INTRODUCTION
Hepatolithiasis refers to primary stones above the confluence of the left and right hepatic ducts, and its main component is brown bile pigment stones. Hepatolithiasis is a disease with regional characteristics. The incidence of hepatolithiasis in Asia is higher than in Europe and America[1]. In recent years, the Japanese literature has reported an incidence of hepatolithiasis showing a downwards trend annually[2], but the outlook in China is still not optimistic, where the incidence in the population is 2%-25%[1], especially in the southwestern region.
Hepatolithiasis is characterized by concealed onset, long disease course, easy recurrence, and many serious complications; the two most serious complications are intrahepatic cholangiocarcinoma and liver cirrhosis. According to the literature, the incidence of intrahepatic cholangiocarcinoma in patients with hepatolithiasis is 1.3%-23.3%[2-6], and the incidence of liver cirrhosis in patients with hepatolithiasis is 3.7%-14.1%[3,7,8]. These two factors are the main causes of death in patients with hepatolithiasis. Therefore, early diagnosis of hepatolithiasis and appropriate treatment methods for intervention are helpful for reducing the incidence of complications, improving prognosis and improving the median survival time of patients[9-12]. At present, there is no exact explanation for the aetiology of hepatolithiasis. Studies at home and abroad suggest that it may be related to lifestyle, biliary bacterial infection[13-21], biliary parasite infection, biliary anatomical variation, gene mutation and abnormal gene expression and other factors[22-31].
SURGICAL TREATMENT OF HEPATOLITHIASIS
At present, the main treatment for hepatolithiasis is surgery, of which there are many methods. Each method has its own advantages and disadvantages. Depending on the characteristics of each case, a suitable surgical method is chosen to obtain the best treatment effect[32-44].
Partial hepatectomy
Hepatolithiasis generally shows a segmental distribution, so hepatectomy is a more effective means for the treatment of hepatolithiasis[45]. Since the first reported the success of partial hepatectomy in two patients with hepatolithiasis in 1956, partial hepatectomy has been widely used in the clinic and has achieved good curative effects. It is one of the main surgical methods for treating hepatolithiasis and can achieve the purpose of removing the focus, contact stricture and hepatolithiasis. At present, partial hepatectomy can be roughly divided into two types: Laparotomy and laparoscopic hepatectomy. Laparotomy for hepatectomy is a lengthy procedure, but the technology is mature, so it is the most widely practiced technique in the clinic[45].
In recent years, Li et al[46] conducted a single-center eight-year empirical study. Fifty-six patients with bilateral hepatolithiasis underwent hepatectomy combined with choledochoscopy for intrahepatic bile duct exploration and lithotripsy. The overall initial success rate was 85.7%, and the final clearance rate was 92.9%. Postoperative complications occurred in 15 patients (26.8%), 14 of whom were treated conservatively, and only 1 patient died of liver failure. Fifty-five patients were followed-up, among which 52 of them had stones removed completely during the first operation, and only 3 patients had residual stones. Among the 52 patients whose stones were removed, 7 (13.5%) experienced recurrence. The incidence of postoperative acute cholangitis was 10.9%. This study revealed that IHBDIL combined with hepatectomy is a safe and effective treatment for complex bilateral hepatolithiasis. However, this study involved a small number of samples and was based in a single center; thus, a larger sample size is needed to confirm the feasibility of this method.
Laparoscopic hepatectomy is a technique that has gradually developed in recent years and has been adopted by an increasing number of physicians because of its rapid recovery, relatively low degree of trauma, low degree of blood loss and low incidence of postoperative complications. Laparoscopic hepatectomy can be combined with laparoscopic ultrasound to monitor the intrahepatic condition in real time during an operation, which greatly improves the operation’s safety, accuracy and thoroughness[47,48].
For patients with intrahepatic and extrahepatic biliary obstruction, Yang et al[49] selected 26 patients with hepatolithiasis, including 25 patients with left hepatolithiasis and 1 patient with right hepatolithiasis. Among the 26 patients, 18 had abdominal pain with jaundice, and 8 had abdominal pain with fever. All 26 patients underwent laparoscopic hepatectomy combined with endoscopic papillary balloon dilation. The operations were successful; only 1 patient experienced bile leakage after the operation, and the hepatolithiasis of the 26 patients was removed without any other complications. Twenty-six patients were followed up for 12 months, and no obvious abnormalities in B-ultrasound or liver function were detected post-operation. This operation is safe and effective in treating patients with intrahepatic and extrahepatic biliary obstruction, but it is difficult and requires experienced surgeons.
Li et al[50] conducted a meta-analysis of open hepatectomy and laparoscopic hepatectomy (involving 1329 cases). The results revealed that intraoperative blood loss in the laparoscopic treatment group was significantly lower [weighted average difference (WMD): 61.56, 95% confidence interval (95%CI): 14.91-108.20, P = 0.01], the recovery of intestinal function was faster (WMD: 0.98, 95%CI: 0.47-1.48, P = 0.01), and the length of hospital stay was shorter (WMD: 3.32, 95%CI: 2.32-4.32, P < 0.00001). In addition, the analysis revealed that there was no significant difference in operation time (WMD: 21.49, 95%CI: 0.27-43.24, P = 0.05), residual stone rate [odds ratio (OR): 0.79, 95%CI: 0.50-1.25, P = 0.31] or stone recurrence rate (OR: 0.34, 95%CI: 0.11-1.08, P = 0.07) between the two groups. In addition, through subgroup analysis, the results of this study show that the effect of laparoscopy in the treatment of hepatolithiasis in the left lateral lobe and left side is satisfactory.
Liu et al[51] conducted a meta-analysis (involving 1352 patients). The results revealed that intraoperative blood loss was significantly lower in patients with hepatolithiasis in the laparoscopic group [standardized mean difference (SMD): -0.52; 95%CI: -0.93 to -0.1; I2 = 91%; P < 0.0001]; the incidence of postoperative complications was lower (OR: 0.52; 95%CI: -0.70 to 0.39;I2 = 0%; P < 0.0001); the recovery of intestinal function was faster (SMD: -1.66; 95%CI: -2.41 to 0.92; I2 = 91%; P < 0.0001); and the hospital stay was shorter (SMD: -0.89; 95%CI: -1.19 to 0.59; I2 = 83%; P < 0.00001). However, in terms of operation time, no significant difference was found between LH and OH (SMD: 0.22; 95%CI: -0.21 to 0.65; I2 = 92%; P = 0.31), and no significant difference was found in the initial residual stone rate (OR: 0.79; 95%CI: -1.25 to 0.50; I2 = 0%; P = 0.31) or stone recurrence rate (OR: 0.67; 95%CI: -1.27 to 0.35 ; I2 = 0%; P = 0.22).
Therefore, the safety and postoperative recovery speed of laparoscopic hepatectomy are better than those of open hepatectomy[52-55]. However, some studies have shown[56,57] that laparoscopic hepatectomy takes longer than open hepatectomy, which is contrary to the results of the previous two studies and may be related to the technical proficiency of surgeons.
Choledochojejunostomy
The main inducing factor of hepatolithiasis is bile duct stricture. Plentz and Malek[58] reported that an average of 24.3% of patients with hepatolithiasis in China also have bile duct stricture. If the bile duct stricture is not removed during operation, even if the stones are removed, there is a high possibility of recurrence because the bile flow velocity will change at the bile duct stricture, and an eddy current may form when the bile flows through this location. It can also stagnate here, providing conditions for the formation of stones. Therefore, the bile duct stricture must be removed during operation. From the invention of Y-shaped anastomosis, which was proposed by Roux in 1897, to the invention of choledochoduodenojejunostomy and Roux-en-Y anastomosis in recent years, this method has improved many times and has achieved good results in patients with hepatolithiasis with bile duct stricture. At present, the most used surgical methods to solve biliary stricture are choledochojejunal Roux-en-Y anastomosis and modified choledochojejunal loop anastomosis[59]. Laparotomy or laparoscopy can also be used.
In recent years, Ejaz et al[60] had modified this method and proposed transantral choledochojejunostomy. A retrospective analysis of 392 patients (70 patients in the improved group and 322 patients in the control group) revealed that there was no significant difference in hospital stay, intraoperative blood loss or incidence of postoperative complications between the two groups compared with traditional choledochojejunostomy (P > 0.05). The incidence of gastric emptying disturbance in the improved group significantly decreased [2 (2.9%) vs 32 (9.9%), P = 0.003], and the time interval of eating fluid postoperation significantly decreased [(64.7 ± 16.3) vs (76.1 ± 24.6) h, P = 0.041]. Gastaca et al[61] proposed the high choledochojejunostomy method. However, regardless of how the operation is improved, its role in treating hepatolithiasis should be "unobstructed drainage" rather than removing choledocholithiasis through choledochojejunostomy. The implementation of choledochojejunostomy can lead to many complications, such as reflux cholangitis[62], biliary infection, anastomotic stricture, and bile duct carcinogenesis[63]. The main causes of these complications are the loss of sphincter function and changes in the intestinal anatomical structure, so clinicians should fully understand the indications for choledochojejunostomy and not perform the operation blindly. For patients with hepatolithiasis, choledocholithiasis should be removed, and the bile duct stricture should be corrected as much as possible before choledochojejunostomy; otherwise, the intrahepatic lesions may not be relieved, and the intestinal contents could flow back into the bile duct, aggravating biliary infection and causing biliary carcinogenesis[64], which can endanger the lives of patients. Moreover, to avoid the occurrence of residual stones and the recurrence of postoperative bile duct stricture, Roux-en-Y anastomosis with a subcutaneous blind loop can be performed. Post-operation, reexamination or cholangiography can be performed through the subcutaneous blind loop, and the biliary stricture can be dilated through this channel to avoid secondary operation.
Cui et al[65] proposed that to preserve the function of the sphincter of Oddi and minimize residual intrahepatic bile duct stones, subcutaneous choledochoplasty should be used. According to their study, 24% (32/146) of patients with recurrent or residual stones can undergo biliary drainage, stone removal and stricture dilatation through the subcutaneous passage, thus avoiding secondary operations. The subcutaneous passage retained by this operation has a certain necessity and practical value.
Laparoscopic choledochojejunostomy is currently advocated for in the clinic, but it has some technical difficulties and requires long-term in-depth study by surgeons[66,67]. Compared with open choledochojejunostomy, laparoscopic choledochojejunostomy can better expose the operative visual field and anatomical structure. Laparoscopic choledochojejunostomy is considered a safe and effective surgical method[67-70].
Biliary tract exploration and lithotomy
This operation is one of the most basic surgical procedures for treating hepatolithiasis. Traditional choledocholithotomy relies only on the experience of surgeons to remove stones, which has great limitations, and thus, the rate of postoperative residual stones is as high as 30%. At present, choledocholithotomy requires choledochoscopy combined with choledochoscopy or ultrasound localization to remove stones, mainly in the common hepatic duct near the hilum of the liver[71]. After all openings are created directly on the liver surface of the diseased area, the stones of the intrahepatic bile duct are removed using a choledochoscope. For critically ill patients with acute biliary obstruction, this operation can quickly relieve bile duct obstruction, control biliary infection, drain bile, relieve patients' symptoms, and create surgical opportunities for secondary hepatectomy in the future. After the operation, the T-tube is indwelled, and the stones are subsequently removed via a choledochoscope through the sinus, which effectively reduces the risk of relaparotomy, significantly increases the stone clearance rate, and reduces the postoperative residual stone rate to 2%-4%. This operation is not only effective for emergency and severe situations but is also effective for patients with a short course of disease or a small number of stones limited to the large bile duct in the liver. Thus, this operation can be the first choice. However, since most patients with hepatolithiasis encountered in the clinic have complex hepatolithiasis, removing the stones simply by choledocholithotomy is difficult, with a high rate of residual stones and recurrence rate of postoperative stones. Thus, it is usually necessary to combine hepatectomy and choledochojejunostomy so that it is possible to remove all stones at once, where the best therapeutic effect can be obtained[72].
Percutaneous transhepatic chledochoscopic lithotripsy
Percutaneous transhepatic punctures can be dated back to 1937. Huard and Hop[73] established a channel via percutaneous transhepatic puncture where they injected contrast media into the bile duct to observe biliary obstruction. In the following decades, this technology was continuously improved and applied by Japanese scientists. In 1974, Takada et al[74] builded upon the concept of percutaneous transhepatic cholangioscopic (PTCS) for establishing biliary access for the treatment of hepatolithiasis for the first time. After decades of development, this technology is becoming increasingly mature in clinical application. At present, for hepatolithiasis, doctors can remove stones by combining lithotripsy and/or lithotripsy equipment under the direct vision of a choledochoscope after percutaneous transhepatic puncture. For bile duct strictures, doctors can also use dilated balloons. For traditional PTCS lithotripsy (PTCSL), the local area is anaesthetized, and the target bile duct is punctured under the guidance of ultrasound or X-ray. After the guide wire is placed, the channel is dilated with an 8F dilator, and finally, the 8F drainage tube is retained. One week post-operation, the sinus is gradually dilated with an 8-16F series dilator once per week, 2F each time. Four weeks post-operation, the stones are removed via fiberoptic choledochoscopy through the sinus. Traditional PTCSL has many shortcomings in terms of treatment, such as a long treatment cycle, the inability of patients to tolerate the pain of sinus dilatation, and high cost; at the same time, the efficiency of stone removal is low, and its clinical application has decreased[75].
Wang et al[76] conducted a comparative study of traditional PTCSs and PTCSLs. A retrospective study was conducted on 118 patients with hepatolithiasis (51 patients treated with PTCS and 67 patients treated with PTCSL) from 2007 to 2014, and the efficacy and safety of the two groups were compared. The results revealed that there was no significant difference in operation time, intraoperative blood loss or blood transfusion between the two groups, and the stone clearance rate in the PTCSL group was significantly better than that in the PTCS group (P = 0.021; OR = 0.201; 95%CI: 0.051-0.785). The recurrence rate of stones was 9% in the PTCSL group and 22% in the PTCS group. The hospitalization time of the PTCSL group was also significantly shorter than that of the PTCS group (P = 0.001; OR = 1.337; 95%CI: 1.132-1.58). Traditional PTCS operation no longer meets the clinical needs for the treatment of hepatolithiasis, but PTOBF is an ideal method for the treatment of hepatolithiasis because of its good curative effect and high safety (Figure 1).
Figure 1 PTOBF stone extraction procedure.
A: Ultrasound-guided percutaneous transhepatic target bile duct puncture; B: Syringe retraction after successful puncture, retraction of bile represents a successful puncture; C: Gradual dilation of the bile duct using 8Fr to 16Fr disposable fascial dilators via guidewire; D: 14Fr protective sheaths to establish choledochoscope access; E: Placement of the choledochoscope via the guidewire; F: Choledochoscopic mesh basket stone extraction.
Liver transplantation
At present, liver transplantation (LT) is considered the last line of defence for the treatment of hepatolithiasis[77]. For patients with hepatolithiasis, the indications for LT are as follows: (1) Patients with primary hepatolithiasis secondary to decompensated biliary cirrhosis complicated with portal hypertension; (2) Diffuse hepatolithiasis of the whole liver combined with recurrent cholangitis, bile duct stricture and obstructive jaundice, which cannot be completely removed by partial hepatectomy, choledochojejunostomy or choledochoscopy, seriously affecting quality of life; and (3) Those who have undergone many operations where the focus of the stone cannot be removed. LT can be used for the treatment of hepatolithiasis, and the quality of life of patients undergoing LT is one of the conditions used to evaluate the suitability of the operation.
McLean et al[78] conducted a questionnaire survey on the quality of life of LT patients with liver diseases. The results revealed that the overall quality of life of LT patients significantly improved after long-term treatment, and the average therapeutic effect was 6.3 (95%CI: 2.1-10.9). Moreover, LT is affected by many factors, such as a shortage of liver sources, high cost of operation, difficulty of LT, many postoperative complications and immune repulsion reactions[79,80], which restrict the development of the operation. Although many researchers worldwide have made progress in recent years to reduce the risks associated with LT[81], there is still a long way to go.
