Alcohol-related liver disease (ALD) remains a leading cause of liver-related morbidity and mortality. Age, fibrosis stage, MELD score and continued alcohol consumption predict outcome in everyday clinical practice. In previous studies increased hepatocyte nuclear area and hepatocyte expression of p21, both markers of senescence, were associated with increased fibrosis stage and a poor outcome in non-alcohol-related fatty liver disease, while increased hepatocyte nuclear area was related to liver dysfunction in ALD cirrhosis. This study, therefore, investigated the pattern of hepatocyte cell cycle phase distribution and hepatocyte p21 expression in relation to outcome in ALD. Liver sections from two cohorts were studied. The first comprised 42 patients across the full spectrum of ALD. The second cohort comprised 77 patients with ALD cirrhosis. Immunohistochemistry assessed hepatocyte expression of cell cycle phase markers and p21. Regenerating liver (n=12) and “normal” liver sections (n=5) served as positive and negative controls, respectively. In the first cohort there was little cell cycle progression beyond G₁/S phase and increased hepatocyte p21 expression (p<0.0001), which correlated independently with fibrosis stage (p=0.005) and an adverse liver-related outcome (p=0.03). In the second cohort, both hepatocyte p21 expression (p<0.001) and MELD score (p=0.006) were associated independently with an adverse liver-related outcome; this association was stronger with hepatocyte p21 expression (AUROC 0.74; p=0.0002) than with MELD score (AUROC 0.59; p=0.13). Further, hepatocyte p21 expression co-localised with increased hepatic stellate cell activation. The findings are consistent with impaired cell cycle progression beyond the G₁/S phase in ALD. The striking independent associations between increased hepatocyte p21 expression and both fibrosis stage and an adverse liver-related outcome in both cohorts suggests hepatocyte senescence plays an important role in ALD. Measuring hepatocyte p21 expression is simple and cheap and in this series was a useful measure of long-term prognosis in ALD.

Human herpesvirus 8 (HHV8) is pathogenic in humans, especially in cases of immunosuppression. We evaluated the risk of HHV8 transmission from liver donors, and its clinical impact in southern Italy, where its seroprevalence in the general population is reported to be as high as 18.3%. We tested 179 liver transplant recipients and their donors for HHV8 antibodies at the time of transplantation, and implemented in all recipients a 12‐month posttransplant surveillance program for HHV8 infection. Of the 179 liver transplant recipients enrolled, 10.6% were HHV8 seropositive before transplantation, whereas the organ donor's seroprevalence was 4.4%. Eight seronegative patients received a liver from a seropositive donor, and four of them developed primary HHV8 infection. Two of these patients had lethal nonmalignant illness with systemic involvement and multiorgan failure. Among the 19 HHV8 seropositive recipients, two had viral reactivation after liver transplantation. In addition, an HHV8 seronegative recipient of a seronegative donor developed primary HHV8 infection and multicentric Castleman's disease. In conclusion, primary HHV8 infection transmitted from a seropositive donor to a seronegative liver transplant recipient can cause a severe nonmalignant illness associated with high mortality. Donor screening for HHV8 should be considered in geographic areas with a high prevalence of such infection.

Fetal hepatocytes have a high regenerative capacity. The aim of the study was to assess treatment safety and clinical efficacy of human fetal liver cell transplantation through splenic artery infusion. Patients with endstage chronic liver disease on the waiting list for liver transplantation were enrolled. A retrospectively selected contemporary matched-pair group served as control. Nonsorted raw fetal liver cell preparations were isolated from therapeutically aborted fetuses. The end points of the study were safety and improvement of the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores. Nine patients received a total of 13 intrasplenic infusions and were compared with 16 patients on standard therapy. There were no side effects related to the infusion procedure. At the end of follow-up, the MELD score (mean ± SD) in the treatment group remained stable from baseline (16.0 ± 2.9) to the last observation (15.7 ± 3.8), while it increased in the control group from 15.3 ± 2.5 to 19 ± 5.7 ( p = 0.0437). The Child-Pugh score (mean ± SD) dropped from 10.1 ± 1.5 to 9.1 ± 1.4 in the treatment group and increased from 10.0 ± 1.2 to 11.1 ± 1.6 in the control group ( p = 0.0076). All treated patients with history of recurrent portosystemic encephalopathy (PSE) had no further episodes during 1-year follow-up. No improvement was observed in the control group patients with PSE at study inclusion. Treatment was considered a failure in six of the nine patients (three deaths not liver related, one liver transplant, two MELD score increases) compared with 14 of the 16 patients in the control group (six deaths, five of which were caused by liver failure, four liver transplants, and four MELD score increases). Intrasplenic fetal liver cell infusion is a safe and well-tolerated procedure in patients with end-stage chronic liver disease. A positive effect on clinical scores and on encephalopathy emerged from this preliminary study.