INTRODUCTION

Biliary stricture complicating living donor liver transplantation (LDLT) is a relatively common complication,occurring in most transplant centres across the world.Improvements in technique, better postoperative care,surgical expertise and immunosuppressive medications have resulted in a decreased incidence of biliary complications over the years[1-3]. The Roux en Y hepaticojejunostomy has given way to duct-to-duct anastomosis (DD)which is the preferred mode of biliary reconstruction in most cases[4-8]. DD is technically easy, enables rapid gastrointestinal recovery, has a lower risk of cholangitis and maintains physiological choledochoenteric continuity[2].Moreover, DD allows an easy endoscopic access to the anastomosis, enabling endotherapy in most cases. Thus,surgical management of biliary strictures following LDLT has slowly been replaced by endoscopic retrograde cholangiography (ERC) with stent placement, which emerged as the first-line therapy during the last few decades[1-3,9-11].

Compared to deceased donor liver transplantation(DDLT), the biliary anastomosis in LDLT is more peripheral, smaller and complex[12,13], resulting in tortuous and angulated strictures, especially due to hypertrophy of the transplanted liver[14]. As a result, the ef ficacy and safety profiles as well as the outcomes of endoscopic management of biliary strictures complicating LDLT represents an area that needs to be viewed in isolation,owing to its unique set of problems and attending complications; it merits a tailored approach, which is yet to be well established.

This review focuses on the pathogenesis, morphology and diagnosis of the endoscopic management of biliary strictures complicating LDLT, as well as some unique problems associated with it. An attempt is made to present the best current management options available as well as rational perspectives on future research in the area.

BILE DUCT STRICTURES: LDLT vs DDLT

LDLT as a treatment for end-stage liver disease is especially popular in most Asian countries, owing to a difficulty in organ procurement from deceased donors[15-17]. However, DDLT constitutes the majority of transplants in the West, being performed within the framework of a uniform, systematic organ allocation programme along with better organ procurement from deceased donors, that ensures shorter waiting periods and allows for the use of DDLT as a standardof-care for end-stage liver disease. As is apparent,this is predicated on a higher number of deceased donors, early referral for liver transplantation, requisite infrastructure and specialised man-power for fair and ef ficient organ allotment; a lack thereof is palpable in Asia, paving the way for robust LDLT programmes,especially in far eastern countries like those in Japan,Hong Kong, China and Korea[17-19].

While the principles of endoscopic therapy for biliary strictures complicating DDLT are similar to those that occur with LDLT, there seems to be some differences in the incidence, morphology and type of strictures, which can be summarised as follows.

Incidence

Bile duct strictures are the most common biliary complication after liver transplantation, accounting for approximately 40% of all biliary complications[7,12,20-23].In general, biliary strictures have been reported to occur in up to 5% of DDLT cases[24,25]. On the other hand, those of LDLT have been reported to occur more frequently: 7.3%-60.0% in right-lobe grafts[4,12,26-28]and 24% in left lateral segment grafts[29]. In a study by Gomez et al[30], biliary strictures occurred more frequently following LDLT than in DDLT [10/30 (33.3%)vs 27/357 (7.6%), respectively].

Morphology

Owing to the use of a smaller graft in LDLT (as compared to the whole liver in DDLT), the calibre of the bile ducts used for the anastomosis is smaller, often having a disparity between the recipient and donor ducts. Surgical anastomosis in these cases demand technical expertise and experience in working with small ducts in order to create an anastomosis that is free of tension and has an adequate luminal diameter to enable free flow of bile. As a result, strictures developing in this situation will have a unique morphology and sometimes bizarre configurations. Attempts have been made to classify these strictures based on cholangiographic appearance,size and number of ducts, all of which may have bearing on the outcome of endoscopic management[31].

对这43个点的高程误差进行求和统计，其值为1.664 m，说明无显著系统性偏差。从地形图等高线情况看，较好地表达了黄土地貌受雨水冲蚀形成的鸡爪形沟壑的等高线特性。

Aetiology and type of stricture

Posttransplant biliary strictures can be classified as anastomotic strictures (AS) and nonanastomotic strictures(NAS). AS is more common in LDLT patients than in DDLT patients. This system of classification as AS or NAS is extremely useful as clinical outcomes and treatment modalities of the two types are somewhat different[1]. AS account for about 80% of biliary strictures after LDLT[32].Factors contributing to the development of AS include technical problems of the biliary anastomosis, ischemia or bile leaks[33]. Although the effect of ischemia is far more pronounced in NAS, it might also play a significant role in AS. AS usually present later in the course of the posttransplant recovery[34], with a median interval of 5-8 mo after the liver transplantation[20,35,36]. It usually is a single, sometimes tortuous stricture, at or within 5 mm of the anastomotic site[33].

“康川新城”位于西宁市湟中县多巴镇，是西宁(国家级)经济技术开发区甘河工业园区为甘河、汉东和大才地区被征地农民建设的统一安置社区。“康川新城”下辖三个小区，共居住着被征地的15个行政村的汉、回、土、藏、蒙古族等不同民族的农民。“康川新城”是西宁市 “农转居”地区——村落变更为社区，农民转变为居民的典型代表。社区矫正这一舶来品在我国的发展本来就尚不成熟，而在这新兴的“农转居”地区，受地理环境、社区规划、宗教信仰等因素的影响，在实践中就出现了更多的问题。

NAS, on the other hand, usually results from hepatic artery injury or thrombosis, causing irreversible biliary fibrosis due to ischemia[1]. Other causes which have been implicated include long cold ischemia time or ABO type incompatibility[33,37]. Of all biliary strictures after liver transplantations, NAS accounts for only 10%-25%[11,13,22]. In a Japanese study, NAS accounted for only 6% of all biliary strictures and occurred in 5 of the 273 LDLT patients (2%)[13]. In another study with 339 patients undergoing right lobe LDLT, only 11 patients (10%) developed NAS, while 121 patients(36%) developed AS, accounting for more than 90% of the biliary strictures in that patient cohort[22]. The Mayo Clinic Hospital in Arizona reported only 3 of 110 LDLT patients (3%) developing ischemic-type strictures[11].

BILIARY STRICTURES COMPLICATING LDLT

Incidence and pathophysiology

Biliary complications continue to be the most common complication after LDLT, having a reported incidence of 20%-43%, with biliary strictures accounting for 3%-40% of cases. Most biliary strictures present in the first year following the liver transplantation[9,22,36,38,39](Table 1).

With increasing experience in LDLT, in most Asian countries there has been a decrease in overall incidence of biliary complications, from 30% in the initial years to around 15%-25% in recent years[3,6,20,25,31,40]. Highvolume LDLT centres in Tokyo and Hong Kong, having extensive experience in management of biliary strictures,report a relatively steady rate of biliary strictures, of 20%-25%[8,41]. In an elegant study by Morioka et al[21]from the Kyoto University, LDLT recipients were divided into three time cohorts which differed with regard to case experience. They found that while the rate of bile leak significantly decreased with experience, there were no differences in the development of biliary strictures among the three groups (19%, 28% and 26% in the three groups; P = 0.290). In a similar study from the University of Toronto, Shah and colleagues[20] did not find any difference in the rate of biliary strictures after chronological stratification of their patient cohort into the first 65 cases and the next 65 cases. However, a recent study by Kim et al[36] did show that patients who underwent more recent procedures were less likely to have biliary strictures, suggesting a small but important role of surgical expertise on the risk of biliary strictures.

7 Hwang S, Lee SG, Sung KB, Park KM, Kim KH, Ahn CS, Lee YJ, Lee SK, Hwang GS, Moon DB, Ha TY, Kim DS, Jung JP,Song GW. Long term incidence, risk factors, and management of biliary complications after adult living donor liver transplantation.Liver Transpl 2006; 12: 831 838 [PMID: 16528711 DOI: 10.1002/lt.20693]

1.切实保障中小企业的发展。政府部门需要加强立法，通过相关的法律规定来推动中小企业的有序发展，为中小企业提供良好的环境。从整个中小企业的发展以及社会经济发展的方向，重视中小企业的发展，加强中小企业的规范，对中小企业的管理模式进行科学有效地设计，密切关注中小企业的发展方向，包括中小企业的资金运用以及中小企业的战略决策等，逐步推动中小企业产业结构的升级。

Multiple causative factors with intersecting and often overlapping pathophysiological pathways make it impossible to implicate a single factor that can predictably lead to stricture formation. A useful approach would be to aggregate individual factors as a composite score for prognostication, early diagnosis and treatment.

Diagnostic challenges

32 Thethy S, Thomson BNj, Pleass H, Wigmore SJ, Madhavan K,Akyol M, Forsythe JL, James Garden O. Management of biliary tract complications after orthotopic liver transplantation. Clin Transplant 2004; 18: 647 653 [PMID: 15516238 DOI: 10.1111/j.1399 0012.2004.00254.x]

Among the factors detected by laboratory tests,bilirubin, alkaline phosphatase, gamma-glutamyl transferase and the transaminases are assessed initially.However, these tests are nonspecific, with limited diagnostic role for differentiating a biliary cause from a hepatocellular aetiology for the symptoms. Liver biopsy is extremely valuable to differentiate biliary strictures from acute cellular rejection, but since it is an invasive procedure with possible complications, it should be reserved for cases with a high degree of suspicion for rejection.

Imaging studies

Currently, the diagnosis of biliary strictures depends heavily on cross-sectional imaging, which classically demonstrates an anastomotic narrowing. Initial imaging with ultrasonography of the abdomen with Doppler study is carried out to examine the intrahepatic biliary radicles, along with vascular patency. However, the sensitivity of ultrasonography to detect biliary dilatation in the posttransplant patient is as low as 38%-66%,thereby rendering it unreliable as a sole screening modality for the diagnosis of biliary strictures[56-58]. A scan by hepatobiliary iminodiacetic acid scintigraphy is excellent for detecting bile leaks[59]; however, its role in detecting biliary strictures is poor, with a sensitivity of around 60%[59,60]. Computed tomography is useful for detection of fluid collections and non-biliary lesions,having a higher spatial resolution than magnetic resonance imaging[61]. However, it is grossly inadequate for the diagnosis of biliary strictures, unless used in conjunction with the injection of biliary contrast agents,like iodipamide meglumine. These contrast agents have been found to be unsafe, with higher incidence of allergic reactions; as such, the use of computed tomography for biliary strictures has fallen out of favour in most centres.

研究型资源是学科建设与发展的基础。为了实现更深层次的文献服务，可以考察资源与学科评估、学术评价的相关性，以ESI，SCIE，NATURE自然指数评估等来源期刊为参照，分析学科期刊资源的保障率、保障水平［11］，为学术期刊的调整与订购提供依据。对用户迫切需要的领域权威期刊或新兴期刊，可以采用单电子期刊订购模式，为用户提供精准服务。

Magnetic resonance cholangiography (MRC) has emerged as a reliable noninvasive tool to detect biliary strictures complicating LDLT. The presence of bile within the ducts allows for accurate delineation of the biliary tree, which can highlight the anastomotic stricture with diagnostic sensitivity and specificity in excess of 90%[62-64]. MRC can provide detailed imaging of the entire biliary tract and is especially useful for complex and intrahepatic strictures. Moreover, it can provide a roadmap for therapeutic interventions. MRC has a high negative predictive value that prevents unnecessary procedures[65,66]. The limitations of MRC include lack of interventional capability and high cost as a routine diagnostic modality. It has also been found to have a high rate of false positives.

Most LDLT recipients with DD can show a narrowing of the anastomotic site in the absence of a ‘functionally significant obstruction’ (FSO). Here, FSO is defined as a critical obstruction at the anastomotic site that results in a clinically significant impedance to bileflow, evidenced by clinical symptoms and biochemical alterations of cholestasis. In our centre, a unique set of metrics are applied in the MRC to indicate FSO. While most literature alludes to a dilated proximal duct and a narrowing as pathognomonic of a stricture[3], we have found it useful to use the ratio of the proximal duct diameter to the recipient ductal diameter to signify FSO.This approach is based on the hypothesis that a FSO should cause impedance of bileflow that will result in the hold-up of bile above the stricture, causing dilatation and higher diameter on MRC, along with collapse of the recipient bile duct below the anastomosis, due to lack of bile flow across the stricture resulting in a smaller ductal diameter on the MRC. The resultant ratio may provide valuable clues as to the severity of obstruction at the anastomosis and enable a singular, reproducible definition of biliary strictures that can potentially dictate further treatment with better outcomes. The management approach practised in our centre using this method of diagnosing biliary strictures complicating LDLT is shown in Figure 1. However, prospective trials in multicentric populations are required before widespread application of this de finition in the management protocol for biliary strictures.

Endoscopic management (endotherapy)

Endoscopic management (endotherapy) is usually the first line of treatment for biliary strictures complicating LDLT and includes ERC with biliary sphincterotomy, balloon dilatation and stent placement[11,30,31]. Endotherapy is the mainstay of treatment and is usually the only avenue outside of surgery used in a majority of patients.However, endotherapy in LDLT recipients may be dif ficult because of complex strictures with multiple ductal anastomoses in bizarre configurations[1]. It is a point of contention whether balloon dilation in isolation or balloon dilation with stent placement is superior for the treatment of biliary strictures. A higher complication rate notwithstanding, stent placement after balloon dilation should be the standard of care in these patients[67,68].Moreover, endotherapy has the advantage over percutaneous transhepatic cholangiography because it enables the placement of multiple large-calibre stents,and is more physiological and less invasive.

Who will bene fit from endotherapy?

Various studies have tried to identify factors influencing the outcome of endoscopic management in postLDLT biliary strictures (Table 2). The detection of these factors would help in streamlining the decision-making process and ideal patient selection for endotherapy. Donor characteristics, and pretransplant and posttransplant factors have been found to influence the endoscopic outcomes[9,22,31,43,69]. Chang et al[22] reported an overall success rate of only 48%, especially for patients with NAS (P = 0.016) and strictures associated with posttransplant hepatic artery stenosis/thrombosis (P= 0.016). Kim et al[70] reported that only the interval between LDLT and the first ERC had an effect on the outcome with endotherapy and, contrary to other reports, that longer stricture duration had a better outcome (P = 0.041). Swan neck deformity in rightlobe LDLT was also seen as a risk factor for dif ficult endoscopic procedure as well as poorer outcomes. Finally,bile leaks were found to be one of the most important risk factors for stricture formation as well as poorer stricture resolution with endotherapy[70]. Kato et al[31]reported a 51% overall rate of stricture resolution in postLDLT biliary strictures with DD and noted bile leaks as the major cause of stent failure[9]. Our previous study showed HAT, multiple biliary anastomosis and older donor age to be significant predictors of poor outcome to endotherapy.

A paucity of conclusive evidence in the background of heterogenous patient populations and endoscopic management protocols make it difficult to identify a subgroup of patients who will respond to endotherapy in a predictable fashion. In this regard, uniform criteria for diagnosis of biliary strictures as FSO may aid in identifying patients with a significant stricture amenable to endotherapy, an approach that needs further validation.

When to intervene?

The timing of intervention has been an area that has lacked adequate validation. Usually, ERC in the first few weeks after LT is considered dangerous, due to the risk of damage to the anastomosis. This, however, is more applicable for bile leaks, as opposed to strictures since the development of strictures usually takes a long time.It is important to note that strictures that develop in the first 6 mo are more likely to respond to endotherapy than strictures that present late[20,69].

A subgroup of patients that merit further study in-cludes those who present with asymptomatic biochemical alterations, liver biopsy inconclusive of rejection and imaging studies showing an anastomotic narrowing.The question of whether to wait it out or subject the patient to aggressive endotherapy protocols is a particularly harrowing one. On the one hand, there is considerable data which have demonstrated that a delay in treatment may be a significant determinant of poor response to endotherapy[71,72]. In a study by Buxbaum et al[69] it was noted that a longer waiting time for ERCP was related with a greater likelihood of failure with endotherapy. However, the quantitative finding did not reach statistical significance. In our previous report,we found a similar inverse relationship between time to ERC and endoscopic success, but again the finding was not statistically significant[69]. However, in the study by Shah et al[20], a similar patient subgroup was kept under follow-up with close observation and most were found to be stricture-free during the long-term follow-up.

It would seem plausible that a delay in ERC with stent placement should lead to a suboptimal success owing to establishment and organisation of the fibrosis;however, the identification of strictures that merit treatment, as opposed to those that can be managed conservatively, warrants further study. Again, in this regard, the concept of FSO alluded to earlier may provide some valuable insights. Yet, larger studies exploring the accurate definition of FSO are needed before any recommendations are made, and current practice of early ERC with stent placement after balloon dilation should be continued until proven otherwise.

Protocol for endoscopic management of strictures

Ideal endoscopic management protocols include ERC with endoscopic sphincterotomy, balloon dilatation and stent placement. Repeated ERC at 2- to 3-mo intervals with up-sizing of the stent or the use of multiple stents with or without repeated balloon dilation for at least 1 year is the most preferred protocol across transplant centres globally[2,3]. However, the need for balloon dilation of the strictures prior to the placement of endoprosthesis is not universally accepted, with some endoscopists opting for stent placement alone in the first ERC, followed by balloon dilations in subsequent ERC. Yet, there is no data that suggests superiority of this method over both balloon dilation and stent placement at the first ERC.

In 2003, Park et al[73] described an alternate protocol wherein patients without a significant narrowing on ERC are dilated with a balloon after sphincterotomy and a 5F nasobiliary catheter is placed above the stricture.This has many theoretical advantages in that it is easy to perform a cholangiogram to assess improvement of the stricture and obtain bile samples for culture;thus, occlusion of the drain is readily diagnosed and does not necessitate a repeat endoscopy to remove the catheter[73]. However, it is not a widespread endoscopic protocol because of reduced patient acceptance with no uniform data on therapeutic superiority. An ideal approach to this decision should involve careful consideration of the time interval between the ERC and liver transplantation, the ductal diameters and length of the stricture before coming to a decision on the use of both balloon dilation and stent therapy.

The need for endoscopic sphincterotomy has also been examined, with a few authors proposing stent placement across an intact sphincter of Oddi to reduce the incidence of cholangitis and pancreatitis[13,74].However, there is no data corroborating this perceived risk of cholangitis. Moreover, we have found that the incidence of postERC pancreatitis is lower in liver transplantation patients than in the general patient population - a finding that was also observed in a multicentric study by Law and colleagues[75]. This can be due to as yet unidentified effects of immunosuppressants on the inflammatory cascade that drives post ERC pancreatitis, representing an area that needs further study.

The major disadvantage of endoscopic therapy is the necessity for frequent procedures required for stent exchanges, which may increase complications in addition to increased cost of care. Stent exchanges are usually performed every 2-3 mo to avoid stent occlusion and cholangitis. Most of the studies in this regard have been on DDLT patients, but it seems reasonable to apply the same protocol in LDLT patients. Few studies[76]have performed stent exchanges and dilation every 2 wk and shown a superior success rate. Tabibian et al[77]showed that a stent therapy protocol wherein stent exchanges are performed only once the patient is symptomatic is superior to protocol-driven procedures.However, it would seem pragmatic to exchange the stents every 3 mo for a minimum of four exchanges over a 1 year period and give a stent-free trial provided the last cholangiogram shows stricture resolution.

Some Japanese groups advocate the placement of‘inside stents’, whereby the plastic stent is completely in the bile duct with an intact sphincter, reducing the duodenobiliary reflux and consequently preventing cholangitis[13,14,74,78]. This is postulated to improve stent patency rates, with fewer ERC requirements and lower incidence of cholangitis as it prevents duodenobiliary reflux. The University of Kyoto reported use of a similar strategy, with modified Amsterdam stents placed inside the bile duct in 94/118 LDLT patients (80%) and yielding a stricture resolution rate of 68%[74]. Tsujino and colleagues[2] at the University of Tokyo, in as-yet unpublished data, have alluded to their experience in the area with 63 LDLT recipients who underwent inside stent placement. The median interval for stent exchange was as high as 161 d, with cumulative risk of stent dysfunction being 12.3% at 6 mo and 18.1% at 12 mo[2].

Another promising approach is the use of the selfexpanding metal stent (SEMS). SEMS was introduced to overcome the need for repeated procedures in conjunction with providing better and faster stricture resolution in these patients, owing to the larger diameter(30F) of the stents. The initial use of uncovered SEMS proved to be a disaster because of high rates of complications due to stent ingrowth and over-growth causing stent occlusion, formation of biliary sludge and stones within the stents, and more importantly vascular complications in the long term[79-82]. Covered (c)SEMS was subsequently introduced and seemed to counter most of the disadvantages of the uncovered SEMS (Table 3). The ease of endoscopic removal of cSEMS makes them an ideal treatment modality for benign biliary strictures.

Randomised controlled trials in DDLT patients comparing SEMS with multiple plastic stents have shown they are similar with respect to stricture resolution, but SEMS required fewer interventions compared to plastic stents[83,84]. A recent meta-analysis also showed no superiority of SEMS over multiple plastic stenting, but supported the use of SEMS owing to shorter treatment time and fewer procedures[85]. Very few reports have explored the role of SEMS in LDLT patients[86-88]. In an elegant study by Jang et al[89], a short fully-covered SEMS with a waist in the centre to prevent migration(Kaffes stent by Taewoong Medical, Seoul, South Korea)(Figure 2) was used in 35 LDLT patients with refractory strictures. The cases showed an excellent response rate, with 83% stricture resolution and 6% migration[89].However, the safety and ef ficacy of SEMS in LDLT is yet to be understood. At our centre, cSEMS was deployed in 4 LDLT recipients with refractory biliary strictures.However, stent occlusion due to sludge and stones was seen in 3/4 patients (75%) (unpublished data),necessitating additional plastic stent placement inside the cSEMS.

The placement of cSEMS in high anastomotic strictures may also lead to blockage of secondary branches of the bile duct and subsequent biliary stasis in those segments. Tsujino and colleagues[71] at the University of Tokyo advocate the placement of inside stents along with covered SEMS to counter this problem,and this approach seems to hold promise pending future studies. A particularly distressing complication of cSEMS is stent migration, which is reported in 16%-33% of cases[83,88]. The rate of stent migration seems to be higher in LDLT patients than other patients with benign biliary strictures[90]. Finally, the placement of cSEMS may aid duodenobiliary reflux due to disruption of the sphincter mechanism and possibly result in ascending cholangitis.

Endoscopic management: Outcome

In order to discuss therapeutic efficacy, a uniform de finition of biliary strictures has to be established. Most studies have used multiple criteria for endoscopic success,and these include symptomatic and/or biochemical improvement, imaging studies showing resolution of stricture, and absence of recurrence of cholestasis requi-ring endoscopic/percutaneous interventions[9,14,31,69,91].It would seem bene ficial to study these patients at two time points - one assessing the response after a protocolbased endotherapy practice for a minimum of 1 year, and a more long-term evaluation to assess rate of recurrence and need for repeat interventions. Both these treatment endpoint scans provide valuable insights on the course of AS and will help in establishing a uniform treatment protocol and follow-up.

In the study by Buxbaum et al[69], long-term success was evaluated as a treatment goal and a 68% success rate was found. In our previous report, stricture resolution at the end of 1 year was only 48%[31]. This low rate of stricture resolution may be due to a larger proportion of patients who had multiple biliary anastomoses, older donor age and/or a nonuniform endoscopy protocol applied for management. Future studies likely need to look at a composite outcome,combined with better patient selection criteria, which can yield uniform and predictable results of therapeutic ef ficacy for endotherapy.

In the event of technical failure of ERC, which is de fined as inability to cross the stricture with a guidewire,a percutaneous transhepatic cholangiography with biliary drainage via a percutaneous catheter can be performed[70,73]. It is usually successful, especially in patients with cholangitis who need urgent biliary drainage.Percutaneous transhepatic cholangiography with drainage is still a second-line therapy, as it is invasive and carries risk of complications like bleeding, pseudoaneurysm of the hepatic artery, bile leaks, infection, arterioportal fistula and portal vein thrombosis[45,92]. Patient compliance is also poor, and it is usually combined with an ERC in a rendezvous procedure at our centre. Using this technique, we have been able to get across the stricture in most patients. All our patients who have undergone the rendezvous procedure had subsequent successful ERC with stent exchanges, and documented resolution of stricture. We found that it is safe and precludes surgery in most patients with a primary endoscopic failure.

此外，通过适当加大对公路大中修工程的养护强度，能够为驾驶人员提供更好的出行环境。从公路大中修工程中的养护人员角度来分析，要结合公路路况，收集大量的路况数据，并对该段路况进行全面调查，严格按照公路大中修养护方案实施养护，结合养护过程中遇到的难题，制定针对性较强的解决对策。

NOVEL INSIGHTS AND AREAS OF FUTURE RESEARCH

As in any scientific work, the formulation of the problem is paramount for the development of a solution which more often than not is obvious to a trained clinician.To that end, the de finition of biliary strictures in most studies is not uniform and needs to be re-examined.In the study by Buxbaum and colleagues[69], cholangiographic appearance of narrowing in a patient with altered liver functions were treated with endoscopy.In the study conducted at the University of Toronto,however, only symptomatic alterations of liver function tests in conjunction with a narrowing on imaging were considered for endoscopic management[20]. In our study on LDLT recipients, we also included asymptomatic patients with biochemical and imaging features of biliary obstruction[31]. This nonuniform de finition is reflected in the varying success rates of endotherapy reported from these three studies (68%, 81% and 48% respectively).

A stricture that responds to endoscopic therapy should be regarded as a ‘true’ stricture, or more appropriately a FSO. This may provide a multidimensional definition of biliary strictures that has the potential to streamline patients into mutually exclusive treatment pathways and ensure therapeutic efficacy. The ratio between donor duct diameter and the recipient ductal diameter on the MRC in conjunction with a subjective assessment of contrast drainage across the stricture during the ERC to indirectly signify the functional impedance to bileflow of the stricture has been found to be useful in our centre, having a superior therapeutic ef ficacy of 83% in preliminary findings (unpublished data). This approach to seek out an obstruction that is functionally significant in a symptomatic patient may yield a patient group who will be predictably responsive to endotherapy.

However, it is important to understand that endotherapy may not be the answer for all strictures across the board. As Abraham H Maslow remarked - ‘If the only tool you have is a hammer, it is tempting to treat everything as if it were a nail’; it is important to realise that certain patients with biliary strictures of an unfavourable morphology will not respond as well to endotherapy. The correct identification of the patients who will respond to endotherapy is the need of the hour.The development of innovative modalities, newer stent designs and endoscopic accessories needs to propel future work in this area, especially for those patients who are refractory to stent therapy.

REFERENCES

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6 Sugawara Y, Makuuchi M. Advances in adult living donor liver transplantation: a review based on reports from the 10th anniversary of the adult to adult living donor liver transplantation meeting in Tokyo. Liver Transpl 2004; 10: 715 720 [PMID:15162463 DOI: 10.1002/lt.20179]

There seems to be several possible factors other than poor surgical expertise that result in bile duct injury and subsequent strictures. Among these, an important cause of strictures is postoperative bile leak that causes local inflammation and fibrosis[23,38,42,43]. Other factors identified include older donor age[20], preoperative model of end-stage liver disease score[40,43], multiple biliary ducts[43], graft cold ischemia time[41,44], bile duct diameter[44,45], acute cellular rejection[41] and hepatic artery thrombosis (HAT). As evident, most of these factors lead to ischemic injury of the bile duct, eventually culminating in strictures. While ischemia is a major factor in NAS, it also plays a major role in the development of AS. This is because the bile duct epithelium is particularly vulnerable to ischemia, as compared to hepatocytes or vascular endothelium[46-48]. Local ischemic insults can also arise from devascularisation at the time of hilar dissection. Moreover, oxygen supply to the biliary tract is solely supplied by the hepatic artery. Therefore, HAT can lead to severe ischemic stress on the bile duct, resulting in fibrosis and strictures. HAT is a major determinant of NAS[49] and complex, long AS[46] that are usually dif ficult to manage endoscopically. In addition, technical factors like the number of biliary anastomosis, discrepancy in ductal diameters, unavailability of biliary microsurgical modalities, and aberrant biliary anatomy have been found to be significant risk factors for the development of biliary strictures[1,46,50,51] Moreover, endoscopic management is particularly affected in patients with multiple biliary anastomoses[31].

8 Kyoden Y, Tamura S, Sugawara Y, Matsui Y, Togashi J, Kaneko J, Kokudo N, Makuuchi M. Incidence and management of biliary complications after adult to adult living donor liver transplantation.Clin Transplant 2010; 24: 535 542 [PMID: 19849703 DOI:10.1111/j.1399 0012.2009.01124.x]

9 Kato H, Kawamoto H, Tsutsumi K, Harada R, Fujii M, Hirao K,Kurihara N, Mizuno O, Ishida E, Ogawa T, Fukatsu H, Yamamoto K, Yagi T. Long term outcomes of endoscopic management for biliary strictures after living donor liver transplantation with duct to duct reconstruction. Transpl Int 2009; 22: 914 921 [PMID:19497069 DOI: 10.1111/j.1432 2277.2009.00895.x]

10 Chang JH, Lee I, Choi MG, Han SW. Current diagnosis and treatment of benign biliary strictures after living donor liver transplantation. World J Gastroenterol 2016; 22: 1593 1606 [PMID:26819525 DOI: 10.3748/wjg.v22.i4.1593]

11 Hsieh TH, Mekeel KL, Crowell MD, Nguyen CC, Das A, Aqel BA, Carey EJ, Byrne TJ, Vargas HE, Douglas DD, Mulligan DC, Harrison ME. Endoscopic treatment of anastomotic biliary strictures after living donor liver transplantation: outcomes after maximal stent therapy. Gastrointest Endosc 2013; 77: 47 54[PMID: 23062758 DOI: 10.1016/j.gie.2012.08.034]

12 Gondolesi GE, Varotti G, Florman SS, Muñoz L, Fishbein TM, Emre SH, Schwartz ME, Miller C. Biliary complications in 96 consecutive right lobe living donor transplant recipients.Transplantation 2004; 77: 1842 1848 [PMID: 15223901]

13 Yazumi S, Yoshimoto T, Hisatsune H, Hasegawa K, Kida M,Tada S, Uenoyama Y, Yamauchi J, Shio S, Kasahara M, Ogawa K, Egawa H, Tanaka K, Chiba T. Endoscopic treatment of biliary complications after right lobe living donor liver transplantation with duct to duct biliary anastomosis. J Hepatobiliary Pancreat Surg 2006; 13: 502 510 [PMID: 17139423 DOI: 10.1007/s00534 005 1084 y]

14 Tsujino T, Isayama H, Sugawara Y, Sasaki T, Kogure H, Nakai Y, Yamamoto N, Sasahira N, Yamashiki N, Tada M, Yoshida H, Kokudo N, Kawabe T, Makuuchi M, Omata M. Endoscopic management of biliary complications after adult living donor liver transplantation. Am J Gastroenterol 2006; 101: 2230 2236 [PMID:16952286 DOI: 10.1111/j.1572 0241.2006.00797.x]

16 Lo CM. Deceased donation in Asia: challenges and opportunities.Liver Transpl 2012; 18 Suppl 2: S5 S7 [PMID: 22961949 DOI:10.1002/lt.23545]

当靶板中的应力波衰减到不能使靶板继续进行塑性流动时，靶板内将发生弹性或非弹性作用，导致坑体自由表面出现较小的膨胀、坑壁表面的层裂及坑内材料的再结晶等情况。研究表明：超高速柱状弹丸对厚靶的侵彻成坑具有以下特点：

15 Lee SG. Asian contribution to living donor liver transplantation. J Gastroenterol Hepatol 2006; 21: 572 574 [PMID: 16638101 DOI:10.1111/j.1440 1746.2006.04283.x]

17 Rela M, Reddy MS. Living donor liver transplant (LDLT) is the way forward in Asia. Hepatol Int 2017; 11: 148 151 [PMID:28097531 DOI: 10.1007/s12072 016 9780 z]

3 Wadhawan M, Kumar A. Management issues in post living donor liver transplant biliary strictures. World J Hepatol 2016; 8: 461 470[PMID: 27057304 DOI: 10.4254/wjh.v8.i10.461]

3)相同网架高度下，斜放四角锥三层网架焊接球节点较少，在跨中高度7.6 m时，采用斜放四角锥网架仅有12个焊接球节点，而同样高度下，正放四角锥网架要130个焊接球节点。

19 Ng KK, Lo CM. Liver transplantation in Asia: past, present and future. Ann Acad Med Singapore 2009; 38: 322 310 [PMID:19434335 DOI: 10.1055/s 2008 1071097]

35 Olthoff KM, Merion RM, Ghobrial RM, Abecassis MM, Fair JH,Fisher RA, Freise CE, Kam I, Pruett TL, Everhart JE, Hulbert Shearon TE, Gillespie BW, Emond JC; A2ALL Study Group.Outcomes of 385 adult to adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg 2005;242: 314 323, discussion 323 discussion 325 [PMID: 16135918]

20 Shah SA, Grant DR, McGilvray ID, Greig PD, Selzner M, Lilly LB, Girgrah N, Levy GA, Cattral MS. Biliary strictures in 130 consecutive right lobe living donor liver transplant recipients:results of a Western center. Am J Transplant 2007; 7: 161 167[PMID: 17227565 DOI: 10.1111/j.1600 6143.2006.01601.x]

21 Morioka D, Egawa H, Kasahara M, Ito T, Haga H, Takada Y,Shimada H, Tanaka K. Outcomes of adult to adult living donor liver transplantation: a single institution’s experience with 335 consecutive cases. Ann Surg 2007; 245: 315 325 [PMID: 17245187 DOI: 10.1097/01.sla.0000236600.24667.a4]

22 Chang JH, Lee IS, Choi JY, Yoon SK, Kim DG, You YK, Chun HJ, Lee DK, Choi MG, Chung IS. Biliary Stricture after Adult Right Lobe Living Donor Liver Transplantation with Duct to Duct Anastomosis: Long Term Outcome and Its Related Factors after Endoscopic Treatment. Gut Liver 2010; 4: 226 233 [PMID:20559526 DOI: 10.5009/gnl.2010.4.2.226]

23 Zimmerman MA, Baker T, Goodrich NP, Freise C, Hong JC,Kumer S, Abt P, Cotterell AH, Samstein B, Everhart JE, Merion RM. Development, management, and resolution of biliary complications after living and deceased donor liver transplantation:a report from the adult to adult living donor liver transplantation cohort study consortium. Liver Transpl 2013; 19: 259 267 [PMID:23495079 DOI: 10.1002/lt.23595]

1．2．2 结构式家庭治疗 研究组20例患儿，在服药的同时给予每2周1次的结构式家庭治疗。接受家庭治疗的人员，主要是与患者长期生活在一起的重要家庭成员，如父母、祖父母或外祖父母。每次家庭治疗时间90min，由受过SFT专业培训的治疗师主持。每个病例个案平均治疗4次。收集首次访谈记录、家谱图及患儿心理测量的结果，以及家庭治疗记录与结果分析判断。

24 Colonna JO 2nd, Shaked A, Gomes AS, Colquhoun SD, Jurim O, McDiarmid SV, Millis JM, Goldstein LI, Busuttil RW.Biliary strictures complicating liver transplantation. Incidence,pathogenesis, management, and outcome. Ann Surg 1992; 216:344 350; discussion 350 352 [PMID: 1417184 DOI: 10.1097/0000 0658 199209000 00014]

25 Soejima Y, Taketomi A, Yoshizumi T, Uchiyama H, Harada N, Ijichi H, Yonemura Y, Ikeda T, Shimada M, Maehara Y.Biliary strictures in living donor liver transplantation: incidence,management, and technical evolution. Liver Transpl 2006; 12:979 986 [PMID: 16721777 DOI: 10.1002/lt.20740]

26 Testa G, Malagó M, Valentín Gamazo C, Lindell G, Broelsch CE.Biliary anastomosis in living related liver transplantation using the right liver lobe: techniques and complications. Liver Transpl 2000;6: 710 714 [PMID: 11084056 DOI: 10.1053/jlts.2000.18706]

27 Bak T, Wachs M, Trotter J, Everson G, Trouillot T, Kugelmas M, Steinberg T, Kam I. Adult to adult living donor liver transplantation using right lobe grafts: results and lessons learned from a single center experience. Liver Transpl 2001; 7: 680 686[PMID: 11510011 DOI: 10.1053/jlts.2001.26509]

28 Kawachi S, Shimazu M, Wakabayashi G, Hoshino K, Tanabe M, Yoshida M, Morikawa Y, Kitajima M. Biliary complications in adult living donor liver transplantation with duct to duct hepaticocholedochostomy or Roux en Y hepaticojejunostomy biliary reconstruction. Surgery 2002; 132: 48 56 [PMID: 12110795]

29 Azoulay D, Marin Hargreaves G, Castaing D, RenéAdam,Bismuth H. Duct to duct biliary anastomosis in living related liver transplantation: the Paul Brousse technique. Arch Surg 2001; 136:1197 1200 [PMID: 11585515 DOI: 10.1001/archsurg.136.10.1197]

30 Gómez CM, Dumonceau JM, Marcolongo M, de Santibañes E, Ciardullo M, Pekolj J, Palavecino M, Gadano A, Dávolos J.Endoscopic management of biliary complications after adult living donor versus deceased donor liver transplantation.Transplantation 2009; 88: 1280 1285 [PMID: 19996927 DOI:10.1097/TP.0b013e3181bb48c2]

治疗前莫西沙星组和左氧氟沙星组患者凝血相关指标比较，差异无统计学意义(P＞0.05)。治疗后两组患者FIB水平低于治疗前，AT-Ⅲ水平、血小板计数和凝血酶时间均高于治疗前，差异具有统计学意义(P＜0.05);治疗后，莫西沙星组患者FIB水平低于左氧氟沙星组，莫西沙星组AT-Ⅲ水平、血小板计数和凝血酶时间均高于左氧氟沙星组，差异具有统计学意义(P＜0.05)。见表2。

31 Rao HB, Ahamed H, Panicker S, Sudhindran S, Venu RP.Endoscopic therapy for biliary strictures complicating living donor liver transplantation: Factors predicting better outcome. World J Gastrointest Pathophysiol 2017; 8: 77 86 [PMID: 28573070 DOI:10.4291/wjgp.v8.i2.77]

The most common clinical presentation of biliary strictures complicating LDLT is a cholestatic pattern of liver function test results, with or without symptoms of obstructive jaundice, such as icterus or pruritus.However, other causes of cholestatic jaundice, such as graft rejection (acute or chronic), recurrence of primary disease (hepatitis B/C), fibrosing cholestatic hepatitis C, sepsis or drug-induced cholestasis[46], make the diagnosis of biliary strictures particularly challenging[52].A high index of suspicion is warranted in such patients,especially since they rarely have abdominal pain due to hepatic denervation and immunosuppressants[53-55]. The diagnostic protocol practised in most centres involves a composite approach with clinical features, laboratory evaluation, imaging studies and liver biopsy.

33 Balderramo D, Navasa M, Cardenas A. Current management of biliary complications after liver transplantation: emphasis on endoscopic therapy. Gastroenterol Hepatol 2011; 34: 107 115[PMID: 20692731 DOI: 10.1016/j.gastrohep.2010.05.008]

34 Simoes P, Kesar V, Ahmad J. Spectrum of biliary complications following live donor liver transplantation. World J Hepatol 2015; 7:1856 1865 [PMID: 26207167 DOI: 10.4254/wjh.v7.i14.1856]

“粮改饲”试点项目实施两年来，发展了清苑县三丰牧草制品有限公司、河北盛世兆苜丰农业服务有限公司、海勋奶牛专业合作社等一大批青贮饲料专业收贮企业。专业青贮企业在青贮补贴、地上青贮设施建设补贴政策与养殖场相同。建设标准化青贮饲料供应基地，将青贮饲料商品化，通过项目补贴降低供应价格，专业青贮企业为中小型养殖场提供物美价廉的青贮饲料，开拓青贮饲料产业化发展的道路。专业青贮企业的青贮饲料大量向山西、内蒙、张家口销售。

注射用阿奇霉素治疗小儿支原体肺炎疗效与安全性的系统评价 …………………………………………… 林巧楠等（22）：3146

36 Kim PT, Marquez M, Jung J, Cavallucci D, Renner EL, Cattral M, Greig PD, McGilvray ID, Selzner M, Ghanekar A, Grant DR.Long term follow up of biliary complications after adult right lobe living donor liver transplantation. Clin Transplant 2015; 29:465 474 [PMID: 25740227 DOI: 10.1111/ctr.12538]

3.习近平新时代中国特色社会主义思想是中国特色社会主义理论体系的重要组成部分。国外学者认为，习近平围绕中国梦、党的建设、祖国统一、依法治国、科学发展等方面的语言表述，为中国特色社会主义理论体系增添了新的时代内容，是当代马克思主义中国化的最新成果。台湾《旺报》2014年8月21日刊文说，习近平与邓小平改革道路相近，都坚定改革信念。邓小平当年曾说“中央没有钱，你们自己搞，要杀出一条血路来”。习近平则说，“敢于啃硬骨头，敢于涉险滩，就没有过不去的火焰山。”[7]德国《明镜》周刊说，邓小平是中国改革的总设计师，习近平将紧跟邓的脚步，加快根本性改革。

“音美”指译诗押韵,且音有轻重,相间如原诗之平仄(即音乐美)。音美是诗歌最为明显的特征之一，形式与内容是辨证统一的。只注重音步、节奏的韵律翻译法和既注意音步又要押韵的谐韵翻译法都因只注重音韵问题忽视其他的方面而无法获得令人满意的译文，而且，刻意追求音韵往往会束缚译者创造性的发挥，结果可能导致意义上的损失。[3]“音美”效果的实现，在于译者本身的水平和能力，因此译者在翻译过程中，必须权衡各种因素做出取舍。

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