Nguyen, Justin H.

AbstractGraft‐versus‐host disease (GVHD) is a rare, fatal complication following orthotopic liver transplantation (OLT). To date, several risk factors have been proposed, but reports on these factors have been inconclusive. This is a retrospective, case–control study of prospectively collected data from 2775OLTs performed at our institution. Eight cases ofGVHDafterOLTwere diagnosed on the basis of the patient's clinical characteristics, and the findings were confirmed with skin and colonic biopsies. Each case was matched to three controls based on the diagnosis of liver disease, recipient's age, and blood group. Univariate and multivariate analyses were performed to identify risk factors associated with the development ofGVHDafterOLT. The univariate and multivariate analyses identified two main risk factors associated with development ofGVHDinOLTrecipients, a difference between recipient and donor age of >20 yr, and any human leukocyte antigen classImatches. Taking these two risk factors into consideration while matching prospective donors and recipients may reduce further incidence ofGVHDinOLTpatients. However, further studies are recommended to validate these findings.

Intracardiac thrombosis (ICT) during orthotopic liver transplantation (OLT) is an uncommon event. However, it is a devastating complication with high mortality when it occurs. This study aimed to identify possible predisposing factors for ICT during OLT. We retrospectively identified the cases of all patients with ICT during OLT at our institution from 1998 to 2014. Of 2750 OLTs performed, 10 patients had ICT intraoperatively. The patients' immediate prethrombosis intraoperative hemodynamic and coagulation values and thromboelastography (TEG) data were reviewed. Preexisting venous thrombosis, atrial fibrillation, and the prior placement of a transjugular intrahepatic portosystemic shunt for portal hypertension were noted in several patients and may be related to ICT during OLT. A high Model of End‐Stage Liver Disease score, low cardiac output, and sepsis did not appear to be associated with ICT. ICT occurred in some patients without the administration of antifibrinolytic agents. TEG and coagulation parameters did not appear to be helpful in predicting the onset of ICT. Four patients had ICT in both right‐ and left‐sided heart chambers; none of these 4 patients survived. All 6 patients with only right‐sided thrombus survived. In those who survived, improved hemodynamics and clot disappearance on transesophageal echocardiography (TEE) occurred over time, even without the use of thrombolytics. Whether this is because of endogenous thrombolysis or distal clot propagation into the pulmonary vasculature, or both, is unclear. Tissue plasminogen activator may have a role in the resuscitation procedure. In conclusion, without the routine use of TEE during OLT, the incidence of ICT will remain an under‐recognized event. Liver Transpl 21:1280‐1285, 2015. © 2015 AASLD.

Background. Graft pretreatment to limit postoperative damage has the advantage of overcoming a current issue in liver transplantation (LT). The strategic potential of graft pretreatmentin vivoby a specific agonist forγ-aminobutyric acid receptor (GABAR) was investigated in the rat LT model with a small-for-size graft (SFSG).Methods. Recipient rats were divided into three groups according to donor treatments and recipient surgeries: (i) saline and laparotomy, (ii) saline and split orthotopic liver transplantation (SOLT) with 40%-SFSG, and (iii) GABAR agonist and SOLT with 40%-SFSG. Survival was evaluated. Blood and liver samples were collected 6 h after surgery. Immunohistological assessment for apoptotic induction and western blotting for 4-hydroxynonenal, ataxia-telangiectasia mutated kinase (ATM), histone H2AX, phosphatidylinositol-3 kinase (PI3K), Akt, and free radical scavenging enzymes were performed.Results. Pretreatment by GABAR showed improvement in survival, histopathological assessment, and biochemical tests. Apoptotic induction and oxidative stress were observed after SOLT with an SFSG, and this damage was limited by GABAR regulation. GABAR regulation appeared to reduce DNA damage via the ATM/H2AX pathway and to promote cell survival via the PI3K/Akt pathway.Conclusions. Pretreatmentin vivoby GABAR regulation improves graft damage after SOLT with an SFSG. This strategy may be advantageous in LT.

AimIf progressive liver injury and subsequent hepatic encephalopathy can be prohibited in fulminant liver failure (FLF), it would be ideal for intensive care of FLF and provide an expanded opportunity for liver transplantation (LT). We hypothesized that matrix metalloproteinase (MMP)‐9 plays an important role in FLF progression, and investigated MMP‐9 behaviors in a murine FLF model, especially at the coma stage.MethodsThe murine FLF model with azoxymethane recapitulates FLF in humans. The detailed coma status was evaluated, on the assumption that LT is indicated at early, but not late, stage 3. To investigate whether MMP‐9 deletion or reduction has beneficial effects, an MMP‐9 inhibitor (GM6001) and transfection of tissue inhibitor of metalloproteinases (TIMP)‐1 cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP‐1 plasmid transfection 24 h before disease onset; and FLF with TIMP‐1 plasmid transfection 48 h before disease onset. Neurological findings, including survival, were followed. Samples were obtained at early and late stage 3. Biochemical examinations and histopathological assessments were performed. The expression and function of MMP‐9 and TIMP‐1 were evaluated by western blotting and zymography. A brain permeability study was also performed.ResultsMMP‐9 was strongly increased in FLF. The MMP‐9 inhibitions worked well, and prolonged the survival, interval to stage 3 and duration of early stage 3. MMP‐9 inhibition improved the liver and subsequent brain injuries at early stage 3, with no remarkable improvements at late stage 3.ConclusionMMP‐9 has therapeutic potential for FLF progression.

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

Background . Glycemic control following total pancreatectomy (TP) has been thought to be difficult to manage. Diffuse intraductal papillary mucinous neoplasm (IPMN) is a potentially curable precursor to pancreatic adenocarcinoma, best treated by TP. Objective . Compare glycemic control in patients undergoing TP for IPMN to patients with type 1 diabetes mellitus (DM). Design/Setting . Retrospective cohort. Outcome Measure . Hemoglobin A1C(HbA1C) at 6, 12, 18, and 24 months after TP. In the control group, baseline was defined as 6 months prior to the first HbA1c measure. Results . Mean HgbA1C at each point of interest was similar between TP and type I DM patients (6 months (7.5% versus 7.7%, P = 0.52 ), 12 months (7.3% versus 8.0%, P = 0.081 ), 18 months (7.7% and 7.6%, P = 0.64 ), and at 24 months (7.3% versus 7.8%, P = 0.10 )). Seven TP patients (50%) experienced a hypoglycemic event compared to 65 type 1 DM patients (65%, P = 0.38 ). Limitations . Small number of TP patients, retrospective design, lack of long-termfollowup. Conclusion . This suggests that glycemic control following TP for IPMNcan be well managed, similar to type 1 DM patients. Fear of DM following TP for IPMN should not preclude surgery when TP is indicated.

Abstract Background Progressive familial intrahepatic cholestasis (PFIC) results in liver cirrhosis during the disease course, although the etiology includes unknown mechanisms. Some PFIC patients require liver transplantation (LT). Methods In this study, 11 patients with PFIC type 1 (PFIC1) and 3 patients with PFIC type 2 (PFIC2) who underwent living‐donor LT (LDLT) were evaluated. Results Digestive symptoms after LDLT were confirmed in 10 PFIC1 recipients (90.9%); 8 PFIC1 recipients showed steatosis after LDLT (72.7%), which began during the early postoperative period (71.5 ± 55.1 days). Seven of the eight steatosis‐positive PFIC1 recipients (87.5%) showed a steatosis degree of ≥80%, which was complicated with steatohepatitis and resulted in fibrosis. Cirrhotic findings persisted in six PFIC1 recipients even after LDLT (54.5%), and three PFIC1 recipients finally died. The survival rates of the PFIC1 recipients at 5, 10, and 15 years were 90.9%, 72.7%, and 54.5%, respectively. In contrast, the PFIC2 recipients showed good courses and outcomes without any steatosis after LDLT. Conclusions The clinical courses and outcomes after LDLT are still not sufficient in PFIC1 recipients owing to steatosis/steatohepatitis and subsequent fibrosis, in contrast to PFIC2 recipients. PFIC2 is good indication for LDLT. PFIC1 patients require LT during the disease course; therefore, we suggest that the therapeutic strategies for PFIC1 patients, including the timing of LDLT, under the donor limitation should be reconsidered. The establishment of more advanced treatments for PFIC1 patients is required to improve the long‐term prognosis of these patients.