Aad P. van den Berg

Increased cancer risk after liver transplantation: a population-based study

BACKGROUND/AIMS Development of de novo malignancies emerges as a serious long term complication after liver transplantation. METHODS We reviewed the medical records of 174 adult one-year survivors for de novo malignancies. The observed cancer rates were compared with the expected cancer rates in the Dutch population. RESULTS Twenty-one of the 174 patients developed 23 malignancies (12%). Skin and lip cancer accounted for 12 of the 23 malignancies (52%). Only one patient had a B-cell lymphoma. The cumulative risk for de novo malignancy was 6, 20, and 55% at 5, 10, and 15 years after transplantation, respectively. The overall relative risk (RR) as compared with the general population was 4.3 (95% confidence interval 2.4-7.1). Significantly increased RRs were observed for non-melanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5). Multivariate analysis showed that an age > 40 years and pretransplant use of immunosuppression were significant risk factors. CONCLUSIONS An increased risk of cancer exists after liver transplantation, for both for skin/lip cancer, and other solid tumors. Older age and the use of immunosuppression are risk factors.

Anastomotic biliary strictures after liver transplantation: Causes and consequences

We retrospectively studied the prevalence, presentation, results of treatment, and graft and patient survival of grafts developing an anastomotic biliary stricture (AS) in 531 adult liver transplantations performed between 1979 and 2003. Clinical and laboratory information was obtained from the hospital files, and radiological studies were re‐evaluated. Twenty‐one possible risk factors for the development of AS (variables of donor, recipient, surgical procedure, and postoperative course) were analyzed in a univariate and stepwise multivariate model. Forty‐seven grafts showed an anastomotic stricture: 42 in duct‐to‐duct anastomoses, and 5 in hepaticojejunal Roux‐en‐Y anastomoses. The cumulative risk of AS after 1, 5, and 10 years was 6.6%, 10.6%, and 12.3% respectively. Postoperative bile leakage (P = 0.001), a female donor/male recipient combination (P = 0.010), and the era of transplantation (P = 0.006) were independent risk factors for the development of an AS. In 47% of cases, additional (radiologically minor) nonanastomotic strictures were diagnosed. All patients were successfully treated by 1 or more treatment modalities. As primary treatment, endoscopic retrograde cholangiopancreaticography (ERCP) was successful in 24 of 36 (67%) cases and percutaneous transhepatic cholangiodrainage in 4 of 11 (36%). In the end 15 patients (32%) were operated, all with long‐term success. AS presenting more than 6 months after transplantation needed more episodes of stenting by ERCP, and more stents per episode compared to those presenting within 6 months and recurred more often. Graft and patient survival were not impaired by AS. Liver Transpl 12:726–735, 2006.

Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases

Background and aim: Isolated polycystic liver disease (PCLD) is characterized by the presence of multiple cysts in the liver in the absence of polycystic kidneys. The clinical profile of PCLD is poorly defined and we set up a study for the clinical characteristics of PCLD.

Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases

BACKGROUND/AIMS The clinical relevance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver disease is unclear. Defining the antigenic specificities of ANCA in these diseases may improve their clinical significance. METHODS We studied the target antigens of ANCA in 88 patients with autoimmune hepatitis, 53 patients with primary biliary cirrhosis, and 55 patients with primary sclerosing cholangitis by indirect immunofluorescence, antigen-specific enzyme-linked immunosorbent assays, and immunodetection on Western blot, using an extract of whole neutrophils as a substrate. We related the data to clinical symptoms of autoimmune liver disease. RESULTS By indirect immunofluorescence, ANCA were present in 74% of patients with autoimmune hepatitis, 26% of patients with primary biliary cirrhosis, and 60% of patients with primary sclerosing cholangitis. Major antigens were catalase, alpha-enolase, and lactoferrin. The presence of ANCA as detected by indirect immunofluorescence was associated with the occurrence of relapses in autoimmune hepatitis, with decreased liver synthesis function in primary biliary cirrhosis and in primary sclerosing cholangitis, and with increased cholestasis in primary sclerosing cholangitis. ANCA of defined specificities had only limited clinical relevance. CONCLUSIONS ANCA as detected by indirect immunofluorescence seem associated with a more severe course of autoimmune liver disease. The target antigens for ANCA in these diseases include catalase, alpha-enolase, and lactoferrin. Assessment of the antigenic specificities of ANCA in autoimmune liver disease does not significantly contribute to their clinical significance.

Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback techniques in adults

Abstract:  The aim of this study is to analyse a single centres experience with two techniques of liver transplantation (OLT), conventional (CON‐OLT) and piggyback (PB‐ES), and to compare outcome in terms of survival, morbidity, mortality and post‐operative liver function as well as operative characteristics. A consecutive series (1994–2000) of 167 adult primary OLT were analysed. Ninety‐six patients had CON‐OLT and 71 patients had PB‐ES. In PB‐ES group two revascularization protocols were used. In the first protocol reperfusion of the graft was performed first via the portal vein followed by the arterial anastomosis (PB‐seq). In the second protocol the graft was reperfused simultaneously via portal vein and hepatic artery (PB‐sim). One‐, 3‐ and 5‐yr patient survival in the CON‐OLT and PB‐ES groups were 90, 83 and 80%, and 83, 78 and 78%, respectively (p = ns). Graft survival at the same time points was 81, 73 and 69%, and 78, 69 and 65%, respectively (p = ns). Apart from the higher number of patients with cholangitis and sepsis in CON‐OLT group, morbidity, retransplantation rate and post‐operative liver and kidney function were not different between the two groups. The total operation time was not different between both groups (9.4 h in PB‐ES vs. 10.0 h in CON‐OLT), but in PB‐ES group cold and warm ischaemia time (CIT and WIT), revascularization time (REVT), functional and anatomic anhepatic phases (FAHP and AAHP) were significantly shorter (8.9 h vs. 10.7 h, 54 min vs. 63 min, 82 min vs. 114 min, 118 min vs. 160 min and 87 min vs. 114 min, respectively, p < 0.05). RBC use in the PB‐ES group was lower compared to the CON‐OLT group (4.0 min vs. 10.0 units, p < 0.05). Except for WIT and REVT there were no differences in operative characteristics between PB‐Sim and PB‐Seq groups. The WIT was significantly longer in PB‐Sim group compared with PB‐Seq group (64 min vs. 50 min, p < 0.05); however REVT was significantly shorter in PB‐Sim group (64 min vs. 97 min, p < 0.05). Results of this study show that both techniques are comparable in survival and morbidity; however PB‐ES results in shorter AAHP, FAHP, REVT and WIT as well as less RBC use. In the PB‐ES group there seems to be no adavantage for any of the revascularization protocols.

Mycophenolate mofetil: role in autoimmune hepatitis and overlap syndromes.

Aliment Pharmacol Ther 2011; 34: 335–343

Inflammatory bowel disease after liver transplantation: a role for cytomegalovirus infection

Objective. Despite the use of immunosuppressive drugs, recurrent and de novo inflammatory bowel disease (IBD) can develop after orthotopic liver transplantation (OLT). Cytomegalovirus (CMV) infection has been suggested to play a role in the pathogenesis of IBD. The aim of this study was to investigate the role of CMV infection in the development of IBD after OLT. Material and methods. All 84 patients who underwent transplantation for primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) in our center between May 1987 and June 2002 and who survived the first year after transplantation were included in the study. Diagnosis of active CMV infection was made using the pp65–antigenemia assay. Results. Thirty-one of the 84 patients (37%) had IBD prior to OLT. Eighteen patients (21%) experienced IBD after OLT, either as flare-up (n=12) or de novo (n=6), at a median of 1.4 years (range 0.3 to 6.3) after OLT. Forty-eight percent of all patients experienced CMV infection after OLT, at a median of 27 days (range 8 to 193). CMV infection was primary in half the patients. At 1, 3, and 5 years after OLT, active IBD-free survival without CMV infection was 91, 88, and 88%, respectively. With CMV infection these figures were 93, 82, and 67%. De novo IBD was seen only in those who had experienced a CMV infection (p=0.02). Conclusions. In patients transplanted for end-stage PSC or AIH, active IBD, especially de novo IBD, occurred more often in patients who experienced CMV infection in the postoperative period. This finding supports a pathogenic role for CMV in the development of IBD.

Prevalence of prednisolone (non)compliance in adult liver transplant recipients

Limited evidence is available concerning (non)compliance with the immunosuppressive regimen in adult liver transplant recipients. In our study we prospectively assessed prednisolone (non)compliance in 108 adult liver transplant recipients using electronic event monitoring (EEM) in an outpatient setting. The EEM is a pill bottle fitted with a cap containing a microelectronic circuit that registers date and time of bottle openings and closings. Median taking compliance was 100% (range 60–105%), median dosing compliance was 99% (range 58–100%); median timing compliance (TIC) was 94% (42–100%). A drug holiday (DH) of ≥48 h was found in 39% of the patients of ≥72 h in 16% of the patients. Using EEM in liver transplant recipients, we found an overall high level of compliance for prednisolone, except that TIC was low in about one third of the patients. Age below 40 years was found a significant risk factor for decreased TIC and for DHs of ≥48 h.

HLA-DR expression on monocytes and systemic inflammation in patients with ruptured abdominal aortic aneurysms

IntroductionMortality from ruptured abdominal aortic aneurysms (RAAA) remains high. Severe systemic inflammation, leading to multi-organ failure, often occurs in these patients. In this study we describe the level of HLA-DR expression in a consecutive group of patients following surgery for RAAA and compare results between survivors and non-survivors. A similar comparison is made for IL-6 and IL-10 levels and Sequential Organ Failure Assessment (SOFA) scores.MethodsThis is a prospective observational study. Patients with RAAA were prospectively analysed. Blood samples were collected on days 1, 3, 5, 7, 10 and 14. The fraction of CD-14 positive monocytes expressing HLA-DR was measured by flow-cytometry. IL-6 and IL-10 levels were measured by ELISA.ResultsThe study included 30 patients with a median age of 70 years, of which 27 (90%) were men. Six patients died from multiple organ failure, all other patients survived. The SOFA scores were significantly higher in non-survivors on days 1 through 14. HLA-DR expression on monocytes was significantly lower on days 3, 5, 7, 10 and 14 in non-survivors. IL-6 and IL-10 levels were significantly higher in non-survivors on day 1 and days 1 and 3, respectively.ConclusionHLA-DR expression on monocytes was decreased, especially in non-survivors. All patients with RAAA displayed a severe inflammatory and anti-inflammatory response with an increased production of IL-6 and IL-10. Poor outcome is associated with high levels of IL-6 and IL-10 and a high SOFA score in the first three days after surgery, while low levels of HLA-DR expression are observed from day three after RAAA repair.

Analysis of differences in outcome of two European liver transplant centers

Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1‐, 3‐ and 5‐year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per‐operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni‐ and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri‐operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.