HLA-DRB1 donor-recipient mismatch affects the outcome of hepatitis C disease recurrence after liver transplantation

BACKGROUND & AIMS: This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease. METHODS: Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT). RESULTS: A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis. CONCLUSION: This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented.     

Results of endoscopic management of anastomotic biliary strictures after orthotopic liver transplantation.

BACKGROUND/AIMS: Anastomotic biliary strictures are common biliary complications after orthotopic liver transplantation. We assessed the success of endoscopic retrograde cholangio-pancreaticography (ERCP) in the treatment and outcome of post-liver transplantation anastomotic biliary strictures in a university hospital, retrospectively. METHODS: Thirty-three ERCPs were performed in 20 of 162 adult liver transplant recipients with duct to duct anastomosis. RESULTS: In five patients, ERCP failed because the stricture could not be passed with guidewire. Four patients were treated with balloon dilatation only; two of them are recurrence-free with a follow-up of 24 and 8 months. Eleven patients had balloon dilatation and plastic stent placement as their primary treatment modality. In six of them, the anastomosis remained patent for the rest of the follow-up (22+/-13 months). Five patients had stricture recurrence after first stenting which necessitated re-stenting; four of them required a third, and three had a fourth stenting. CONCLUSIONS: Endoscopic balloon dilatation and stenting are safe and effective means of treatment of anastomotic biliary strictures following liver transplantation.     

The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis

BACKGROUND AND AIMS: We used a multistate modeling approach to assess the effect of ursodeoxycholic acid (UDCA) therapy on the natural course of primary biliary cirrhosis (PBC), which remains controversial. METHODS: Our population included 262 patients with PBC who had received 13-15 mg/kg UDCA daily for a mean of 8 years (range, 1-22 years). Data were analyzed using a multistate Markov model, with histologic stage progression, death, and orthotopic liver transplantation (OLT) as main end points. Survival without OLT was compared with that predicted by the updated Mayo model and with the expected survival in the control population. RESULTS: Forty-five patients developed cirrhosis, 20 underwent OLT, and 16 died by the censor date. Ten deaths were due to liver disease. The overall survival rates were 92% at 10 years and 82% at 20 years. Survival rates without OLT were 84% and 66% at 10 and 20 years, respectively, which were slightly lower than the survival rate of an age- and sex-matched control population (relative risk [RR], 1.4; P = .1) but better than the spontaneous survival rate as predicted by the updated Mayo model (RR, .5; P < .01). The survival rate of patients in stage 1 and 2 was similar to that in the control population (RR, .8; P = .5), whereas the probability of death or OLT remained significantly increased in treated patients in late histologic stages (RR, 2.2; P < .05). CONCLUSIONS: Treatment with UDCA alone normalizes the survival rate of patients with PBC when given at early stages. However, there is a continued need for new therapeutic options in patients with advanced disease.     

Endoscopic management of biliary strictures after liver transplantation

Bile duct strictures remain a major source of morbidity after orthotopic liver transplantation （OLT）. Biliary strictures are classified as anastomotic or non-anastomotic strictures according to location and are defined by distinct clinical behaviors. Anastomotic strictures are localized and short. The outcome of endoscopic treatment for anastomotic strictures is excellent. Nonanastomotic strictures often result from ischemic and immunological events, occur earlier and are usually multiple and longer. They are characterized by a far less favorable response to endoscopic management, higher recurrence rates, graft loss and need for retransplantation. Living donor OLT patients present a unique set of challenges arising from technical factors, and stricture risk for both recipients and donors. Endoscopic treatment of living donor OLT patients is less promising. Current endoscopic strategies for biliary strictures after OLT include repeated balloon dilations and placement of multiple side-by-side plastic stents. Lifelong surveillance is required in all types of strictures. Despite improvements in incidence and long term outcomes with endoscopic management, and a reduced need for surgical treatment, the impact of strictures on patients after OLT is significant. Future considerations include new endoscopic technologies and improved stents, which could potentially allow for a decreased number of interventions, increased intervals before retreatment, and decreased reliance on percutaneous and surgical modalities. Thisreview focuses on the role of endoscopy in biliary strictures, one of the most common biliary complications after OLT.     

Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis

BACKGROUND AND AIMS: The hepatopulmonary syndrome (HPS) has been defined by chronic liver disease, arterial deoxygenation, and widespread intrapulmonary vasodilation. Mortality of patients with HPS is considered to be high, but the effect of HPS on survival in patients with cirrhosis remains unclear. METHODS: A total of 111 patients with cirrhosis were studied prospectively by using transthoracic contrast echocardiography for detection of pulmonary vasodilation, blood gas analysis, and pulmonary function test. Twenty different clinical characteristics and survival times were noted. RESULTS: Twenty-seven patients (24%) had HPS. Their mortality was significantly higher (median survival, 10.6 months) compared with patients without HPS (40.8 mo, P < 0.05), even after adjusting for liver disease severity (2.9 vs. 14.7 months in Child-Pugh class C with [n = 15] and without HPS [n = 35, P < 0.05]; 35.3 vs. 44.5 months in Child-Pugh class B with [n = 7] and without HPS [n = 23, P = NS]), and exclusion of patients who underwent liver transplantation during follow-up (median survival 4.8 vs. 35.2 months, P = 0.005). Causes of death were mainly nonpulmonary and liver-related in the 19 patients with and the 35 patients without HPS who died. In multivariate analysis, HPS was an independent predictor of survival besides age, Child-Pugh class, and blood urea nitrogen. Mortality correlates with severity of HPS. CONCLUSIONS: The presence of HPS independently worsens prognosis of patients with cirrhosis. This should influence patient management and scoring systems and accelerate the evaluation process for liver transplantation.     

Benign biliary strictures: current endoscopic management

Endoscopic treatment is the mainstay of therapy for benign billiary strictures, and surgery is reserved for selected patients in whom endoscopic treatment fails or is not feasible. The endoscopic approach depends mainly on stricture etiology and location, and generally involves the placement of one or multiple plastic stents, dilation of the stricture(s), or a combination of these approaches. Knowledge of biliary anatomy, endoscopy experience and a well-equipped endoscopy unit are necessary for the success of endoscopic treatment. This Review discusses the etiologies of benign biliary strictures and different endoscopic therapies and their respective outcomes. Data on newer therapies, such as the placement of self-expandable metal stents, and the treatment of biliary-enteric anastomotic strictures is also reviewed.     

Complications of the treatment of endoscopic biliary strictures developing after liver transplantation

Background

Bile duct strictures remain a major source of morbidity after orthotopic liver transplantation (OLT). Endoscopic management by the conventional methods of biliary dilatation and/or stent placement has been successful, but sometimes severe complications occur, necessitating prolonged therapy. The aim of this study is to clarify the complications of the endoscopic approach for endoscopic dilatation and/or stent placement.

Method

Of 46 patients who underwent living-donor liver transplantation, 10 were diagnosed as having anatomic biliary strictures by endoscopic retrograde cholangiopancreatography (ERCP). Two patients developing biliary strictures after deceased-donor liver transplantation were also enrolled in the study. For the purpose of comparison, 302 patients with a total of 550 consecutive ERCP cases (including 115 patients with 250 malignant bile duct strictures) were recruited in this study. Success rate, number of endoscopy sessions, the median procedure time for ERCP, and incidence of complications including post-ERCP pancreatitis were compared in the OLT cases and other cases.

Results

The following results were obtained in the OLT cases, malignant stricture cases, and all cases, respectively: mean number of endoscopy sessions was 3.62, 2.17, and 1.94 (P?=?0.0216, P?P?=?0.0327, P?=?0.0093); and severe pancreatitis occurred in 2 cases of OLT. In a univariate analysis for post-ERCP pancreatitis, OLT was extracted as the only significant risk factor.

Conclusions

Endoscopic maneuvering for biliary dilatation and/or stent placement following OLT was associated with a higher risk of post-ERCP pancreatitis than the use of the same technique for the treatment of malignant biliary stricture. Endoscopic treatment after OLT was a significant risk factor for post-ERCP pancreatitis.     

Sphincterotomy-associated biliary strictures: features and endoscopic management

BACKGROUND: "Sphincterotomy stenosis" is a recognized late complication of endoscopic biliary sphincterotomy. The narrowing is limited to the biliary orifice and can be managed simply by repeat sphincterotomy. A similar but poorly characterized post-sphincterotomy complication involves narrowing that extends from the biliary orifice for a variable distance along the bile duct, beyond the duodenal wall. This lesion cannot be managed by repeating the sphincterotomy. METHODS: Six patients (3 men) are described with sphincterotomy associated biliary strictures, all smooth and high grade, presenting at a median of 19 months (range 8 to 60 months) after sphincterotomy. Further sphincterotomy was not possible as an intra-duodenal segment of bile duct was no longer visible. Endoscopic management consisted of serial incremental stent exchange at 2- to 4-month intervals. The goal of therapy was to place two 11.5F stents side-by-side. RESULTS: Stricture resolution was documented by cholangiography in all patients. One patient with a stricture resistant to treatment required three 10F stents side-by-side, and another underwent treatment to a maximum of adjacent 11.5F and 7F stents. Two 11.5F stents were eventually placed in the other four patients. Overall median duration of stent placement was 12.5 months. At a median of 26.5 months of stent-free follow-up, all patients remain asymptomatic. CONCLUSION: Sphincterotomy-associated biliary strictures are a distinct late complication of biliary sphincterotomy. These recalcitrant lesions are not amenable to repeat sphincterotomy; however, the results of this study suggest that they may be managed successfully by serial placement of stents of incrementally increasing diameter.     

Scheduled endoscopic treatment of biliary anastomotic and nonanastomotic strictures after orthotopic liver transplantation

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Postoperative biliary anastomotic strictures after pancreaticoduodenectomy

BackgroundBiliary anastomotic stricture (BAS) is an uncommon complication of pancreaticoduodenectomy (PD). As PDs are performed more frequently, BAS may become a more common pathologic entity requiring clinical engagement. The aim of this study was to report the incidence of BAS in the modern era of pancreatic surgery and identify risk factors associated with it.MethodsPatients undergoing PD at the Johns Hopkins Hospital between 2007 and 2016 were identified using an institutional registry and clinicopathological features were analyzed to identify risk factors associated with BAS.ResultsOf 2125 patients identified, 103 (4.9%) developed BAS. Factors independently associated with BAS included laparoscopic approach (HR:2.83,95%CI:1.35–5.92, p = 0.006), postoperative pancreatic fistula (HR:2.45,95%CI:1.56–4.16,p < 0.001), postoperative bile leak (BL) (HR:5.26,95%CI:2.45–11.28,p < 0.001), and administration of adjuvant radiation therapy (HR:6.01,95%CI:3.19–11.34,p < 0.001). Malignant pathology was associated with lower rates of BAS (HR:0.52,95%CI:0.30–0.92, p = 0.025). BL was associated with higher rates of early-BAS (HR:16.49,95%CI:3.28–82.94, p = 0.001) while use of Vicryl suture for biliary enteric anastomosis was associated with lower rates of early-BAS (HR:0.20,95%CI:0.05–0.93, p = 0.041).ConclusionApproximately 5% of patients undergoing PD experience BAS. Multiple factors are associated with the development and timing of BAS.     

Progress in the endoscopic management of benign biliary strictures

Benign biliary strictures can now be effectively treated with endoscopic therapy in a variety of clinical situations. Despite recent developments in imaging techniques (endoscopic ultrasound and magnetic resonance imaging), it is often difficult to differentiate benign from malignant biliary strictures. The sensitivity of tissue diagnosis (cytology and needle biopsy) at endoscopic retrograde cholangiopancreatography (ERCP) remains poor (40-50%), and further diagnostic methods are required. Endoscopic therapy offers a definitive treatment in 70-90% of patients following post-operative biliary stricture, including anastomotic strictures following liver transplant. Endoscopic therapy successfully achieves symptomatic, biochemical, and cholangiographic response, and may improve survival in patients with primary sclerosing cholangitis. Strictures secondary to chronic pancreatitis are resistant to standard endoscopic therapy and metallic endoprotheses have been trialed with varying success. Endoscopic therapy is technically difficult and should be performed in specialized centres using a multidisciplinary approach.     

Intrahepatic biliary strictures after liver transplantation

Biliary complication has been one of the most common complications after liver transplantation. Nonanastomotic strictures and dilatations involving the intrahepatic biliary tree have been recognized as biliary complications. These lesions were reported to be associated with hepatic artery thrombosis; prolonged preservation time; ABO-incompatible organs; and immunological injury, including injuries to vascular endothelial cells (chronic rejection) and the bile duct (primary sclerosing cholangitis). However, the etiology of these lesions appeared to be mostly related to ischemic injury. Anatomical research on the arterial supply of the bile duct has provided further insights into bile duct blood supply and its surgical implications. The biliary tract is supplied with arterial blood by a vasculature called the peribiliary vascular plexus. Any injury to the peribiliary vascular plexus may contribute to ischemic death of the biliary system mucosa. At many points, the process of liver transplantation exposes the endothelial cells and peribiliary vascular plexus to ischemic injury. The majority of intrahepatic biliary strictures (IHBS) are diffuse or bilateral. A percutaneous or an endoscopic approach has been used as the initial treatment. However, a low threshold for surgical intervention (retransplantation) should be adopted, because these patients demonstrate high mortality. The aim of this article is to review the anatomy, etiology, clinical picture, diagnosis, management, and prognosis of IHBS after liver transplantation.     

Successful endoscopic management of gastrojejunal anastomotic strictures after Roux-en-Y gastric bypass

BACKGROUND: Roux-en-Y gastric bypass is the most frequently performed bariatric surgery for morbid obesity. Gastrojejunal anastomotic strictures are a relatively frequent postoperative complication. OBJECTIVE: To evaluate the clinical outcomes and therapeutic response to through-the-scope balloon dilation performed to treat anastomotic strictures after Roux-en-Y gastric bypass surgery. DESIGN: Single-center, retrospective study. SETTING: Academic medical center. PATIENTS: Between 1997 and 2005, 801 patients with morbid obesity underwent Roux-en-Y gastric bypass surgery at our institution. MAIN OUTCOME MEASUREMENTS: The development of an anastomotic stricture after Roux-en-Y gastric bypass surgery. The response to through-the-scope balloon dilation after diagnosis. RESULTS: Forty-three of 801 patients (5.4%) developed an anastomotic stricture (26 of 294 open surgeries [8.8%]; 17 of 507 laparoscopic surgeries [3.4%]; P < .001). Strictures were dilated to 15.5 +/- 0.4 mm. There were no perforations or clinically significant bleeding after dilation; 93% of the strictures were successfully managed with 1 or 2 endoscopic sessions. Dilation to at least 15 mm did not affect weight loss at 1 year when compared with the group without a stricture (percentage excess weight loss: stricture group, 76%; no stricture group, 74%). LIMITATIONS: Single-center, retrospective study. CONCLUSIONS: Endoscopic balloon dilation is a safe and effective method for the management of gastrojejunostomy strictures after Roux-en-Y gastric bypass. Dilation to at least 15 mm is safe and decreases the need for further endoscopic dilation.     

Benign biliary strictures: Endoscopic management

Over the past 2 decades, endoscopic retrograde cholangiopancreatography with stricture dilation and stent placement has gradually become the first-line treatment modality for the vast majority of benign biliary strictures (BBSs). Stricture remediation with progressive placement of multiple plastic stents with 3 months interval stent exchange during a period of one year has excellent long-term results in patients with postoperative BBSs. Covered self-expandable metal stents (SEMS) are a reasonable alternative to multiple plastic stenting, especially in patients with chronic pancreatitis. The use of covered SEMS should be limited to carefully selected cases of postoperative BBSs. Uncovered SEMS are contraindicated for any type of BBSs. Understanding of the etiology and exclusion of malignancy is essential for optimal treatment in some types of biliary strictures, especially in the case of autoimmune cholangiopathy and primary sclerosing cholangitis.