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Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive immunoglobulin M (IgM) antibodies in activating complement after hepatic IR and liver resection. Natural IgM antibodies that recognize danger-associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection. Antibody-deficient Rag1-/- mice were protected from hepatic IRI, but had increased hepatic injury and an impaired regenerative response after 70% partial hepatectomy (PHx). We identified two IgM monoclonal antibodies (mAbs) that specifically reversed the effect of Rag1 deficiency in both models; B4 (recognizes Annexin IV) and C2 (recognizes subset of phospholipids). Focusing on the B4-specific response, we demonstrated sinusoidal colocalization of IgM and C3d in Rag1-/- mice that were reconstituted with B4 mAb, and furthermore that the Annexin IV neoepitope is specifically and similarly expressed after both hepatic IR and PHx in wild-type (WT) mice. A single-chain antibody construct (scFv) derived from B4 mAb blocked IgM binding and reduced injury post-IR in WT mice, although, interestingly, B4scFv did not alter regeneration post-PHx, indicating that anti-Annexin IV antibodies are sufficient, but not necessary, for the regenerative response in the context of an entire natural antibody repertoire. We also demonstrated expression of the B4 neoepitope in postischemic human liver samples obtained posttransplantation and a corollary depletion in IgM recognizing the B4 and C2 neoepitopes in patient sera following liver transplantation. Conclusion: These data indicate an important role for IgM in hepatic IRI and regeneration, with a similar cross-species injury-specific recognition system that has implications for the design of neoepitope targeted therapeutics. (Hepatology 2018;67:721-735).

BACKGROUND Steatotic liver grafts are excluded for partial liver transplantation because of increased risk of primary nonfunction. Mechanisms underlying the failure of fatty partial liver grafts (FPG) remain unknown. This study investigated whether inducible nitric oxide synthase (iNOS) plays a role in failure of FPG. METHODS Fatty livers were induced by feeding rats a high-fat high-fructose diet for 2 weeks. Hepatic triglyceride was approximately 9-fold higher in rats fed the high-fat high-fructose diet than those fed a low-fat low-fructose diet. Lean and fatty liver explants were reduced in size ex vivo to approximately one third, stored in the University of Wisconsin cold storage solution for 2 hr, and implanted. RESULTS Posttransplantational hepatic iNOS expression and reactive nitrogen species (RNS) formation (nitrite and nitrate levels and 3-nitrotyrosine adducts) increased more profoundly in FPG than in lean partial grafts (LPG). Serum alanine aminotransferase and bilirubin were 2- and 5.5-fold higher after transplantation of FPG than LPG. 5-Bromo-2'-deoxyuridine incorporation was 25% in LPG but only 5% in FPG, and graft weight increased by 64% in LPG while remaining unchanged in FPG. All rats that received FPG died, whereas all those receiving LPG survived. N-(1-naphtyl)ethylendiamine dihydrochloride (5 microM), a specific iNOS inhibitor, largely blunted the production of RNS, prevented the increase of alanine aminotransferase and bilirubin, restored liver regeneration, and improved survival of FPG. Mitochondrial cytochrome c oxidase-IV, ATP synthase-beta, and NADH dehydrogenase-3 decreased markedly in FPG, and these effects were blocked by N-(1-naphtyl)ethylendiamine dihydrochloride. CONCLUSION Thus, hepatic steatosis causes failure of partial liver grafts, most likely by increasing RNS that leads to mitochondrial damage and dysfunction.

Effective biomarkers for predicting prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy is urgently needed. The purpose of this study is to evaluate the value of the preoperative peripheral aspartate aminotransferase to white blood cell count ratio (AWR) for the prognostication of patients with HCC. Clinical data of 396 HCC patients who underwent radical hepatectomy were retrospectively analyzed. The patients were divided into the low-AWR group (AWR ≤5.2) and the high-AWR group (AWR >5.2); univariate analysis, Kaplan–Meier method analysis, and the multivariate analysis by Cox regression were conducted, respectively. The results showed that AWR was associated with alpha-fetoprotein (AFP), tumor size, Barcelona clinic liver cancer (BCLC) stage, portal vein tumor thrombus (PVTT), and alanine aminotransferase (ALT) in HCC. AWR > 5.2, AFP > 100 ng/mL, size of tumor >6 cm, number of multiple tumors, B-C of BCLC stage, PVTT, and distant metastasis were predictors of poorer disease-free survival (DFS) and overall survival (OS). Except for recurrence, which was an independent predictor for OS only, AWR >5.2, size of tumor >6 cm, and PVTT were independent predictors of both DFS and OS. We concluded that preoperative AWR > 5.2 was an adverse predictor of DFS and OS in HCC after hepatectomy, AWR might be a novel prognostic biomarker in HCC after curative resection.

There are many methods to assess liver function, but none of them has been verified as fully effective. The purpose of this study is to establish a comprehensive method evaluating perioperative liver reserve function (LRF) in patients with primary liver cancer (PLC). In this study, 310 PLC patients who underwent liver resection were included. The cohort was divided into a training set (n = 235) and a validation set (n = 75). The factors affecting postoperative liver dysfunction (POLD) during preoperative, intraoperative, and postoperative periods were confirmed by logistic regression analysis. The equation for calculating the preoperative liver functional evaluation index (PLFEI) was established; the cutoff value of PLFEI determined through analysis by receiver-operating characteristic curve was used to predict postoperative liver function. The data showed that body mass index, international normalized ratio, indocyanine green (ICG) retention rate at 15 minutes (ICGR15), ICG elimination rate, standard remnant liver volume (SRLV), operative bleeding volume (OBV), blood transfusion volume, and operative time were statistically different (all P