Composition of bile after orthotopic liver transplantation

In 20 adult patients undergoing orthotopic liver transplantation (OLT), we studied longitudinally for the first 3 weeks after OLT the composition of bile with regard to differences between surviving and non-surviving patients and between patients with more or less rejection and the relation between bile and serum concentrations. The analyzed biliary components were bilirubin, cholesterol, bile acids, phospholipids, copper, iron, glucose, urea, creatinine, ammonia, protein, sodium, potassium, chloride, pH, bicarbonate, calcium and phosphate. After the 1st day the composition of bile was often different from reference values. In most patients deviations of the hepatic excretion function were found. Especially, a sharp fall was noticed in the biliary concentrations of cholesterol and copper. The composition of bile was not helpful in predicting the histologic degree of rejection or the ultimate outcome of the patients. Changes in bile glucose, electrolyte, urea, and creatinine concentrations were positively related to serum concentrations. We conclude that for the compounds analyzed the composition of bile after OLT is not only influenced by the state of the liver but also by the overall metabolic state of the patient.     

Grading of cellular rejection after orthotopic liver transplantation

All 684 post-orthotopic liver transplantation (OLT) liver biopsies performed at the Royal Free Hospital (RFH) between 1988 and 1993, from 120 patients, were reviewed in order to try to define the relative importance of the histological features of immunosuppressionresponsive cellular rejection. Twenty histological features considered to be possible contributors to the diagnosis of cellular rejection were documented in a binary (presentlabsent) fashion. These features in 106 biopsy specimens obtained 1 to 8 days after OLT were analyzed using stepwise logistic discriminant analysis. All clinical and treatment records were reviewed, and each biopsy specimen was assigned to a diagnostic category depending on these records and follow-up information. Important determinants of the histological diagnosis of cellular rejection (which occurred in 84 of the 106 cases) were moderate/severe mixed portal inflammation, eosinophils, endotheliitis, and bile duct damage. When these all occurred together, the odds of rejection increased 3.6-fold. The original histological diagnosis was recorded, and each biopsy specimen showing cellular rejection was regraded according to the specific criteria of Snover et al., Demetris et al., and a novel RFH scoring system. The latter consists of evaluating portal inflammation, endotheliitis, eosinophils, and bile duct damage, each on a 0 to 3 scale (none, mild, moderate, or severe, respectively) and summation. The resulting cellular rejection score thus can range from 0 to 12. The agreement between the different scoring systems was analyzed using K statistics, and there was good concordance (K, 0.64 to 0.78), despite different histological criteria being used to derive each score. Each system showed a similar degree of sensitivity (87% to 96%). The specificity ranged from 59% to 77%. We conclude that the histological diagnosis of cellular rejection relies mainly on the previously described features of mixed portal inflammation, endotheliitis, eosinophils, and duct damage. There is scope for unification and simplification of the existing grading systems, which depend on differing criteria, and we suggest one such scheme.     

Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation.

In this study we evaluated the association between cytomegalovirus infection alone or in relation to human leukocyte antigen matching and the development of vanishing bile duct syndrome, a form of chronic hepatic allograft rejection. A total of 81 consecutive liver transplant recipients were studied. Cytomegalovirus infection developed in 46 recipients (57%), and vanishing bile duct syndrome occurred in 9 recipients (11%). Cytomegalovirus infection developed in only five of the nine patients with vanishing bile duct syndrome. Univariate analysis of pretransplant recipient/donor cytomegalovirus serological tests and human leukocyte antigen typing showed they were not significant risk factors for the development of vanishing bile duct syndrome. Time-dependent analysis of cytomegalovirus infection after transplantation as a risk factor for vanishing bile duct syndrome, in a multivariate analysis with human leukocyte antigen match, showed no statistical significance. In our study, no association was found between cytomegalovirus infection alone or in relation to class I or II human leukocyte antigen match and the subsequent development of vanishing bile duct syndrome.     

胆管消失综合征1例报告

<正>胆管消失综合征(VBDS)最早见Sherlock报道,是以肝内胆管减少为病理学特征,以胆汁淤积为主要临床表现的综合征[1]。病因中包括发育、代谢和免疫学异常、血管病变、感染、淋巴病、药物等因素,真正病因及发病机制尚不明确,临床较为少见[2]。1病历资料患者,女,56岁,无业,因"间断乏力1年"于2011年4月8日入院。既往19年前行剖宫产手术;口服避孕药17年(为短     

Reversible vanishing bile duct syndrome induced by carbamazepine

Carbamazepine, a widely used anticonvulsant, can induce hepatotoxicity, usually evolving with an acute hepatitis that ceases after drug withdrawal. Carbamazepine-induced vanishing bile duct syndrome (VBDS) is a rare complication and has seldom been reported in the medical literature. This report presents a case of a 26-year-old male who had onset of epilepsy at 12 months of age and was initially treated with phenobarbital. Carbamazepine (1200 mg/day) was added in June 1996 when he was 22 years old to control the frequency of seizures. Two years later, during a routine investigation, elevation of serum gamma-glutamyltransferase (GGT) levels was detected. For this reason, the patient was weaned off carbamazepine, followed 6 months later by complete withdrawal of the drug. The first liver biopsy disclosed total absence of interlobular bile ducts (IBD) in 30 portal tracts. Fourteen months later, a control biopsy showed the presence of IBD in eight of 14 portal tracts. There was also a decrease of GGT levels detected 27 months after withdrawal of carbamazepine. This case illustrates the ductopenic effect of carbamazepine when used for a prolonged time, as reported in three previous publications. However, this is the first case in which there was a remission of the VBDS and bile duct regeneration after withdrawal of the drug.     

Mycophenolate mofetil for drug-induced vanishing bile duct syndrome

Amoxicillin/clavulanate is associated with liver injury, mostly of a cholestatic pattern. While outcomes are usually benign, progression to cirrhosis and death has been reported. The role of immunosuppressive therapy for patients with a protracted course is unclear. We report the case of an elderly patient who developed prolonged cholestasis secondary to amoxicillin/clavulanate. Vanishing bile duct syndrome was confirmed by sequential liver biopsies. The patient responded to prednisone treatment, but could not be weaned off corticosteroids, even when azathioprine was added. Complete withdrawal of both prednisone and azathioprine was possible by using mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor. Sustained remission has been maintained for more than 3 years with low-dose mycophenolate mofetil.     

Vanishing bile duct syndrome after drug-induced liver injury

BackgroundVanishing bile duct syndrome (VBDS) is a serious cholestatic liver disease that can be a complication of drug-induced liver injury (DILI). While journals have published case reports of this condition, large studies on a cohort of these patients are lacking. We aimed to compile published case reports and case series of patients with VBDS and DILI to describe the clinical and laboratory characteristics of the disease and identify factors associated with good and poor outcomes.MethodsWe included case reports and case series of VBDS secondary only to DILI. We extracted demographic, clinical, laboratory, treatment, and exposure data from each case report and categorized cases by outcome, good versus poor. We defined poor outcomes as cases with severe long-term complications or death. We analyzed risk factors for poor outcomes using logistic regression.ResultsWe identified a total of 59 eligible cases. Of those, 39 (59%) were female, the median age was 36 (IQR:12–58), and 18 (31%) were pediatric cases (≤18 years). The most common offending drug class was antibiotics, especially beta-lactams. Patients with increased total bilirubin (OR=4.69; 95% CI=1.55–15.49; p = 0.008), increased direct bilirubin (OR=6.50; 95% CI=1.34–48.91; p = 0.034), lower liver synthetic activity (OR=0.11; 95% CI=0.02–0.55; p = 0.013), and older age (OR=3.31; 95% CI=1.15–10.04; p = 0.029) were more likely to develop poor outcomes.ConclusionsIn patients with VBDS and DILI, antibiotics were the most common offending agents. Higher total and direct bilirubin levels were associated with poor outcomes.     

Role of interventional therapy in hepatic artery stenosis and non-anastomosis bile duct stricture after orthotopic liver transplantation

AIM: To analyze the clinical manifestations and the effectiveness of therapy in patients with orthotopic liver transplantation (OLT)-associated hepatic artery stenosis (HAS) and non-anastomosis bile duct stricture. METHODS: Nine cases were diagnosed as HAS and non-anastomosis bile duct stricture. Percutaneous transluminal angioplasty (PTA) was performed in four HAS cases, and expectant treatment in other fi ve HAS cases; percutaneous transhepatic bile drainage, balloon dilation, stent placement were performed in all nine cases. RESULTS: Diffuse intra-and extra-bile duct stricture was observed in nine cases, which was associated with bile mud siltation and biliary infection. Obstruction of the bile duct was improved obviously or removed. Life span/ follow-up period was 13-30 mo after PTA of four HAS cases, 6-23 mo without PTA of other fi ve cases. CONCLUSION: Progressive, non-anastomosis, and diffuse bile duct stricture are the characteristic manifestations of HAS and non-anastomosis bile duct stricture after OLT. These are often associated with bile mud siltation, biliary infection, and ultimate liver failure. Interventional therapy is signifi cantly benefi cial.     

Cytomegalovirus infection persists in the liver graft in the vanishing bile duct syndrome.

Cytomegalovirus infection is one factor implicated in the cause of the vanishing bile duct syndrome complicating liver transplantation. To further investigate the role of cytomegalovirus in this syndrome, we studied serial liver biopsy material by in situ hybridization for cytomegalovirus DNA using a highly sensitive technique that allows the localization of viral replication. Cytomegalovirus DNA was identified in hepatocytes in 10 of 12 patients with the vanishing bile duct syndrome, 1 of whom had no serological evidence of cytomegalovirus infection. It was also present in all 18 patients with uncomplicated cytomegalovirus infection but was not identified in any of 10 subjects with transplants who had neither complication. Nine of the patients in this series underwent a diagnostic liver biopsy at 1 wk and subsequently had cytomegalovirus infection develop; cytomegalovirus DNA was identified in liver tissue of all nine patients, indicating that cytomegalovirus replication commences at an early stage. In those with uncomplicated cytomegalovirus, infection occurred earlier (p less than 0.05) but was eliminated more quickly (p less than 0.0005), and the number of infected hepatocytes was greater (p less than 0.05) when compared with those with the vanishing bile duct syndrome; in these, cytomegalovirus DNA was detectable until death or retransplantation. Cytomegalovirus DNA was never identified in either biliary or endothelial tissue. These data indicate that the vanishing bile duct syndrome is associated with persistent cytomegalovirus replication within hepatocytes.     

Late-onset acute rejection after living donor liver transplantation

INTRODUCTION Standard regimens for immunosuppressive therapy after liver transplantation include calcineurin inhibitors and steroids, which result in a reduced incidence of acute rejection and improved recipient survival[1]. The long- term complications o…     

40例临床肝移植血管和胆管重建经验

目的：总结第三军医大学西南医院肝移植时血管及胆管重建的经验。方法：回顾性分析40例肝移植时血管重建，胆道重建的方法及效果。结果：本研究肝移植病例围手术期死亡6例，手术病死率为15．0％，并发症为：肺部感染18例，多器官功能衰竭5例；腹腔内出血4例：ARDS8例；肝动脉血栓形成1例，胆漏1例，脑出血1例，存最长的1例为31个月，有15例生存期超过1年。结论：良好的血管和胆管重建技术是确保肝移植手术成功的关键。     

Pathogenesis and treatment of bile duct loss after liver transplantation

The bile duct is one of the main targets of immune reaction after liver transplantation. Bile duct loss, termed ductopenia or vanishing bile duct syndrome, is a typical pathological finding of chronic rejection (CR). The mechanism of bile duct loss in allograft rejection is twofold: T‐cell mediated cytotoxicity and ischemic sequelae caused by obliterative arteriopathy. Whether or not CR is reversible remains controversial. Accumulating data show the reversibility of bile duct injury caused by immunoreaction, but not the reversibility of injuries caused by ischemia. In our living‐related liver transplantation program at Kyoto University Hospital, the incidence of ductopenia, which indicates the incidence of CR, was 14 of 423 patients (3.3%), comparable to the result for cadaveric liver transplantation. The onset was within 1 year, except in 2 patients. Of the 14 patients with ductopenia, 2 recovered without re‐transplantation, and of the remaining 12 patients, 7 underwent re‐transplantation, and the other 5 died without a chance of re‐transplantation. The diagnosis of ductopenia was based on the pathological findings, which specify that more than 50% of the portal triad does not contain visible bile ducts. Recently, staging criteria of CR were proposed by an international panel, who recommended splitting CR into an early stage and a late stage. At present, no specific immunosuppressive regimen for CR has been developed; however, early diagnosis based on these new criteria, and the earlier implementation of enforced immunosuppression, with conventional drugs, may be beneficial for a further reduction in CR.     

Ductal regeneration in vanishing bile duct syndrome in Hodgkin's lymphoma

We present the case of a 17-year-old male patient with Hodgkin's lymphoma (nodular sclerosis) in the mediastinum. During the postoperative period treatment with erythromycin was started and the patient developed progressive jaundice and cholestasis. Treatment modified for the lymphoma was initiated, which achieved complete remission and subsequent improvement and resolution of the cholestasis. Histological study of the liver revealed massive loss of bile ducts. After resolution of the cholestasis, consecutive biopsies revealed ductal proliferation. The present report therefore illustrates a case of ductopenia or vanishing bile duct syndrome (VBDS) with ad integrum regeneration of the bile ducts simultaneous with lymphoma remission. Because the 2 possible causes, erythromycin toxicity and Hodgkin's lymphoma, occurred simultaneously, the etiology of the VBDS cannot be definitively established.     

Recovery of bile secretion following orthotopic liver transplantation

Recovery of hepatic function following orthotopic liver transplantation includes the ability to produce 'adequate' bile. What constitutes adequate bile flow, however, has not previously been defined. The present study was undertaken to characterize biliary water and electrolyte secretion following hepatic transplantation. Bile was sampled from nine liver transplant recipients for 15-25 consecutive days during chronic t-tube biliary drainage. Liver biopsies and t-tube cholangiograms were unremarkable in all patients. During the first post-operative day mean bile flow, bile salt concentration, [BS], and bile salt output (BSO) were 60.0 microliters/min, 6.8 mM and 0.41 mumol/min, respectively. [BS] increased over days 1-5 and then plateaued at 12.2 mM over days 6-25 post-transplant. BSO and bile flow increased over days 1-12 before achieving steady-state values of 4.52 mumol/min and 334.7 microliters/min, respectively. In each patient bile flow increased linearly with increasing BSO. Choleretic index (CI), varied from 36.9-77.1 microliters/mumol (mean: 50.7 +/- 8.8). The y-intercept for this relationship ranged from 52.4-156.9 microliters/min (mean: 95.9 +/- 81.8). Only primary bile salts (82% cholate and 17% chenodeoxycholate), were observed in the bile of each patient. Biliary electrolyte concentrations were similar to that observed in plasma. Each was relatively unaffected by changes in bile flow and BSO. Electrolyte outputs increased linearly with respect to both BSO and bile flow. We conclude that recovery of bile secretion following orthotopic liver transplantation occurs gradually over a 10-12 day period and is strongly dependent upon bile salt secretion.     

Recurrence of the Budd-Chiari syndrome after orthotopic liver transplantation.

Obstruction of the hepatic venous outflow with or without involvement of the vena cava results in the Budd-Chiari syndrome (BCS). BCS may be limited to the liver but there is a variety of systemic disorders forming the etiology of BCS in the majority of cases. Surgery has a major impact on treatment of the BCS within a wide range of therapeutic strategies. The ultimate option of surgical management of the BCS is orthotopic liver transplantation (OLTx). The case of a patient with recurrent disease more than 5 years after OLTx for BCS due to paroxysmal nocturnal hemoglobinuria is analyzed with complete documentation. The literature is reviewed and the probable underlying causes for recurrent disease after OLTx for BCS are discussed including therapeutic consequences.     

Endoscopic therapy of anastomotic bile duct strictures occurring after liver transplantation

BACKGROUND: Optimal therapy for anastomotic biliary strictures occurring after orthotopic liver transplantation (OLT) remains to be defined. We reviewed our experience with endoscopic therapy for such strictures and contrasted it with reported data. METHODS: Endoscopic therapy was performed with balloon dilation alone; no patients received an endoprosthesis. Responses were characterized as good if the patient improved clinically and no subsequent procedures were required after one or more dilations within a 3-month period; partial if clinically significant obstruction resolved but cholestasis persisted or there was a need for further endoscopic management beyond the initial 3 months; poor if subsequent surgery or percutaneous procedures were required; and failed if endoscopic access or dilation could not be accomplished. RESULTS: Fifteen patients underwent 23 endoscopic retrograde cholangiopancreatographies for post-OLT anastomotic strictures. Postprocedure follow-up averaged 25.2 months. Cholangiography was successful in all 23 procedures; free duct access was achieved in 22 of 23 procedures. The strictures were successfully accessed for dilation in 11 of 15 patients and in 19 of 23 procedures. Outcome was deemed good in 4 (27%), partial in 3 (20%), and poor in 5 (33%) patients. Endoscopic therapy failed in 3 (20%). Poor outcomes were due to the early recognition of severe lesions (2 treated surgically) or to short-term responses to dilation alone (3). The procedural complication rate of 17.4% included 3 episodes of transient cholangitis (i.e., elevation of liver enzymes associated with fever that lasted less than 3 days) and 1 self-limited episode of postsphincterotomy bleeding, which required the transfusion of 2 units packed red blood cells. In published series the combined success rate of balloon dilation alone for treatment of anastomotic strictures is 41%, whereas for dilation plus stent placement it is 75%. CONCLUSION: Endoscopic balloon dilation alone is not a reliable method of therapy for anastomotic strictures occurring after OLT. Dilation followed by short- to intermediate-term stent placement appears to provide a more durable result.