Initial analysis of liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population.

We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers.

The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities.

Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.

Hepatic veno-occlusive disease (HVOD) after liver transplantation (LT) is almost always a fatal complication. We assessed the outcomes of HVOD in a single institute and analyzed a literature-based cohort.

We reviewed the medical records of recipients of LT performed between 1995 and 2020 at our institute and the literature on HVOD after LT. We then analyzed the clinical features based on a "pooled" cohort of cases identified in our institute and reported in the literature.

HVOD was diagnosed in 3 of 331 LT recipients, all of whom died in hospital, on days 164, 12, and 13, respectively. Our comprehensive review of the literature, as well as our cases, identified eight cases of HVOD that developed within 14 days after LT (early-onset type). Early-onset HVOD had a significantly worse prognosis than HVOD that developed beyond 2 weeks after LT (non-early-onset type), which was identified in 22 cases (25.0% vs. 86.1% of the 3-month graft survival rate). The most common causes of early-onset and non-early-onset types were acute cellular rejection (50%) and drug-induced disease (50%), respectively.

Early-onset HVOD developing within 14 days after LT has a poor prognosis.

Antibody-mediated rejection (AMR) after liver transplantation is uncommon but sometimes has a grave prognosis. We herein describe a 40-year-old man who developed simultaneous acute cellular rejection and acute AMR due to de novo donor-specific anti-human leukocyte antigen antibodies after living donor liver transplantation. He underwent living donor liver transplantation with his brother-in-law as the donor. Hepatic function deteriorated on postoperative day 6, and a liver biopsy revealed histologic findings of typical acute cellular rejection. However, steroid pulse therapy and thymoglobulin did not produce a clinical response, and his liver function dramatically deteriorated on postoperative day 13 (aspartate aminotransferase, 2787 IU/L; total bilirubin, 14.1 mg/dL). We diagnosed acute AMR based on positive immunohistochemical staining for C4d in portal areas and added plasma exchange and high-dose intravenous immunoglobulin after rituximab. The patient's clinical state improved and ultimately resolved. To our knowledge, this is the first report of dual antibody treatment for simultaneous acute cellular rejection and acute AMR induced by de novo donor-specific anti-human leukocyte antigen antibodies. Despite his fulminant clinical course, we successfully rescued the recipient with immediate anti-humoral therapy. The rapid treatment decision and adequate understanding of the mechanisms of anti-humoral therapy were crucial to overcoming acute AMR in this case.

Unexplained acute failure of an initially functioning liver graft early post-transplant has been described as Seventh-Day Syndrome (7DS). The aims of this study were to describe the clinical syndrome in detail based on an institutional case series and literature review.

A retrospective review of adult patients that underwent deceased donor liver transplantation at our institution between January 2010 and 2020 was performed to identify patients that developed 7DS. Relevant clinical variables were obtained from medical records. Existing cases in the literature were identified by a systematic literature search according to PRISMA guidelines. Pooled analysis was used to describe the incidence, retransplantation, and mortality rate. Histological findings from institutional and published literature cases were collected and appraised.

Six of 1,907 liver transplantations at our institution (0.3%) developed 7DS. Seven case series, describing 42 patients with 7DS, and two single case reports were identified from literature review. Pooled incidence of 7DS was low (2.1%, 95%CI: 0.7-3.9%) and associated with high mortality (74.8%, 95%CI: 49.2-94.6%). Retransplantation was performed in 23/42 (55%) patients and 4/23 (17%) survived. Review of histology showed frequent intrahepatic thrombi and arteritis. Rejection, with features of potential antibody mediated rejection, often preceded or accompanied progressive zonal coagulative necrosis and hemorrhage.

7DS is a rare clinical syndrome after liver transplantation and associated with high mortality. Antibody-mediated rejection, as suggested in early reports, is likely to be involved in the pathogenesis. Early recognition would allow rapid clinical diagnostics and expedited decisions, such as treatment of AMR if diagnosed or early retransplantation.

This study was aimed to examine the clinical utility and impact of the 2016 Banff criteria for acute antibody-mediated rejection (acute AMR) in patients with liver transplantation. Among adult patients with donor-specific antibody (DSA) assays performed between 2015 and 2020, cases with proved DSA (mean fluorescent index >2000) and matched liver biopsy available were reviewed. Among 55 patients identified, 28 (51%) had class I DSA, 45 (82%) had class II DSA and 18 (33%) had both. Mild, moderate and severe microvasculitis were observed in 11 (20%), 2 (4%) and 1 (2%) case, respectively. Diffuse immunoreactivity to C4d on portal microvascular endothelia was confirmed in 5 cases (9%), which met the criteria of definite (n=2) or suspicious for acute AMR (n=3). Cases of acute AMR more commonly had class I DSA (100% vs. 46%; p=0.027) or both class I and II DSA (80% vs. 28%; p=0.018) than cases of non-acute AMR. One case of pure acute AMR with veno-occlusion was successfully treated with plasma exchange. The remaining 4 cases had features of combined acute AMR/T cell-mediated rejection (TCMR), and two progressed to ductopenic rejection within 3 weeks. In conclusion, only 9% of DSA-positive patients met the Banff criteria for acute AMR, necessitating careful morphological and immunohistochemical assessments of the allograft biopsies according to the proposed standards. Combined acute AMR/TCMR was more common than isolated acute AMR, and additional AMR in TCMR cases may be associated with rapid progression to ductopenic rejection.

The liver has traditionally been regarded as resistant to antibody-mediated rejection (AMR). AMR in liver transplants is a field in its infancy compared to kidney and lung transplants. In our case we present a patient with alpha-1-antitrypsin disease who underwent ABO compatible liver transplant complicated by acute liver failure (ALF) with evidence of antibody mediated rejection on allograft biopsy and elevated serum donor-specific antibodies (DSA). This case highlights the need for further investigations and heightened awareness for timely diagnosis.

A 56 year-old woman with alpha-1-antitrypsin disease underwent ABO compatible liver transplant from a deceased donor. The recipient MELD at the time of transplant was 28. The flow cytometric crossmatches were noted to be positive for T and B lymphocytes. The patient had an uneventful recovery postoperatively. Starting on postoperative day 5 the patient developed fevers, elevated liver function tests, distributive shock, renal failure, and hepatic encephalopathy. She went into ALF with evidence of antibody mediated rejection with portal inflammation, bile duct injury, endothelitis, and extensive centrizonal necrosis, and C4d staining on allograft biopsy and elevated DSA. Despite various interventions including plasmapheresis and immunomodulating therapy, she continued to deteriorate. She was relisted and successfully underwent liver retransplantation.

This very rare case highlights AMR as the cause of ALF following liver transplant requiring retransplantation.