those of the PCC - HL group at the time of the initial diagnosis (P < 0.05). The resectability rate for the PCC + HL group was 31.1% and for the PCC - HL group, 26.8% (P > 0.05). Surgical mortality rates were 3.8% in the PCC + HL group and 3.6% in the PCC - HL group (P > 0.05). The morbidity rate was much higher in the PCC + HL group than in the PCC - HL group (P < 0.01). The 1-, 3-, and 5-year survival rates were 35.5%, 20.5%, and 16.5% in the PCC + HL group and 27.2%, 8.8%, and 7.8% in the PCC - HL group (P > 0.05). In conclusion, the presence of hepatolithiasis hindered an exact diagnosis of underlying cholangiocarcinoma preoperatively, precipitated biliary sepsis which affected resectability, and increased postoperative morbidity. Hepatolithiasis per se, however, did not influence the long-term survival.

A study of CEA, CA 19-9 and CA 125 in biliary tract diseases.

Sixty-six patients were classified into three groups; control group A was (n = 24), group B those with hepatolithiasis (n = 24) and group C those with the bile duct carcinoma (n = 18). All patients had accepted operation and the patients bile and serum were send for determination with radioimmuno assay. The positive rate of serum CEA were 4.17%, 37.5% and 66.67% for the control, hepatolithiasis and bile duct carcinoma groups respectively. The positive rate of serum CA 19-9 were 8.33%, 25% and 61.11% for the control, hepatolithiasis and bile duct carcinoma respectively. The positive rate of serum CA 125 were 5%, 0% and 31.25% for control, hepatolithiasis and bile duct carcinoma groups respectively. The sensitivity level of serum CEA, CA 19-9 and CA 125 for the bile duct carcinoma group was 66.67%, 61.11% and 31.25% respectively. The diagnostic accuracy for bile duct carcinoma with regard to bile CEA was 94.44% but the accuracy ratio was only 45.24%. The bile concentration of CA 19-9 level of more than 1200 ng/ml were 75% and 61.11% for the hepatolithiasis and bile duct carcinoma group and none in control group. The bile concentration of CA 125 more than 200 ng/ml was 43.75% in the bile duct carcinoma and none in control or hepatolithiasis group. Finally, the concentration of CA 19-9 will be effected not only by tumor itself but also by severe infection in the hepatolithiasis patients. The sensitivity of CA 125 was low but accuracy was high for the diagnosis of the bile duct carcinoma.