The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

In patients who undergo liver transplantation for alcoholic liver disease (ALD), alcohol relapse is common. A return to abusive or excessive drinking likely decreases overall survival; however, the effects of alcohol use on allograft outcomes and histopathology are less well defined. We reviewed all cases of liver transplantation with ALD as an indication between January 1, 1995 and December 31, 2007. Allograft outcomes and histopathological results were compared for patients who relapsed into alcohol use and patients who maintained abstinence. Three hundred patients who underwent transplantation for ALD during this period survived at least 1 year, and 48 (16.0%) relapsed into alcohol use that came to clinical attention. The pattern of relapse was a single event for 10 patients (20.8%), intermittent relapses for 22 patients (45.8%), and continuous heavy drinking for 16 patients (33.3%). Continuous heavy drinking was associated with allograft loss in a univariate Cox proportional hazards analysis [hazard ratio (HR) 5 2.43, 95% confidence interval (CI) 5 1.26-4.68, P 5 0.008] and in a multivariate Cox proportional hazards regression (HR 5 2.57, 95% CI 5 1.32-5.00, P 5 0.006). A matched-pair analysis that controlled for the hepatitis C virus status and the time to biopsy compared the results of allograft histopathology for patients who relapsed into alcohol use and patients who maintained abstinence. Significant steatosis [odds ratio (OR) 5 3.46, 95% CI 5 1.29-9.31, P 5 0.01], steatohepatitis (OR 5 6.2, 95% CI 5 1.70-22.71, P 5 0.006), and advanced (stage 3 or higher) fibrosis (OR 5 23.18, 95% CI 5 3.01-177.30, P 5 0.003) were associated with alcohol relapse. In conclusion, alcohol relapse after liver transplantation (particularly heavy drinking) is associated with decreased graft survival and advanced allograft fibrosis.

Emerging magnetic resonance imaging (MRI) biomarkers of hepatic steatosis have demonstrated tremendous promise for accurate quantification of hepatic triglyceride concentration. These methods quantify the “proton density fat-fraction” (PDFF), which reflects the concentration of triglycerides in tissue. Previous in vivo studies have compared MRI-PDFF with histologic steatosis grading for assessment of hepatic steatosis. However, the correlation of MRI-PDFF with the underlying hepatic triglyceride content remained unknown. The aim of this ex vivo study was to validate the accuracy of MRI-PDFF as an imaging biomarker of hepatic steatosis. Using ex vivo human livers, we compared MRI-PDFF with magnetic resonance spectroscopy-PDFF (MRS-PDFF), biochemical triglyceride extraction and histology as three independent reference standards. A secondary aim was to compare the precision of MRI-PDFF relative to biopsy for the quantification of hepatic steatosis. MRI-PDFF was prospectively performed at 1.5T in 13 explanted human livers. We performed co-localized paired evaluation of liver fat content in all nine Couinaud segments using single-voxel MRS-PDFF (n=117), tissue wedges for biochemical triglyceride extraction (n=117), and five core biopsies performed in each segment for histologic grading (n=585). Accuracy of MRI-PDFF was assessed through linear regression with MRS-PDFF, triglyceride extraction and histology. Intra-observer agreement, inter-observer agreement and repeatability of MRI-PDFF and histologic grading were assessed through Bland-Altman analyses. MRI-PDFF showed an excellent correlation with MRS-PDFF (r=0.984; CI: 0.978–0.989) and strong correlation with histology (r=0.850; CI: 0.791–0.894) and triglyceride extraction (r=0.871; CI: 0.818–0.909). Intra-observer agreement, inter-observer agreement and repeatability showed a significantly smaller variance for MRI-PDFF than for histologic steatosis grading (all p<0.001). Conclusion MRI-PDFF is an accurate, precise and reader-independent non-invasive imaging biomarker of liver triglyceride content, capable of steatosis quantification over the entire liver.

NAFLD recurrence is common in the first 5 years postliver transplantation and is associated with features of the metabolic syndrome. Although NAFLD recurrence was not associated with higher mortality in our cohort, cardiovascular mortality and morbidity were common, suggesting that the metabolic syndrome is an important link to NAFLD recurrence and cardiovascular deaths posttransplantation.

In patients with hilar cholangiocarcinoma, concomitant hepatic resection is associated with improved DFS, DSS, and decreased hepatic recurrence. Therefore, hepatectomy combined with bile duct resection should be considered standard treatment.