Non-inflammatory centrilobular sinusoidal fibrosis in pediatric liver transplant recipients under tacrolimus withdrawal
Aim: We hypothesized that non‐inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living‐donor liver transplantation. Methods: In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earl...
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| Published in | Hepatology research Vol. 42; no. 9; pp. 895 - 903 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Melbourne, Australia
Blackwell Publishing Asia
01.09.2012
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1386-6346 1872-034X 1872-034X |
| DOI | 10.1111/j.1872-034X.2012.01003.x |
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| Abstract | Aim: We hypothesized that non‐inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living‐donor liver transplantation.
Methods: In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow‐up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed.
Results: In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0–4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF‐improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non‐improved patients (P = 0.0245).
Conclusion: NICSF might be an indicator of inadequate immunosuppression in long‐term followed recipients and its mechanism may be due to immune reactions including humoral immunity. |
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| AbstractList | We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver transplantation.
In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow-up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed.
In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0-4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF-improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non-improved patients (P = 0.0245).
NICSF might be an indicator of inadequate immunosuppression in long-term followed recipients and its mechanism may be due to immune reactions including humoral immunity. We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver transplantation.AIM We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver transplantation. In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow-up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed.METHODS In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow-up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed. In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0-4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF-improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non-improved patients (P = 0.0245).RESULTS In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0-4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF-improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non-improved patients (P = 0.0245). NICSF might be an indicator of inadequate immunosuppression in long-term followed recipients and its mechanism may be due to immune reactions including humoral immunity.CONCLUSION NICSF might be an indicator of inadequate immunosuppression in long-term followed recipients and its mechanism may be due to immune reactions including humoral immunity. Aim: We hypothesized that non‐inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living‐donor liver transplantation. Methods: In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow‐up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed. Results: In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant ( P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0–4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF‐improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non‐improved patients ( P = 0.0245). Conclusion: NICSF might be an indicator of inadequate immunosuppression in long‐term followed recipients and its mechanism may be due to immune reactions including humoral immunity. Aim: We hypothesized that non‐inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living‐donor liver transplantation. Methods: In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow‐up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed. Results: In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0–4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF‐improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non‐improved patients (P = 0.0245). Conclusion: NICSF might be an indicator of inadequate immunosuppression in long‐term followed recipients and its mechanism may be due to immune reactions including humoral immunity. |
| Author | Ogura, Yasuhiro Teramukai, Satoshi Yoshizawa, Atsushi Miyagawa-Hayashino, Aya Uemoto, Shinji Ogawa, Kohei Haga, Hironori Egawa, Hiroto Kaido, Toshimi Okamoto, Shinya |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22524409$$D View this record in MEDLINE/PubMed |
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| Notes | istex:2EDA74CBC6FD289DBF548164D92D19846AD290DF ArticleID:HEPR1003 ark:/67375/WNG-K282N7G0-Z Author contribution Disclosure Hiroto Egawa organized the study and wrote the manuscript; Aya Miyagawa‐Hayashino and Hironori Haga were responsible for pathological work; Satoshi Teramukai performed statistical analysis; Hidenori Ohe collected clinical data; Shinya Okamoto, Yasuhiro Ogura, Fumitaka Oike and Toshimi Kaido were responsible for patient care; and Shinji Uemoto supervised the study. None of the authors of this manuscript reported biomedical financial interests or potential conflicts of interest. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
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| References | Dixon LR, Crawford JM. Early histologic changes in fibrosing cholestatic hepatitis C. Liver Transpl 2007; 13: 219-26. Wallace WD, Reed EF, Ross D, Lassman CR, Fishbein MC. C4d staining of pulmonary allograft biopsies: an immunoperoxidase study. J Heart Lung Transplant 2005; 24: 1565-70. Scheenstra R, Peeters PMGJ, Verkade HJ, Gouw AS. Graft fibrosis after pediatric liver transplantation: ten years of follow-up. Hepatology 2009; 49: 880-6. Egawa H, Inomata Y, Uemoto S et al. Hepatic vein reconstruction in 152 living-related donor liver transplantation patients. Surgery 1997; 121: 250-7. Abraham SC, Freese DK, Ishitani MB, Krasinskas AM, Wu TT. Significance of central perivenuritis in pediatric liver transplantation. Am J Surg Pathol 2008; 32: 1479-88. French METAVIR Cooperative Study Group. Intraobserver and interobserver variation I liver biopsy interpretation in patient's with chronic hepatitis C. Hepatology 1994; 20: 15-20. Hubscher SG. Central perivelilitis: a common and potentially important finding in late posttransplant liver biopsies. Liver Transpl 2008; 14: 596-600. Tanaka K, Inomata Y, Kaihara S. Living-Donor Liver Transplantation. Surgical Techniques and Innovation. Barcelona: Prous Science, 2003. Ekong UD, Melin-Aldana H, Seshadri R et al. Graft histology characteristics in long-term survivors of pediatric liver transplantation. Liver Transpl 2008; 14: 1582-7. Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-9. Fouquet V, Alves A, Branchereau S et al. Long-term outcome of pediatric liver transplantation for biliary atresia: a 10-year follow-up in a single center. Liver Transpl 2005; 11: 153-60. Banff Working Group, Demetris AJ, Adeyi O, Bellamy CO et al. Liver biopsy interpretation for causes of late liver allograft dysfunction. Hepatology 2006; 44: 489-501. Aw MM, Verma A, Rela M, Heaton N, Mieli-Vergani G, Dhawa A. Long-term outcome of mycophenolate mofetil rescue therapy for resistant acute allograft rejection in pediatric liver transplant recipients. Liver Transpl 2008; 14: 1303-8. Takatsuki M, Uemoto S, Inomata Y et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 2001; 72: 449-54. Yoshitomi M, Koshiba T, Haga H et al. Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation 2009; 87: 606-14. Sakashita H, Haga H, Ashihara E et al. Significance of C4d staining in ABO-identical/compatible liver transplantation. Mod Pathol 2007; 20: 676-84. Saad S, Tanaka K, Inomata Y et al. Portal vein reconstruction in pediatric liver transplantation from living donors. Ann Surg 1998; 227: 275-81. Egawa H, Uemoto S, Takada Y et al. Initial steroid bolus injection promotes vigorous CD8+ alloreactive responses toward early graft acceptance immediately after liver transplantation in humans. Liver Transpl 2007; 13: 1262-71. Evans HM, Kelly DA, McKiernan PJ, Hubscher S. Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology 2006; 43: 1109-17. Haga H, Egawa H, Fujimoto Y et al. Acute humoral rejection and C4D immunostaining in ABO blood type incompatible liver transplantation. Liver Transplant 2006; 12: 457-64. 2001; 72 2009; 87 2006; 12 2006; 43 2006; 44 1997; 121 1995; 22 2008; 14 2008; 32 2003 1998; 227 2007; 20 2005; 11 2009; 49 2007; 13 2005; 24 1994; 20 e_1_2_6_20_2 Tanaka K (e_1_2_6_9_2) 2003 e_1_2_6_8_2 e_1_2_6_7_2 e_1_2_6_18_2 e_1_2_6_19_2 e_1_2_6_4_2 e_1_2_6_3_2 e_1_2_6_6_2 e_1_2_6_5_2 French METAVIR Cooperative Study Group (e_1_2_6_12_2) 1994; 20 e_1_2_6_13_2 e_1_2_6_2_2 e_1_2_6_10_2 e_1_2_6_11_2 e_1_2_6_21_2 e_1_2_6_16_2 e_1_2_6_17_2 e_1_2_6_14_2 e_1_2_6_15_2 |
| References_xml | – reference: Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-9. – reference: Haga H, Egawa H, Fujimoto Y et al. Acute humoral rejection and C4D immunostaining in ABO blood type incompatible liver transplantation. Liver Transplant 2006; 12: 457-64. – reference: Tanaka K, Inomata Y, Kaihara S. Living-Donor Liver Transplantation. Surgical Techniques and Innovation. Barcelona: Prous Science, 2003. – reference: Takatsuki M, Uemoto S, Inomata Y et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 2001; 72: 449-54. – reference: Evans HM, Kelly DA, McKiernan PJ, Hubscher S. Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology 2006; 43: 1109-17. – reference: Sakashita H, Haga H, Ashihara E et al. Significance of C4d staining in ABO-identical/compatible liver transplantation. Mod Pathol 2007; 20: 676-84. – reference: Aw MM, Verma A, Rela M, Heaton N, Mieli-Vergani G, Dhawa A. Long-term outcome of mycophenolate mofetil rescue therapy for resistant acute allograft rejection in pediatric liver transplant recipients. Liver Transpl 2008; 14: 1303-8. – reference: Wallace WD, Reed EF, Ross D, Lassman CR, Fishbein MC. C4d staining of pulmonary allograft biopsies: an immunoperoxidase study. J Heart Lung Transplant 2005; 24: 1565-70. – reference: Egawa H, Inomata Y, Uemoto S et al. Hepatic vein reconstruction in 152 living-related donor liver transplantation patients. Surgery 1997; 121: 250-7. – reference: Saad S, Tanaka K, Inomata Y et al. Portal vein reconstruction in pediatric liver transplantation from living donors. Ann Surg 1998; 227: 275-81. – reference: Egawa H, Uemoto S, Takada Y et al. Initial steroid bolus injection promotes vigorous CD8+ alloreactive responses toward early graft acceptance immediately after liver transplantation in humans. Liver Transpl 2007; 13: 1262-71. – reference: Hubscher SG. Central perivelilitis: a common and potentially important finding in late posttransplant liver biopsies. Liver Transpl 2008; 14: 596-600. – reference: Dixon LR, Crawford JM. Early histologic changes in fibrosing cholestatic hepatitis C. Liver Transpl 2007; 13: 219-26. – reference: Yoshitomi M, Koshiba T, Haga H et al. Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation 2009; 87: 606-14. – reference: French METAVIR Cooperative Study Group. Intraobserver and interobserver variation I liver biopsy interpretation in patient's with chronic hepatitis C. Hepatology 1994; 20: 15-20. – reference: Ekong UD, Melin-Aldana H, Seshadri R et al. Graft histology characteristics in long-term survivors of pediatric liver transplantation. Liver Transpl 2008; 14: 1582-7. – reference: Scheenstra R, Peeters PMGJ, Verkade HJ, Gouw AS. Graft fibrosis after pediatric liver transplantation: ten years of follow-up. Hepatology 2009; 49: 880-6. – reference: Fouquet V, Alves A, Branchereau S et al. Long-term outcome of pediatric liver transplantation for biliary atresia: a 10-year follow-up in a single center. Liver Transpl 2005; 11: 153-60. – reference: Abraham SC, Freese DK, Ishitani MB, Krasinskas AM, Wu TT. Significance of central perivenuritis in pediatric liver transplantation. Am J Surg Pathol 2008; 32: 1479-88. – reference: Banff Working Group, Demetris AJ, Adeyi O, Bellamy CO et al. Liver biopsy interpretation for causes of late liver allograft dysfunction. 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| Snippet | Aim: We hypothesized that non‐inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living‐donor liver... Aim: We hypothesized that non‐inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living‐donor liver... We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver... |
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| SubjectTerms | centrilobular fibrosis immunosuppression liver transplantation protocol biopsy weaning |
| Title | Non-inflammatory centrilobular sinusoidal fibrosis in pediatric liver transplant recipients under tacrolimus withdrawal |
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