Importance of liver biopsy findings in immunosuppression management: Biopsy monitoring and working criteria for patients with operational tolerance

Abstract

Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term Abbreviations: ACR, acute cellular rejection; AIH, autoimmune hepatitis; AMR, antibody-mediated rejection; C4d, complement component 4d; DSA, donor-specific antibody; GGT, gamma-glutamyl transpeptidase; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; IPTH, idiopathic posttransplant hepatitis; IS, immunosuppression; LFT, liver function test; LT, liver transplantation; OLT, orthotopic liver transplantation; OT, operational tolerance; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.The Banff Working Group on Liver Allograft Pathology is a multidisciplinary group comprising pathologists, hepatologists, transplant surgeons, immunologists, and tissue typing experts devoted to the study of various aspects of liver allograft structural integrity, (dys)function, and histopathology. Most importantly, this group strives to develop recommendations for standardized diagnostic histopathological and testing criteria for causes of liver allograft injury/dysfunction, and these recommendations are updated as needed. The group relies on a combination of evidence-based literature reviews and critiques, multidisciplinary experience-based expertise, directed studies, discussions, and consensus building (which occurs during intense biennial working-session international meetings and Internet-based discussions). The members of the group include the following: Oyedele Adeyi (Toronto General Hospital),

ABO-compatible liver allograft antibody-mediated rejection

“…Re-institution or increasing immunosuppression decreased C4d deposits and stabilized or reversed perivenular fibrosis[131]. It is tempting to speculate that the lymphocytic portal and perivenular inflammation in HCV- patients and tissue C4d deposits in DSA+ recipients might be related to each other and represent subclinical combined chronic AMR/TCMR that manifests biochemically after IS lowering[43,124]. …”

“…Whether antibodies are contributing to obliterative arteriopathy not detected in peripheral needle biopsy or other, non-obvious pathology is uncertain. Except for obliterative arteriopathy, many candidate lesions are also caused by technical complications[70,123,124]. Determining the relative contribution of each insult will be challenging and require liver biopsy adequacy as defined by AASLD[132]/Banff Working[124] guidelines for liver biopsy adequacy: 2 passes with a 16 gauge needle >20 mm and >11 portal tracts to monitor fibrosis[133].…”

Post-transplant liver biopsy and the immune response: lessons for the clinician

“…Furthermore, liver biopsy has also been used in several studies where patients have undergone complete withdrawal of immunosuppression to induce 'operational tolerance' [207]. The Banff working group on liver allograft pathology have recently outlined guidelines to help interpret biopsy changes in transplant recipients who are being considered for immunosuppression reduction or withdrawal [208].…”

IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

“…[6][7][8][9][10][11][12] However, DSA can also injure allografts via antibody dependent cell-mediated cytotoxicity (ADCC) and degranulation of inflammatory cells through the binding of Fc receptors on cytotoxic T and NK cells. 15 Sixty-seven subjects (43%) were deemed ineligible, secondary to inflammation and/or fibrosis beyond preset thresholds, 16 revealing a significant burden of subclinical chronic graft injury among clinically ideal patients. 14 We recently performed a multicenter analysis of 157 stable, long-term pediatric liver recipients who underwent a liver biopsy to determine eligibility to participate in a trial of immunosuppression withdrawal.…”