Prognostic Importance of Increased Right Ventricular Afterload in Orthotopic Liver Transplantation Recipients With Endstage Cirrhosis.

BACKGROUND: Severely increased right ventricular (RV) afterload is considered a contra-indication for orthotopic liver transplantation (OLT). This study assesses the effects of mildly increased RV afterload on long-term outcome after OLT in relation to RV function. METHODS: 139 OLT recipients (53±12years, 76% male) were included. Preoperative RV afterload was assessed invasively or, if not available, echocardiographically and categorised as normal, high-normal (mean pulmonary artery pressure [PAP] 20-25mmHg or echocardiographic systolic PAP 35-40mmHg) or mildly elevated (mean PAP 25-35mmHg or systolic PAP 40-50mmHg). The association between level of RV afterload, echocardiographic RV function and postoperative outcome was assessed. RESULTS: Right ventricular afterload was high-normal in 17% and mildly elevated in 12% of patients. Patients with elevated RV afterload had higher echocardiographic RV dimensions and left ventricular filling pressures. RV functional parameters were within normal range and not associated with RV afterload. Increased RV afterload was associated with a higher incidence of postoperative haemodynamic complications (8%, 17%, and 29% for normal, high-normal and mildly elevated RV afterload, respectively, p=0.03) and worse survival (8-year survival 74%, 41% and 37% respectively, p=0.01). Preoperative RV function was not associated with outcome after OLT. CONCLUSIONS: Increased RV afterload was associated with increased haemodynamic complications and worse long-term survival in OLT recipients. Right ventricular function in patients with increased RV afterload was within normal range and not associated with postoperative outcome.

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients.

PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure. METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients. RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration. CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Similar liver transplantation survival with selected cardiac death donors and brain death donors.

BACKGROUND: The outcome of orthotopic liver transplantation (OLT) with controlled graft donation after cardiac death (DCD) is usually inferior to that with graft donation after brain death (DBD). This study compared outcomes from OLT with DBD versus controlled DCD donors with predefined restrictive acceptance criteria. METHODS: All adult recipients in the Netherlands in 2001-2006 with full-size OLT from DCD (n = 55) and DBD (n = 471) donors were included. Kaplan-Meier, log rank and Cox regression analyses were used. RESULTS: One- and 3-year patient survival rates were similar for DCD (85 and 80 per cent) and DBD (86.3 and 80.8 per cent) transplants (P = 0.763), as were graft survival rates (74 and 68 per cent versus 80.4 and 74.5 per cent; P = 0.212). The 3-year cumulative percentage of surviving grafts developing non-anastomotic biliary strictures was 31 per cent after DCD and 9.7 per cent after DBD transplantation (P < 0.001). The retransplantation rate was similar overall (P = 0.081), but that for biliary stricture was higher in the DCD group (P < 0.001). Risk factors for 1-year graft loss after DBD OLT were transplant centre, recipient warm ischaemia time and donor with severe head trauma. After DCD OLT they were transplant centre, donor warm ischaemia time and cold ischaemia time. DCD graft was a risk factor for non-anastomotic biliary stricture. CONCLUSION: OLT using controlled DCD grafts and restrictive criteria can result in patient and graft survival rates similar to those of DBD OLT, despite a higher risk of biliary stricture.

Retrieval of chronic hepatitis C patients. A manifesto for action to eliminate hepatitis C in the Netherlands: the CELINE project.

Chronic hepatitis C virus (HCV) infection is a global public health issue, which is associated with high rates of morbidity and mortality. The development of direct acting antivirals (DAAs) has transformed treatment: they offer us highly-effective therapy with superior tolerability compared to interferon-containing regimens. In 2016, the World Health Organization (WHO) therefore adopted several ambitious viral hepatitis elimination targets, aiming for a 90% reduction in new infections and a 65% reduction in mortality by 2030. The ultimate goal is to eliminate HCV completely. It is reasonable that these goals may be achieved in the Netherlands due to the low prevalence of chronic HCV, the availability of DAAs, and excellent healthcare infrastructure. This paper describes a national effort to curtail the HCV epidemic in the Netherlands through an HCV retrieval and linkage to care project (CELINE: Hepatitis C Elimination in the Netherlands).

Liver transplantation in a patient with encapsulating peritoneal sclerosis.

Encapsulating peritoneal sclerosis (EPS) is a poorly understood condition in which excess fibrosis results in an encasement of the small bowel, which can clinically result in obstruction. The condition is thought to be related to the persistent expression of transforming growth factor beta on mesothelial cells causing proliferation of subserosal fibroblasts, massive production of extracellular matrix and loss of mesothelial cells. We report a patient with liver cirrhosis in whom the diagnosis of EPS was made. During laparotomy for liver transplantation the complete peritoneum was found to be thickened, consisting of white sheets; liver transplantation was deferred. Histological examination showed peritoneal sclerosing fibrosis. Immunosuppressive medication was started and a difficult but successful liver transplantation followed. If EPS is diagnosed during laparotomy for organ transplantation, adjusted immunosuppression is preferred as calcineurin inhibitors such as cyclosporin and tacrolimus may accelerate EPS while prednisone and some other drugs may stop progression.

[Dutch study on the optimal treatment strategy for patients with a first or second occurrence of gastro-oesophageal variceal bleeding: the TIPS-TRUE trial]. / Nederlandse studie naar de beste behandelstrategie bij patiënten met een eerste of tweede oesofagus- of maagvaricesbloeding: de TIPS-TRUE-trial.

The main options for secondary prevention of gastrooesophageal variceal bleeding are endoscopic therapy and treatment with propranolol. Creation ofa transjugular intrahepatic portosystemic shunt (TIPS) is currently considered a valuable secondary 'rescue' treatment when other therapies fail. Recent data suggest that the use of covered stents markedly increases the efficacy of TIPS, compared with conventional uncovered stents. Therefore, a multicentre randomised trial was designed to compare the effects of TIPS using covered stents with those of endoscopic therapy plus propranolol in patients with a first or second episode ofgastro-oesophageal variceal bleeding. TIPS will be performed in 4 university centres with relevant expertise. The trial will hopefully gain nationwide support, and all centres in The Netherlands are cordially invited to participate.

['Will I receive a liver transplant in time?'; chance of survival of patients on the liver transplant waiting list]. / 'Komt mijn nieuwe lever wel op tijd?'.

OBJECTIVE: To calculate the chance of receiving a liver transplant for patients on the liver transplant waiting list in the Netherlands. DESIGN: Retrospective cohort research. METHOD: Data of all patients in the Netherlands on the waiting list for liver transplantation, from the introduction of the model of end-stage liver disease score on 16th December 2006 through to 31st December 2013 were collected. Survival analysis was computed with competing risk analyses. RESULTS: A total of 851 patients were listed, of whom 236 patients with hepatocellular carcinoma, 147 patients with primary sclerosing cholangitis, 142 patients with post-alcoholic liver disease, 93 patients with metabolic liver disease, 78 with viral hepatitis and 155 patients listed for other indications. The median waiting time till transplantation was 196 days. The chance to be transplanted at two years from listing was 65% and the risk of death was 17%. Patients with metabolic liver disease had the highest chance of undergoing liver transplantation. Patients with viral hepatitis were at highest risk of death while on the list, as well as having the lowest chance of undergoing liver transplantation. CONCLUSION: Our study shows a 65% chance of getting transplanted in time after a median waiting time of 6 months in the Netherlands. Sadly, 1 in 6 patients die before liver transplantation can be performed, with the highest risk of death occurring in patients with viral hepatitis.

Individualized population pharmacokinetic model with limited sampling for cyclosporine monitoring after liver transplantation in clinical practice.

BACKGROUND: We recently developed and validated limited sampling models (LSMs) for cyclosporine monitoring after orthotopic liver transplantation based on individualized population pharmacokinetic models with Bayesian modelling. Aim To evaluate LSM in practice, and to seek optimal balance between benefit and discomfort. METHODS: In 30 stable patients, more than 6 months after orthotopic liver transplantation, previously switched from trough- to 2 h post-dose (C2)-monitoring, we switched to 3-monthly LSM 0,1,2,3 h-monitoring. During 18 months we evaluated dose, creatinine clearance, calculated area under the curve, intra-patient pharmacokinetic variability and ability to assess systemic exposure by several previously validated LSMs. RESULTS: Within patients, there was variability of cyclosporine-area under the curve with the same dose (CV of 15%). Compared to C2-monitoring, there was no significant difference in dose (P = 0.237), creatinine clearance (P = 0.071) and number of rejections. Some models showed excellent correlation and precision with LSM 0,1,2,3 h comparing area under the curves (0,2 h: r(2) = 0.88; 0,1,3 h: r(2) = 0.91; 0,2,3 h: r(2) = 0.92, all P < 0.001) with no difference in advised dose. CONCLUSIONS: The limited sampling model, with only trough- and 2-h sampling, yields excellent accuracy and assesses systemic exposure much better than C2 with less bias and greater precision. Considering the calculated intra-patient variability, more precision is redundant, so LSM 0,2 h seems the optimal way of cyclosporine-monitoring.

Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review.

Alpha-I antitrypsin (AIAT) is an acute-phase protein that is produced in liver cells. AIAT deficiency is a hereditary disease which is defined by the hepatic production of an abnormal protein that can not be released into the plasma. This leads to deficiency of plasma AIAT and subsequently to an impaired protection against proteases, resulting in pulmonary disease. Accumulation of the abnormal protein in hepatocytes can lead to liver damage. Serum level measurement, phenotyping and liver biopsy can be used for establishing the diagnosis. Homozygous AIAT deficiency can cause neonatal hepatitis; in adults end-stage liver disease, cirrhosis and hepatocellular carcinoma can develop. There are strong arguments to consider heterozygous AIAT deficiency as an important co-factor in the aetiology of chronic liver disease. Studies have shown that AIAT heterozygosity can be considered a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma. The accumulation of AIAT in the hepatocytes occurs more profoundly in a diseased liver, and as a consequence it affects the natural course of the liver disease. Therapeutic options include augmentation therapy (infusion of purified human plasma AIAT) in pulmonary disease; in end-stage liver disease liver transplantation is an option. For the future, other interventions such as gene therapy or strategies to inhibit polymerisation are promising.

Liver chimerism after allogeneic blood stem cell transplantation.

UNLABELLED: Blood stem cells can mature into elements of many different lineages. We investigated the presence and nature of donor-derived (chimeric) cells within the liver after allogeneic stem cell transplantation. METHODS: Liver biopsy autopsy specimens were examined from nine female patients who had undergone allogeneic bone marrow (n = 6) or peripheral stem cell (n = 3) transplantation from a male donor. To identify the male origin of cells within the liver, in-situ hybridization for Y-chromosomes was performed in conjunction with CD45 staining to identify leucocytes. RESULTS: Hematopoietic stem cell engraftment was confirmed in all nine recipients. Histologic examination of the liver tissue sections revealed 5.6-fold more Y-chromosome-positive than CD45-positive staining cells (P < .02), indicative of considerable nonleucocytic chimerism. This was particularly observed in patients who had developed graft-versus-host disease. CONCLUSIONS: Donor-derived cells can be found in liver tissue specimens after allogeneic stem cell transplantation. A considerable fraction of chimeric (donor-derived) cells appeared to be of nonlymphohematopoietic origin. This finding supports the theory of blood stem cells developing into liver cells of mesenchymal origin.

Donor-derived tuberculosis via orthotopic liver transplantation.

We present a case of donor-derived tuberculosis after liver transplantation, in which the donor origin of the Mycobacterium tuberculosis isolate was made most likely by DNA fingerprinting. Screening for latent tuberculosis of transplant donors originating from high endemic areas with an ex-vivo interferon-gamma release assay should be considered.

Safety of Anti-TNF Treatment in Liver Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND AND AIM: Little is known about the risk of serious infection when combining anti-tumour necrosis factor [TNF] therapy for refractory inflammatory bowel disease [IBD] with immunosuppression after liver transplantation [LT]. Our aim was to investigate the infection risk in this patient group by systematic review and meta-analysis of the available data. METHODS: A search was conducted for full papers and conference proceedings through September 2015, regarding liver transplant recipients and anti-TNF therapy. All studies were appraised using the adapted Newcastle-Ottawa Scale [NOS]. Two reviewers independently extracted patient data [age, duration of follow-up, number of all infections, number of serious infections, time since transplant]. As an additional control population, primary sclerosing cholangitis [PSC]-IBD patients from the Leiden University Medical Center [LUMC] LT cohort were used. Poisson regression was used to compare serious infections (according to International Conference on Harmonisation [ICH] definition) per patien-year follow-up between the anti-TNF and control groups. RESULTS: In all 465 articles and abstracts were identified, of which eight were included. These contained 53 post-LT patients on anti-TNF therapy and 23 post-LT patients not exposed to anti-TNF therapy. From the LUMC LT-cohort, 41 PSC patients with PSC-IBD not exposed to anti-TNF therapy were included as control population. The infection rate for TNF-exposed patients was 0.168 serious infections per patient year, compared with 0.149 in the control patients (rate ratio 1.12 [95% confidence interval: 0.233-5.404, P = 0.886]. When correcting for time since transplant, the infection rate was 0.194 in the TNF-exposed vs 0.115 in the non-exposed [p = 0.219]. CONCLUSIONS: No significant increase in the rate of serious infection was observed in LT recipients with PSC-IBD during exposure to anti-TNF therapy.

Expert clinical management of autoimmune hepatitis in the real world.

BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Risk factors of acute hepatic failure during antituberculosis treatment: two cases and literature review.

Hepatotoxicity is a well-known side effect of antituberculosis treatment (ATT). If not recognised in time, drug-induced hepatitis can develop, which may rapidly progress to acute liver failure. We describe two patients with acute hepatic failure caused by ATT, whose pretreatment liver function had been normal. Both patients successfully underwent liver transplantation. Possible risk factors predisposing towards ATT-induced hepatic failure were evaluated, and at least four risk factors were present in these patients. Although available guidelines do not advocate routine monitoring of liver function during ATT unless baseline values are elevated or in the case of pre-existent liver disease, this is nevertheless common practice. Liver function should always be measured in patients who develop symptoms during ATT, and rising liver function parameters should prompt immediate action to prevent the occurrence of liver failure. This report underscores that regular monitoring of liver function parameters and adherence to guidelines is especially important in patients with risk factors for ATT-induced liver disease. An evaluation of chronic viral hepatitis in risk groups before starting ATT could be worthwhile.

Easy-to-use, accurate and flexible individualized Bayesian limited sampling method without fixed time points for ciclosporin monitoring after liver transplantation.

BACKGROUND: New methods to estimate the systemic exposure to ciclosporin such as the level 2 h after dosing and limited sampling formulas may lead to improved clinical outcome after orthotopic liver transplantation. However, most strategies are characterized by rigid sampling times. AIM: To develop and validate a flexible individualized population-pharmacokinetic model for ciclosporin monitoring in orthotopic liver transplantation. METHODS: A total of 62 curves obtained from 31 patients at least 0.5 year after orthotopic liver transplantation were divided into two equal groups. From 31 curves, relatively simple limited sampling formulas were derived using multiple regression analysis, while using pharmacokinetic software a two-compartment population-pharmacokinetic model was derived from these same data. We then tested the ability to estimate the AUC by the limited sampling formulas and a different approach using several limited sampling strategies on the other 31 curves. The new approach consists of individualizing the mean a priori population-pharmacokinetic parameters of the two-compartment population-pharmacokinetic model by means of maximum a posteriori Bayesian fitting with individual data leading to an individualized population-pharmacokinetic limited sampling model. From the individualized pharmacokinetic parameters, AUC(0-12h) was calculated for each combination of measured blood concentrations. The calculated AUC(0-12h) both from the limited-sampling formulas and the limited-sampling model were compared with the gold standard AUC(0-12h) (trapezoidal rule) by Pearson's correlation coefficient and prediction precision and bias were calculated. RESULTS: The AUC(0-12h) value calculated by individualizing the population-pharmacokinetic model using several combinations of measured blood concentrations: 0 + 2 h (r(2) = 0.94), 0 + 1 + 2 h (r(2) = 0.94), 0 + 1 + 3 h (r(2) = 0.92), 0 + 2 + 3 h (r(2) = 0.92) and 0 + 1 + 2 + 3 h (r(2) = 0.96) had excellent correlation with AUC(0-12h), better than limited sampling formulas with less than three sampling time points. Even trough level with limited sampling method (r(2) = 0.86) correlated better than the level after 2 h of dosing (r(2) = 0.75) or trough level (r(2) = 0.64) as single values without limited sampling method. Moreover, the individualized population-pharmacokinetic model had a low prediction bias and excellent precision. CONCLUSION: Multiple rigid sampling time points limit the use of limited sampling formulas. The major advantage of the Bayesian estimation approach presented here, is that blood sampling time points are not fixed, as long as sampling time is known. The predictive performance of this new approach is superior to trough level and that after 2 h of dosing and at least as good as limited sampling formulas. It is of clear advantage in busy out-patient clinics.

[Three patients with autoimmune hepatitis: the importance of early diagnosis and remission]. / Drie vrouwen met auto-immune hepatitis: het klinisch belang van tijdige diagnose en van remissie.

A 70-year-old woman presented with impaired memory and depressive symptoms and two women aged 53 and 30 years, respectively, presented with general malaise and fatigue. All were diagnosed with and treated for autoimmune hepatitis (AIH). The first patient developed a relapse during treatment withdrawal; she recovered and maintained remission after the initial dose of medication had been restarted and the medication was tapered more gradually. The second patient had an incomplete remission and later developed liver failure; she was eligible for a liver transplant. The third woman became pregnant during treatment and developed a relapse after delivery; remission was induced and maintained after the immunosuppression was temporally increased. AIH is a chronic progressive liver disease characterised by abnormal serum levels of liver enzymes, hypergammaglobulinaemia, auto-antibodies against cell nuclei (ANA), smooth muscle (SMA), or liver and kidney microsomes (LKM), interface hepatitis and the absence of other chronic liver disease. Early diagnosis is essential because therapy can markedly improve prognosis. However, there is no specific diagnostic test for AIH. It is important to induce and maintain remission with immunosuppressive therapy.