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.     

The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation

The acute vanishing bile duct syndrome can be defined as an irreversible, rejection-related condition that affects hepatic allografts within 100 days after orthotopic liver transplantation and whose presence requires retransplantation. We have observed the acute vanishing bile duct syndrome in 5 of 48 consecutive patients (approximately 10%) who underwent orthotopic liver transplantation. In 4 cases, the condition progressed relentlessly within approximately 7 to 11 weeks after orthotopic liver transplantation from mild rejection to severe rejection to acute vanishing bile duct syndrome. A fifth patient had severe rejection in the first week and required retransplantation after 17 days because of thrombotic venoocclusive disease complicating the acute vanishing bile duct syndrome. Clinically, signs of impending acute vanishing bile duct syndrome included abrupt onset of fever and jaundice and marked elevation of serum bilirubin and alkaline phosphatase levels which persisted despite antirejection treatment. Biopsy specimens revealed destructive cholangitis (rejection cholangitis), ductopenia, and, if retransplantation was delayed, presence of noninflammatory, "burnt-out" portal tracts without bile ducts. We recommend to base the diagnosis of acute vanishing bile duct syndrome on documentation of severe ductopenia in at least 20 portal tracts which may require several consecutive needle biopsies. Rejection arteriopathy which was found in 3 of our 5 cases might have been another important diagnostic clue but could not be recognized prior to retransplantation. The pathogenesis of acute vanishing bile duct syndrome is not clear; until the condition had manifested itself, we found no qualitative differences between acute reversible and irreversible rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

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     

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.     

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.     

Current concepts on cytomegalovirus infection after liver transplantation

Cytomegalovirus (CMV) is the most common viral pathogen that negatively impacts on the outcome of liver transplantation. CMV cause febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted allograft. In addition, CMV has been significantly associated with an increased predisposition to allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV on outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is regarded as an essential component to the medical management of liver transplant patients. Two recent guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and at least in one study, such occurrence of late-onset primary CMV disease was significantly associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention are needed, and aggressive treatment of CMV infection and disease should be pursued. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, one should also reduce the degree of immunosuppression. In one recent controlled clinical trial, valganciclovir was found to be as effective and safe as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. In this article, the authors review the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.     

The association between hepatitis C infection and survival after orthotopic liver transplantation

BACKGROUND & AIMS: The effect of hepatitis C viral (HCV) infection on patient and allograft survival after orthotopic liver transplantation is controversial. Hepatitis C recurrence after transplant is inevitable, but studies to date have not found a survival difference between recipients with and without HCV. METHODS: Using data from the United Network for Organ Sharing, we performed a retrospective cohort study of 11,036 patients who underwent 11,791 liver transplants between 1992 and 1998. The hazard rates of patient and allograft survival for patients who were HCV-positive as compared with patients who were HCV-negative were assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including donor, recipient, and transplant center characteristics. RESULTS: Liver transplantation in HCV-positive recipients was associated with an increased rate of death (hazard ratio, 1.23; 95% confidence interval [CI], 1.12-1.35) and allograft failure (hazard ratio, 1.30; 95% CI, 1.21-1.39), as compared with transplantation in HCV-negative recipients. This reduction in survival persisted after adjusting for potential confounders. There was an interaction between HCV and sex (P < 0.001) with the effect of HCV on survival being most pronounced in female recipients (patient survival hazard ratio, 1.56; 95% CI, 1.35-1.81; allograft survival hazard ratio, 1.51; 95% CI, 1.34-1.70). CONCLUSIONS: HCV infection significantly impairs patient and allograft survival after liver transplantation.     

Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation.

In 45 liver transplant recipients, the value of weekly monitoring of cytomegalovirus (CMV) antigenemia for early diagnosis of active CMV infection was compared with serology and rapid viral isolation. Active CMV infection occurred in 23 patients. The sensitivities of the antigenemia assay and serology (of blood) and rapid viral isolation (from blood or urine) were 96%, 96%, 57%, and 70%, respectively. First diagnostic results of these methods were obtained a median of 25, 36, 31, and 49 days, respectively, after transplant. CMV infection was symptomatic in 20 patients; antigenemia was present at the onset of disease in 13 of these. Maximum CMV antigenemia levels were higher in patients with severe disease than in those with mild or asymptomatic infection. CMV antigenemia is a sensitive, early, quantitative marker of active CMV infection after liver transplantation.     

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.     

Risk factors of cytomegalovirus infection after living donor liver transplantation

BACKGROUND/AIMS: Cytomegalovirus (CMV) infection is one of the most common infectious diseases complicating liver transplantation. Data regarding the incidence and results after CMV infection or disease after living donor liver transplantation, however, are limited. METHODOLOGY: A total of 169 patients who underwent living donor liver transplantation in. our department were enrolled in the study. All of the patients were preemptively treated with intravenous ganciclovir (10mg/kg/d) when the pp65 antigenemia assay was positive. The incidence of CMV infection and disease, and risk factors for CMV infection were evaluated. RESULTS: The incidence of CMV infection and CMV disease was 44% and 3%, respectively. Acute rejection was significantly associated with CMV infection. CONCLUSIONS: The incidence of CMV disease was low, suggesting that our strategy might be effective for preventing the development of CMV disease.     

Partial HLA matching and RH incompatibility resulting in graft versus host reaction and Evans syndrome after liver transplantation

We report a case of a 67-year-old male who underwent OLT from a deceased, sex-matched donor. Two months later he developed Evans syndrome and GVHD of the skin. Donor and recipient were matched for HLA-A and -B loci in the direction of rejection but mismatched in the direction of GVHD and fully mismatched for DRB1. These mismatches were permissible for engraftment of donor T-cells but led to GVHD. Chimerism appeared restricted to the T-cell compartment. In this case, partially matched passenger lymphocytes triggered a graft versus host reaction. In addition, alloantibodies caused cytopenias that improved after immunosuppression. HLA typing was critical in confirming this rare diagnosis and elucidating its cause. Recipients of solid organs from donors that are partially matched in the direction of rejection may need to be closely monitored for GVHD.     

Hepatic sarcoidosis with vanishing bile duct syndrome, cirrhosis, and portal phlebosclerosis. Report of an autopsy case

A few cases of sarcoidosis are associated with progressive liver disease, with a wide variety of clinicopathologic features. Herein, we report an autopsy case (65-year-old man). During an examination for liver dysfunction, cirrhosis with cholestatic dysfunction and splenomegaly were found. Needle liver biopsy revealed cirrhosis with lymphocytic piecemeal necrosis, dense septal fibrosis, and ductopenia. In addition, noncaseating epithelioid granuloma was also seen in the periportal region. Ductal enzymes and immunoglobulin M (IgM) levels were elevated, although antimitochondrial antibodies were negative. Instead, angiotensin-converting enzyme was elevated. He died of pulmonary failure and lung cancer. The autopsy liver (1,220 g) showed multinodular cirrhosis with broad and dense septa that divided the parenchyma. Mild lymphoid cell infiltration was seen in the periportal region. About a half of the interlobular bile ducts were lost, and the remaining bile ducts showed prominent periductal fibrosis, resembling sclerosing cholangitis. Interestingly, a few interlobular bile ducts showed chronic nonsuppurative cholangitis with epithelioid granulomas. Intrahepatic portal veins showed luminal narrowing with prominent phlebosclerosis. Hepatobiliary pathologies that resemble primary biliary cirrhosis and primary sclerosing cholangitis and that are followed by vanishing bile duct syndrome, chronic active hepatitis-related cirrhosis, and intrahepatic portal venous phlebosclerosis occur in a single case of sarcoidosis.     

Epidemiology of cytomegalovirus infection after transplantation and immunosuppression.

Viral infections and clinical complications were studied during hemodialysis and after renal transplantation. Active cytomegalovirus infection developed in 96% of patients after renal transplantation; reactivation of herpes simplex, varicella-zoster, and Epstein-Barr viruses was found in 35%, 24%, and 0% of patients, respectively. Cytomegalovirus viremia developed in 42% of patients an average of two months after renal transplantation, lasted 1.75 (+/- 1.5) months (except in one patient with chronic viremia), and was followed by chronic viruria. Higher titers of infectious cytomegalovirus were found in the polymorphonuclear than in the mononuclear leukocyte fraction. Reactivation of a latent infection and, less likely, respiratory infection appear to be the most probable mechanisms of cytomegalovirus infection after renal transplantation. One to three months after transplant, cytomegalovirus infection may be related to fever, arthralgia, pneumonitis, and leukopenia; three to four months after transplant, the virus may be related to hepatitis; and 12-30 months after transplant, it may be related to retinitis in patients with chronic viremia. Although other causes of these complications are possible, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, measles virus, adenovirus, hepatitis B virus, and Toxoplasma gondii appear to be of lesser importance than cytomegalovirus in this respect.