Impact of Antibodies That React With Liver Tissue and Donor-Specific Anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis (original) (raw)
Related papers
Journal of Pediatric Gastroenterology & Nutrition, 2020
Objectives: Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. Methods: We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. Results: AAb were detected in 27 (43,3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (p=0,032) and deceased donor LT (p=0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (p<0,001), and an association was found with the presence of non-specific histologic alterations (p=0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (p<0,001), ALT (p<0,001), AST (p<0,001), γ-GT (p=0,001), IgG (p=0,011) and lower albumin (p=0,029). Fourteen out of 50 (28%) patients were DSA positive, mostly anti-HLA class II. DSA positivity was associated with T cell-mediated rejection (p=0,019), higher total (p=0,033) and direct (p=0,012) bilirubin and γ-GT (p<0,001). Conclusions: The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the
Hepatology research : the official journal of the Japan Society of Hepatology, 2017
Growing evidence suggests a relationship between antibody-mediated rejection (AMR) and early graft failure due to a previously unknown etiology in liver transplantation (LTx). We herein report a three-year-old boy who developed rapid graft failure due to de novo donor-specific antibody (DSA)-driven AMR a week after living donor LTx, requiring a second transplant on the 10th day after the first LTx. The pathology of the first graft showed massive necrosis in zone 3 along with positive C4d and inflammatory cell infiltrates in portal areas. The mean fluorescence intensity (MFI) against HLA-DR15, which was possessed by both the first and the second donor, peaked at 12945 on the day before the second LTx. Anti-thymocyte globulin, plasma exchange along with intravenous immunoglobulin, rituximab and the local infusion of prostaglandin E1, steroids and mesilate gabexiate via portal catheter were provided to save the second graft. To our knowledge, this is the first report to demonstrate a c...
Transplantation Proceedings, 2019
Introduction. The prevalence and impact of pre-existing and de novo anti-HLA donorspecific antibodies (DSAs) after orthotopic liver transplantation (OLT) is still controversial. We investigated the prevalence of DSAs and their implication in the development of allograft dysfunction after OLT. Patients and Methods. A total of 65 liver transplant patients were tested for anti-HLA antibodies, with single antigen bead technology, before, 1, 3, 6, and 12 months after transplantation, and thereafter annually, along with other risk factors. Sixteen out of 65 patients (24.6%) had circulating pre-existing anti-HLA antibodies, and 4 of them (25%) had DSAs. All patients positive for anti-HLA antibodies (100%) presented allograft dysfunction. Fourteen out of 65 patients (21.5%) had circulating de novo DSAs, and 12 out of 14 (85.7%) presented allograft dysfunction. The investigated risk factors for allograft dysfunction were: recipient and donor age, time on the waiting list, cold ischemia time, cytomegalovirus infection, immunosuppression regimen, de novo DSAs, Model for End-Stage Liver Disease, aspartate aminotransferase, alanine aminotransferase, gammaglutamyl transpeptidase (GGT), direct bilirubin and total bilirubin peak post-transplant, and alkaline phosphatase. The multivariate analysis showed that de novo DSAs and time on the waiting list were independent risk factors for allograft dysfunction. Conclusion. Our results show that de novo DSAs are an independent risk factor for allograft dysfunction, along with time on the waiting list.
Human Immunology, 2018
The relevance of pre-existing HLA-antibodies (HLA-Ab) in liver transplantation (LTx) is controversial. While livers are allocated without HLA match or preoperative crossmatch testing, several studies point to an impact of donor specific antibodies (DSA) for acute rejection, bile duct complications or even graft loss. To investigate the role of DSA in long term liver allograft survival we analysed 177 pre transplant sera of first LTx patients with luminex single antigen technology defining a MFI of >1500 as positive. The analyses were done retrospectively, and the DSA results had no impact on graft acceptance or patients' therapy. Three year follow up was available for all patients. 77% of our patients had any HLA-Ab pre transplantation, 55 patients were transplanted with DSA by chance. Acute rejections or ischemic type bile duct lesions (ITBL) were not higher in the DSA group, but ITBL was associated with a higher donor age. There was no difference in long term graft function or survival in patients without HLA-Ab, with non DSA or with DSA (p=0.712). We suggest that determination of pre-existing DSA in first LTx recipients is not appropriate and we conclude that pre-existing DSA in first LTx patients are not a contraindication for liver transplantation.
Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults
Hepatology, 2001
In children, a type of graft dysfunction associated with autoimmune features has been described. We have identified 7 adult liver-transplant (LT) recipients from a series of over 1,000 consecutive transplant recipients who presented between 0.3 years and 7.2 years following transplantation with characteristic symptoms, autoantibody profiles, and histologic findings of autoimmune disease. The indications for transplantation were Ecstasy overdose, alcohol-related cirrhosis, primary sclerosing cholangitis (PSC) (2), primary biliary cirrhosis (PBC), hepatitis C cirrhosis, and cryptogenic cirrhosis. Two patterns of de novo autoantibody development were noted; anti-liver-kidney-microsome (LKM) antibody development at high titer in association with an aspartate transaminase (AST) > 500 and antinuclear (ANA) and antismooth muscle (AMA) antibody development at titers >1/80 with lower AST levels. All cases had elevated IgG. Liver biopsies showed changes of an autoimmune-type hepatitis with portal and periportal hepatitis in association with a marked infiltrate of plasma cells, lymphocytes, and bridging collapse. Two patients lost their grafts because of the disease. Patients were treated with reintroduction of steroids and azathioprine in cases in which it had been withdrawn. Major histocompatibility class I and II mismatching did not incur risk. Eight of 12 liver allografts were acquired from either DRB*0301-or DRB*0401-positive donors, and 4 recipients were DRB*0301-positive. This series illustrates that both symptoms and histologic findings of graft dysfunction compatible with autoimmune hepatitis (AIH) exist in adult LT recipients. Graft loss may be a consequence. This entity may represent a specific type of rejection that should currently be classified as "graft dysfunction mimicking autoimmune hepatitis." (HEPATOLOGY 2001;34:464-470.) From the
Liver Transplantation, 2005
The aim of this study was to analyze the effect of human leukocyte antigen (HLA) class I and HLA-DR mismatching, sharing cross-reactive antigen groups (CREGs), and sharing HLA-DR antigens on the outcome after pediatric liver transplantation. Outcome parameters were graft survival, acute rejection, and portal fibrosis. A distinction was made between full-size (FSLTx) and technical-variant liver transplantation (TVLTx). A total of 136 primary transplants were analyzed. The effect of HLA on the outcome parameters was analyzed by adjusted multivariate logistic and Cox regression analysis. HLA mismatches, shared CREGs, and shared HLA-DR antigens affected neither overall graft survival nor survival after FSLTx. Survival after TVLTx was superior in case of 2 mismatches at the HLA-DR locus compared to 0 or 1 mismatch (P = 0.01) and in case of no shared HLA-DR antigen compared to 1 shared HLA-DR antigen (P = 0.004). The incidence of acute rejection was not influenced by HLA. The incidence of portal fibrosis could be analyzed in 62 1-yr biopsies and was higher after TVLTx than FSLTx (P = 0.04). The incidence of portal fibrosis after TVLTx with 0 or 1 mismatch at the HLA-DR locus was 100% compared to 43% with 2 mismatches (P = 0.004). After multivariate analysis, matching for HLA-DR and matching for TVLTx were independent risk factors for portal fibrosis. In conclusion, an overall beneficial effect of HLA matching, sharing CREGs, or sharing HLA-DR antigens was not observed. A negative effect was present for HLA-DR matching and sharing HLA-DR antigens on survival after TVLTx. HLA-DR matching might be associated with portal fibrosis in these grafts. (Liver Transpl 2005;11:1541–1549.)
Liver Transplantation, 2000
Liver transplant recipients frequently have chronic liver diseases and should be considered for vaccination against hepatitis A virus (HAV). However, persistence of protective antibodies after orthotopic liver transplantation (OLT) has not been shown in this population, which may have implications for future vaccine recommendations. We evaluated the prevalence and epidemiological significance of immunoglobulin G (IgG) antibody to HAV (anti-HAV) in a nonvaccinated population before OLT (immunity from previous exposure) and determined the persistence of IgG anti-HAV at 1 and 2 years after OLT. One hundred consecutive patients were identified who underwent OLT and had at least 2 years of follow-up post-OLT. They were not vaccinated against HAV infection at any time. Clinical data were summarized from medical records, and stored sera were tested for IgG anti-HAV before OLT and at 1 and 2 years after OLT by a commercially available enzyme immunoassay. Of 100 patients, 24 had IgG anti-HAV before OLT. No epidemiological differences were noted between those with or without detectable IgG anti-HAV before OLT. Among patients with detectable IgG anti-HAV before OLT, 4 of 22 patients (18%) and 7 of 24 patients (29%) became negative for IgG anti-HAV at 1 and 2 years post-OLT, respectively. None of the patients with undetectable IgG anti-HAV before OLT became positive at any time. Most of our patients with end-stage liver disease had no serological evidence for immunity against HAV. A significant proportion of patients with detectable protective antibodies before OLT lost their antibodies at 2 years after OLT.
Pediatric Transplantation, 2006
Abstract: Over a 15-yr period of observation, among the 205 children who underwent liver transplantations, one of them developed a particular type of late graft dysfunction with clinical and histological similarity to autoimmune hepatitis. The patient had α1-antitrypsin deficiency and did not previously have autoimmune hepatitis or any other autoimmune disease before transplantation. Infectious and surgical complications were excluded. After repeated episodes of unexplained fluctuations of liver function tests and liver biopsies demonstrating reactive or a biliary pattern, without any corresponding alteration of percutaneous cholangiography, a liver-biopsy sample taken 4 yr after the transplant showed active chronic hepatitis progressing to cirrhosis, portal lymphocyte aggregates, and a large number of plasma cells. At that time, autoantibodies (gastric parietal cell antibody, liver–kidney microsomal antibody, and anti-hepatic cytosol) were positive and serum IgG levels were high. Based on these findings of autoimmune disease, a diagnosis of ‘de novo autoimmune hepatitis’ was made. The treatment consisted of reducing the dose of cyclosporine, reintroduction of corticosteroids, and addition of mycophenolate mofetil. After 19 months of treatment, a new liver-biopsy sample showed marked reduction of portal and lobular inflammatory infiltrate, with regression of fibrosis and of the architectural disruption. At that time, serum autoantibodies became negative. The last liver-biopsy sample showed inactive cirrhosis and disappearance of interface hepatitis and of plasma cell infiltrate. Presently, 9 yr after the transplantation, the patient is doing well, with normal liver function tests and no evidence of cirrhosis. Her immunosuppressive therapy consists of tacrolimus, mycophenolate mofetil, and prednisolone. In conclusion, the present case demonstrates that de novo autoimmune hepatitis can appear in liver-transplant patients despite appropriate anti-rejection immunosuppression, and triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone could sustain the graft and prevent retransplantation.
Outcome and Risk Factors of De Novo Autoimmune Hepatitis in Living-Donor Liver Transplantation
Transplantation, 2004
Background. Graft dysfunction mimicking autoimmune hepatitis (AIH) develops only rarely after liver transplantation for nonautoimmune liver disease. The long-term prognosis and risk factors of de novo AIH after living-donor liver transplantation (LDLT) are unknown. Methods. We review our LDLT series to investigate the incidence and outcome of this form of graft dysfunction, focusing on follow-up histology. Results. Of 633 patients who underwent LDLT at Kyoto University from 1990 to 2002, 13 (2.1%) developed graft dysfunction with interface hepatitis resembling AIH (2 males, 11 females). The median age at LDLT of these 13 patients was 10 years (8 months to 26 years). All received tacrolimus-based immunosuppression. The dysfunction presented at a median interval of 3.1 (0.7-9.5) years after LDLT. Nine had definite AIH, and four had probable AIH at the onset of hepatitis. Patients were followed after a median of 3.5 (0.1-8) years from the onset of de novo AIH. Of 11 patients who underwent follow-up histologic evaluation, 3 underwent retransplantation, and 8 continued to have similar findings on subsequent biopsies, with fluctuations in the amount of necroinflammatory activity and an increase in fibrosis despite treatment. In a multivariate analysis, acute rejection episodes and recipient age between 11 and 15 years at LDLT independently had predictive value for the development of de novo AIH. Human leukocyte antigen-A, B, and DR mismatches and sex mismatch did not influence the occurrence of de novo AIH. Conclusion. This series highlights the more severe histologic outcome of de novo AIH with longer follow-up despite immunosuppressive treatment. De novo AIH may arise from alloimmunologic injury, marked by clinically obvious episodes of acute rejection.