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Biomedical subjects

H J Metselaar

Publications and source records attributed to H J Metselaar.

At least 19 recordsLinked to original sources
PubMed2006

Prednisolone suppresses the function and promotes apoptosis of plasmacytoid dendritic cells.

Organ transplant recipients are highly susceptible to viral infections early after transplantation. Plasmacytoid dendritic cells (PDC) play a major role in antiviral immunity. Therefore, we determined the numbers of circulating PDC after liver transplantation (LTX) and established the effects of immunosuppressive drugs on PDC survival and function. PDC were determined longitudinally in 13 LTX recipients treated with prednisone and cyclosporin or tacrolimus. Purified PDC were cultured with or without clinically relevant concentrations of cyclosporin, tacrolimus or prednisolone. Apoptosis induction was monitored by determination of active caspase-3, nuclear condensation and annexin-V/7AAD staining. After LTX, a 4-fold reduction in the number of circulating PDC was observed (p < 0.01), which recovered partially after discontinuation of prednisone treatment. In vitro, prednisolone induced apoptosis in PDC, while cyclosporin and tacrolimus did not. Higher doses of prednisolone were needed to induce apoptosis in Toll-like receptor (TLR)-stimulated PDC. However, non-apoptosis inducing concentrations of prednisolone suppressed interferon-alpha production, upregulation of co-stimulatory molecules and allo-stimulatory capacity of TLR-stimulated PDC. In conclusion, prednisolone induces apoptosis in PDC, which explains the decline in circulating PDC numbers after transplantation. Moreover, prednisolone suppresses the functions of TLR-stimulated PDC. Therefore, corticosteroid-free immunosuppressive therapy may reduce the number and severity of viral infections after transplantation.

Adult↗
PubMed2005

Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation.

BACKGROUND: The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene encodes for a membrane bound (mCTLA-4) and a soluble (sCTLA-4) isoform, which are both involved in regulation of T cell function. The CTLA-4 +49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; +6230G/A SNP affects the production of sCTLA-4. AIM: To examine whether these functional SNPs influence the rate of rejection after liver transplantation. PATIENTS AND METHODS: Liver graft recipients (n = 483) were genotyped for both SNPs, and haplotypes were reconstructed. Association with rejection was tested by the log rank test using the Kaplan-Meier method with time to the first acute rejection episode as outcome. Multiple analysis of SNPs together with demographic factors was performed by Cox regression. RESULTS: Three haplotypes were observed in the cohort: +49A/+6230A, +49A/+6230G, and +49G/+6230G. The +49A/+6230G haplotype was significantly and dose dependently associated with acute rejection (p = 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional +49A/+6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p = 0.02). Patients who lacked this haplotype had the lowest, carriers an intermediate, and homozygotes the highest risk of acute rejection. CONCLUSION: The CTLA-4 +49A/+6230G haplotype, which encodes for normal mCTLA-4 expression but reduced sCTLA-4 production, is a co-dominant risk allele for acute rejection after clinical liver transplantation. This implies that even under immunosuppression, CTLA-4 is critically involved in the regulation of the human immune response to allogeneic grafts.

Acute Disease↗
PubMed2005

Decrease of CD4+CD25+ T cells in peripheral blood after liver transplantation: association with immunosuppression.

CD25 (IL-2 receptor alpha-chain) marks a population of CD4-positive T cells with a suppressor phenotype. These CD4+CD25+ regulatory T cells can suppress both effector T cells and antigen-presenting cells and have been identified as a principle regulator of tolerance in experimental transplantation models. In the setting of human liver transplantation, however, little is known about the dynamics of these cells in relation to rejection, tolerance, and immunosuppression. In the current study we determined CD4+CD25+ T cell in blood of liver transplant recipients using flow cytometry and investigated a possible link with immunosuppressive therapies. Peripheral blood mononuclear cells (PBMC) of 27 liver transplant patients (pretransplantation and 12 months posttransplantation) and 16 healthy controls were included. We found that the percentages of CD25+ cells within the CD4 T-cell population was significantly reduced in more than two-thirds of patients 1 year after transplantation. Also the total percentage of CD4-positive T cells declined significantly within this period, making the absolute reduction of regulatory T cells after transplantation even more profound. Comparing PBMC samples of patients and healthy controls revealed an increased percentage of CD4+ T cells in the patients before transplantation, probably related to the chronic liver illness. The reduction in CD4+CD25+ T cells after transplantation was similar for different immunosuppression regiments. All patients, however, received calcineurin inhibitors, suggesting a possible suppressive effect of this therapy on regulatory T-cell levels in peripheral blood. Currently, assays for regulatory T-cell activity are used to further support this hypothesis.

Adrenal Cortex Hormones↗
PubMed2005

Hepatitis B immunoglobulins inhibit dendritic cells and T cells and protect against acute rejection after liver transplantation.

The efficacy of anti-viral intravenous immunogobulins (anti-HBs Ig and anti-CMV Ig) in preventing acute rejection after liver transplantation was assessed in a retrospective analysis, and correlated to their effects on immune cells in vitro. HBs Ag-positive liver graft recipients (n = 40) treated prophylactically with anti-HBs Ig had a significantly lower incidence of acute rejection compared with recipients without viral hepatitis (n = 147) (12% vs. 34%; p = 0.012), while the incidence of rejection in HCV-positive recipients (n = 29) was similar to that in the control group. Treatment with anti-CMV Ig (n = 18) did not protect against rejection. In vitro, anti-HBs Ig suppressed functional maturation of and cytokine production by human blood-derived dendritic cells (DC) at concentrations similar to the serum concentrations reached during anti-HBs Ig treatment of liver graft recipients. In addition, anti-HBs Ig inhibited allo-antigen- and lectin-stimulated proliferation of peripheral T cells. Anti-CMV Ig suppressed functional DC-maturation and alloantigen-stimulated T-cell proliferation, but not lectin-driven T-cell proliferation. In conclusion, anti-HBs Ig protects against acute rejection after liver transplantation, probably by functional inhibition of the two principal immune cells involved in allograft rejection, DC and T cells.

Adult↗
PubMed2004

The relative importance of cyclosporine exposure in heart, kidney or liver transplant recipients on maintenance therapy.

We investigated the relationship between cyclosporine exposure and the presence of cyclosporine-related side effects and assessed the advantage of the cyclosporine concentration 2 h post-dose (C(2)) over pre-dose concentration (C(0)) monitoring. Cyclosporine area-under-the-concentration-time curves were measured during the absorption phase (AUC(0-4 h)) in 49 liver, 28 heart and 26 kidney transplant recipients (time since transplantation >6 years) with or without cyclosporine-related side effects on maintenance therapy. The cyclosporine C(0) correlated well with AUC(0-4) (r=0.77), whereas C(2) levels correlated strongly with AUC(0-4) (r=0.92). Although we observed a trend towards higher CsA concentrations in transplant recipients with side effects than in patients without CsA toxicity, the large majority of those differences were not statistically significant. Thus, as cyclosporine exposure was not clearly related to the presence of side effects, and C(0) correlated fairly with AUC(0-4), the advantage of monitoring cyclosporine treatment using C(2) rather than C(0), may be limited for patients on cyclosporine maintenance therapy.

Adult↗
PubMed2004

Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous and intermittent infusion in liver transplant patients.

BACKGROUND: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous infusion might have pharmacodynamic advantages. OBJECTIVES: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation. METHODS: Fifteen patients undergoing liver transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000 mg iv four times daily). Samples were collected during the first 48 h after liver transplantation. Concentrations of CTX and DCTX were determined by HPLC. RESULTS: During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest serum concentration was 5 mg/L in the CI group and levels were undetectable in the BI group. Target serum concentrations of > or =4 mg/L were reached for 100% of the dosing interval during CI and approximately 60% during BI. Post-operatively, the mean concentration in serum after CI was 26 mg/L. The lowest serum concentration was 8 mg/L in the CI group and levels were undetectable after BI. The peroperative pharmacokinetics of CTX in this patient group were deranged and variable, mainly caused by an increased volume of distribution and decreased hepatic clearance. Metabolism was hampered, but DCTX area under the curve (AUC)/CTX AUC ratios varying between 0.7-0.9 were reached peroperatively. Post-operatively, DCTX AUC/CTX AUC ratios were higher (1.1-1.4). Unchanged CTX in bile was approximately 0.1% of the administered dose, leading to concentrations >4 mg/L throughout the dosing interval for both regimens. CONCLUSION: Although an intermittent bolus infusion of CTX 1000 mg produces t > target concentration for 60% of the dosing interval during liver transplantation, serum concentrations may be insufficient during the reperfusion phase. Continuous infusion overcomes this. Post-operatively, CTX clearance is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.

Adult↗
PubMed2003

Expression of CD80 on Kupffer cells is enhanced in cadaveric liver transplants.

In experimental animals inhibition of T cell co-stimulation immediately after organ transplantation effectively prevents rejection. We investigated whether the expression of co-stimulatory molecules is enhanced in cadaveric liver transplants, whether their expression is influenced by the transplantation procedure, and whether variation in expression between liver transplants is related to the occurrence of acute rejection. Expression of CD80, CD86 and the macrophage marker CD68 were determined by immunohistochemistry in biopsies from 40 clinical liver transplants obtained at different time-points during the transplantation procedure, and in normal liver tissue obtained from 10 human livers. Expression of CD80 and CD86 on Kupffer cells was graded by comparison with CD68-staining. In a subgroup CD80 and CD86 mRNA was quantified by real-time detection polymerase chain reaction. CD86 was expressed in all liver transplants and normal livers on the majority of Kupffer cells. CD80 was absent or sporadically expressed in normal liver tissue, but in 18 of 40 liver transplants at least one-quarter of Kupffer cells expressed CD80. CD80- and CD86-mRNA and protein expression in liver transplants did not change during the warm ischaemic and reperfusion phases of the transplantation procedure. CD80-expression on Kupffer cells varied strongly between individual donor livers; this variation was, however, not significantly related to the occurrence of acute rejection after transplantation. In conclusion, in nearly half of cold-preserved cadaveric liver transplants an increased proportion of Kupffer cells express CD80 at the time of transplantation in comparison with normal liver tissue. The expression was not further induced by warm ischaemia and reperfusion. However, the observed variation in CD80-expression between liver transplants is not a accurate predictive measure for acute rejection.

Adult↗
PubMed2002

[The pregnant patient with acute liver disease].

Acute liver disease was diagnosed in three pregnant patients: two 30-year-old women had a 'haemolysis, elevated liver enzymes, low platelets' (HELLP) syndrome and acute fatty liver of pregnancy, respectively, and a 20-year-old woman had acute liver failure due to acute hepatitis B. The first two patients had a caesarean section, the third one delivered her child, which died spontaneously shortly after birth at a gestational age of 23 weeks. She was then treated by liver transplantation. All three patients left the hospital in good condition. Liver diseases in pregnancy may be pregnancy-related, e.g. the HELLP syndrome and acute fatty liver of pregnancy, but they may also be coincidental phenomena, e.g. viral hepatitis. The HELLP syndrome is often associated with pre-eclampsia, and presents with epigastric pain and thrombocytopenia with haemolysis. Acute fatty liver disease and acute liver failure due to hepatitis present with liver insufficiency characterised by anorexia, nausea, coagulopathy, hypoglycaemia and elevated serum ammonia levels. Management depends on the diagnosis and the gestational age; pregnancy complicated by acute fatty liver disease should be terminated while pregnancy complicated by the HELLP syndrome early in pregnancy may be maintained to improve the outcome of the foetus. In acute liver failure due to viral hepatitis, termination of pregnancy alone does not affect the disease.

Abortion, Induced↗
PubMed2002

Liver transplantation and hepatitis C.

End-stage liver disease caused by chronic hepatitis C viral infection is one of the major indications for liver transplantation. However, evidence for ongoing viral replication can already be found days after surgery and may lead sequentially to lobular hepatitis, chronic active hepatitis, fibrosis and liver cirrhosis. In some patients, this evolution is remarkably fast, most probably enhanced by the immunosuppressive therapy. A minority of patients develop a clinical picture of progressive cholestatic liver disease with histological signs of chronic rejection, which may necessitate retransplantation. While the 1- and 5-year survival rates for all patients transplanted because of hepatitis C virus (HCV)-induced liver cirrhosis are satisfactory, severe complications of disease recurrence are nonetheless expected during the first and second decade after liver transplantation. Larger and preferably randomized studies are needed to investigate whether combination therapy with interferon and ribavirin, preferably initiated as soon as possible after liver transplantation, prevents the fast evolution to cirrhosis without the appearance of chronic rejection and the expected complications of recurrent end-stage HCV-induced liver disease. The final goal should be the inhibition of viral replication even before liver transplantation, but other antiviral strategies should probably be used to attain this goal in patients with decompensated cirrhosis. Although the recurrence of a hepatitis C infection and concomitant disease in the liver graft may cause substantial morbidity, end-stage liver disease and liver failure caused by a chronic hepatitis C infection remain good indications for liver transplantation.

Antiviral Agents↗
PubMed2001

A comparison of the costs and effects of liver transplantation for acute and for chronic liver failure.

Little is known about costs and cost-effectiveness of liver transplantation (LTx) for acute liver failure compared to costs and cost-effectiveness of LTx for chronic liver failure. In this study, costs of acute and of chronic LTx patients were determined in a retrospective study. Files of 100 consecutive patients who underwent LTx in 1993-1997 were studied. Costs up to 1 year after LTx were Euro 107,675 (chronic liver failure) and Euro 90,792 (acute liver failure). The difference was mainly caused by higher hospitalisation costs and higher personnel costs for chronic liver failure. Medication costs for acute liver failure were higher, due to a high administration rate of expensive anti-HBs immunoglobulin therapy in patients with viral hepatitis B. LTx for chronic liver failure is more costly and seems to be more cost-effective than LTx for acute liver failure, since 1-year survival is higher in patients who underwent transplantation for chronic liver failure.

Acute Disease↗
PubMed2001

In vitro cytokine production of TNFalpha and IL-13 correlates with acute liver transplant rejection.

Individuals may differ in their capacity to produce cytokines. Since cytokines play a key role in allograft rejection, we investigated whether inter-individual differences in cytokine production by in vitro stimulated PBMC are related to the occurrence of acute liver transplant rejection. Our study group comprised 49 liver transplant recipients and 30 healthy individuals. Rejection, which occurred within one month after liver transplantation, was defined in 22 patients ("rejectors") as biopsy-proven rejection, treated with high dose prednisolone. Patients who never experienced rejection episodes were termed as "nonrejectors" (n=27). PBMC of healthy individuals and of liver transplant recipients, collected late after transplantation (mean 3.5 years), were cultured in the presence and absence of Concanavalin A. The production of TNF-alpha, IFN-gamma, IL-10, and IL-13 was measured in supernatant after 1, 2, 3, 4, and 7 days of cell culture. In cell culture, stimulated PBMC of rejectors were found to produce significantly higher levels of TNF-alpha, while there was a trend towards higher production of IFN-gamma and IL-10 as compared to nonrejectors. After grouping patients into high or low cytokine producers based upon reference levels of the healthy individuals using multivariate analysis it was found that occurrence of acute liver transplant rejection correlated to high production of TNF-alpha and low production of IL-13. After stimulated cell culture PBMC of liver transplant recipients show a differential production of TNF-alpha and IL-13 which is correlated with the occurrence of acute liver transplant rejection.

Acute Disease↗
PubMed2001

Partial liver transplantation.

Since the introduction of the split-liver transplantation procedure 15 years ago a variety of partial liver transplantations have been developed. The earliest form of split-liver transplantation consisted of reduction of a whole liver graft to just the left lateral segment or the left liver lobe, which was then small enough to transplant to a young child. The rest of the liver was discarded. This method partially solved the great need for liver grafts for children but as the remaining part of the liver was discarded the method was in fact detrimental for adults on the waiting list. Further surgical development resulted in splitting of the liver ex vivo into two transplantable partial grafts: the left part to a child and the right lobe to an adult. This procedure was successfully introduced but the complicated logistics resulted in prolonged cold ischemia times for the grafts. In order to keep the cold ischemia time as short as possible, the in situ split-liver technique was developed, in which the liver was split in the post-mortem donor. Refinement of this operation led to results which were superior to those obtained with the ex vivo method; moreover, it opened the door to living-donor liver transplantation. The first successful procedure was performed from a mother to a child, who received the mother's left liver segment. The introduction of this technique resulted over the years in a decrease in the pediatric waiting list to almost zero. As the demand for organs increases every year and the number of donors remains constant in Western countries, the right-lobe living-donor liver transplantation for adults has been introduced. Introduction of all forms of partial liver transplantation has relieved the pressure on waiting lists, especially for children but also for adults. There are, however, serious concerns regarding the high morbidity and mortality rates associated with the living-donor donation procedure.

Adult↗
PubMed2000

[Acute liver failure ascribed to nefazodone: importance of 'postmarketing surveillance' for recently introduced drugs].

A 50-year-old man developed acute liver failure 7 months after nefazodone treatment was initiated. There was no evidence of any aetiology apart from the exposure to the antidepressant drug nefazodone, while the results of repeated histological examinations of the liver were compatible with serious progressive drug-induced hepatitis. This diagnosis was initially disregarded because in the literature no patients with nefazodone-induced hepatitis were reported. However, the drug had only recently been introduced, which meant that relatively infrequent adverse drug reactions might not have been published. Further analyses of databases of the marketing pharmaceutical industry and of the World Health Organization revealed more cases of liver toxicity ascribed to nefazodone, which showed that liver failure may indeed be associated with nefazodone use. Consequently, prescribing doctors have been warned by the pharmaceutical company about this possible adverse drug reaction.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Importance of portal flow diversion in experimental auxiliary partial orthotopic liver transplantation.

BACKGROUND: Auxiliary partial orthotopic liver transplantation (APOLT) has successfully been performed in patients with noncirrhotic metabolic diseases. It remains, however, unclear if intervention in the portal venous inflow is necessary to ensure adequate portal blood flow to graft and host liver. In this experimental study we evaluate the hepatic flow during APOLT. METHODS: Left lateral/medial segmental grafts were transplanted from beagle to dalmatian dogs. Vascular structures were anastomosed end-to-end. The effect of diversion of the portal flow was studied in three groups: in the ligation group (n=3) the host portal vein was tied off, the free flow group (n=6) had random flow to both livers. In the banding group (n=11) the host portal vein was banded with a adjustable strapband to restore the pretransplantation flow distribution. RESULTS: After reperfusion the blood flow through the common portal vein decreased from 49 to 36 ml/kg/min (P<0.03) in all animals. Flow through the left portal vein decreased from 26 to 5 ml/kg/min (P<0.0001). Banding restored the flow in the left portal vein to 12 ml/kg/min, although the flow in the free-flow group remained 4 ml/kg/min. In the ligation group the total portal flow was forced toward the graft leading to the highest perfusion: 24 ml/kg/min (P<0.005). Adverse effect of this ligation was the development of portal hypertension. CONCLUSIONS: This experimental study confirms that diversion of the portal flow is necessary for adequate graft perfusion in APOLT. Banding can restore the pretransplantation flow distribution, without compromising the flow in the common portal vein.

Animals↗
PubMed2000

Massive solitary metastasis of hepatocellular carcinoma in the ovary two years after liver transplantation.

Case report of a 47-year-old woman with a mass in the lower abdomen, was referred to us by the surgeon, two years after orthotopic liver transplantation for hepatocellular carcinoma (HCC). Serum alpha-fetoprotein (AFP), which was elevated at the time of initial diagnosis, was in the normal range. Frozen section examination during exploratory laparotomy showed appearances consistent with metastatic HCC in the ovary. This was confirmed at the final pathological examination. Definitive pathological conclusions were based on the findings of tumor cells arranged in trabecular and papillary aggregates, and the presence of bile-pigment, along with the patients history. This is the sixth case of metastatic HCC in the ovary being described in literature and the first case in which this metastasis was not accompanied by elevated AFP.

Biomarkers, Tumor↗