Marco A. Lacerda

Portal Vein Thrombosis Is a Risk Factor for Poor Early Outcomes After Liver Transplantation: Analysis of Risk Factors and Outcomes for Portal Vein Thrombosis in Waitlisted Patients.

Background Portal vein thrombosis (PVT) is common in patients with cirrhosis, but the risk factors associated with PVT and its impact on outcomes following liver transplantation (LT) are not well defined. The objectives of this study were to determine the impact of PVT on post-LT patient and graft survival, waitlist outcomes, and the factors associated with PVT. Methods A retrospective review of Organ Procurement and Transplant Network waitlist and LT data between 2002 and 2013 identified 48,570 patients undergoing their first LT, with 3321 (6.8%) reported to have PVT at LT. Results Portal vein thrombosis was independently associated with increased 90-day mortality (odds ratio, 1.7; 95% confidence interval, 1.45-1.99; P < 0.001) and graft failure (odds ratio, 1.72; 95% confidence interval, 1.51-1.97; P < 0.001). Portal vein thrombosis at listing was not associated with lower transplant rates, or delisting for death, or deterioration. Only 31% of patients with PVT at LT had PVT reported at listing. The predictors of PVT at LT in patients without PVT at listing included: fatty or cryptogenic liver disease, ascites, diabetes mellitus, and obesity. “New” PVT at LT was associated with longer wait-time, higher rate of model of end-stage liver disease increase, and intermediate 90-day survival rates compared to patients with or without PVT at both listing and LT. Conclusions Portal vein thrombosis at LT is associated with early (90 days) mortality and graft failure, though a likely but undefined reporting bias for more extensive PVT would overstate estimated risks for all PVT. Further study is needed to better define risks of LT with PVT.

Role of cardiac catheterization and percutaneous coronary intervention in the preoperative assessment and management of patients before orthotopic liver transplantation.

Limited data regarding the optimal risk assessment strategy for evaluating candidates for orthotopic liver transplantation (OLT) exist. Our center has adopted a policy of performing cardiac catheterization (CATH) in patients with predefined risk factors, and this is followed by percutaneous coronary intervention (PCI) when it is indicated, even in the presence of negative stress test findings. The aim of this single‐center, retrospective study of all patients who underwent OLT between 2000 and 2010 was to assess the effect of our policy on cardiovascular (CV) complications and survival rates after OLT. Data, including 1‐year all‐cause and CV mortality, postoperative myocardial infarctions (MIs), and frequencies of CATH and PCI, were abstracted. The study was divided into 3 subperiods to reflect the changes in policy over this period: (A) 2000‐2004, (B) 2005‐2008, and (C) 2009‐2010. One thousand two hundred twenty‐one patients underwent OLT between 2000 and 2010. The rate of catheterization increased during the 3 time periods (P < 0.001), as did the rate of PCI (P < 0.05). All‐cause mortality decreased over the periods (P < 0.001), as did the MI rate (P < 0.001). Thirty‐five of the 57 patients requiring PCI had normal stress tests. The mortality rate associated with postoperative MIs was significantly higher than the overall all‐cause mortality rate. In conclusion, a significant improvement in the overall survival rate over the 3 analyzed time periods was noted. Increases in the frequencies of CATH and PCI corresponded to significant reductions in postoperative MIs and 1‐year all‐cause mortality rates. The increased use of CATH and PCI was associated with reduced overall all‐cause mortality through reductions in the incidence of both fatal and nonfatal MIs. Further analyses of the role of stress testing and CATH in evaluating and treating patients before OLT are required to optimize this process. Liver Transpl 20:664‐672, 2014.

Telaprevir with peginterferon/ribavirin for retreatment of null responders with advanced fibrosis post-orthotopic liver transplant

Aggressive recurrence of hepatitis C remains problematic post‐orthotopic liver transplant (OLT). There are limited data on treatment of HCV infection with telaprevir/boceprevir therapy with peginterferon/ribavirin (PR) post‐OLT.

After the Direct-acting Antivirals Are Gone, There Is Still Work to Be Done in the Liver

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 Hwithout hepatocellular carcinoma is the most common indication for orthotopic liver transplantation (OLT) worldwide. Recurrence of hepatitis C posttransplantation has been associated with accelerated graft loss and less frequently with the difficult to manage fibrosing cholestatic hepatitis. Historically, multiple strategies have been undertaken to prevent reinfection of the graft after OLT, but the toxicities of interferon made therapy for hepatitis C in a decompensated patient highly problematic. However, the all-oral direct-acting antiviral (DAA) era that began in December 2013 with the approval of sofosbuvir and ribavirin has revolutionized hepatitis C therapy in the transplant and nontransplant settings. The optimal management of the patient with hepatitis Crelated cirrhosis with or without transplant as an option remains problematic. Multiple strategies have been adopted, including DAA therapy to achieve a sustained virologic response (SVR) before and proceeding with OLT if no improvement, proceeding with OLT without therapy, treating hepatitis C to clear HCV RNA virus before OLT to minimize reinfection of the new graft, and no therapy if liver disease is advanced. All of these strategies have strengths and weaknesses depending on availability of DAAs, expected waiting time on the transplant list, as well as having the availability of OLT or not as an option. The report in this issue of Gastroenterology provides important insights into intrahepatic viral kinetics in patients with hepatitis C related cirrhosis who receive DAA therapy before OLT. Gambato et al measured HCV RNA in explants by polymerase chain reaction (PCR) from 39 patients who received antiviral therapy before OLT. The clinical outcomes of these patients have been previously reported with 33 of 39 individuals achieving posttransplant virologic response (pTVR), and 6 patients relapsing after transplantation. They noted HCV RNA was still detected in explants by PCR testing in two-thirds of the individuals (22 of 33) who achieved pTVR as well as 4 of 6 individuals who relapsed after OLT. In the 39 individuals who had undetectable serum HCV RNA, a similar pTVR was achieved regardless of whether or not intrahepatic HCV RNA was detected. Only 6 of 39 individuals had completed antiviral therapy at the time of OLT and all of the patients included in this analysis had not yet achieved SVR, giving clinicians a window to the intrahepatic

Su1018 The Role of Anticoagulation for Portal Vein Thrombosis Prior to Orthotopic Liver Transplantation

Portal vein thrombosis (PVT) is common complication in the setting of end stage liver disease. The presence of PVT in the setting of orthotopic liver transplantation (OLT) can be associated with the need for additional anastomoses and potentially reduced survival. The goal of anticoagulation is to achieve partial recanalization to allow end-to-end portal vein anastomosis. Our AIM was to determine the impact of anticoagulation for PVT when indicated on recanalization of the portal vein at the time of OLT and on post OLT outcomes. Methods : This is a single center retrospective study of all patients who underwent OLT who were previously diagnosed with PVT between March 2011 and July 2014. The study included all patients over age 18 with PVT diagnosed by CT or MRI and who subsequently underwent OLT. Data abstracted included demographic data, anatomic extent of PVT, presence/type of anticoagulation, effect on PVT, complications of anticoagulation, and outcomes after transplant including use of jump graft and survival. PVT was classified as occlusive or non-occlusive involving portal vein with or without extension. The decision to anticoagulate was made by a multidisciplinary team at selection conference. Results: 43/333 (13%) patients were diagnosed with PVT before OLT by axial imaging. Median age was 59 years (IQR= 52-63), 27/43 male, median BMI 28 (IQR= 25.7-33), median MELD score 20 (IQR= 17-25). PVT was diagnosed at median of 338 days prior to OLT. In 30/43 patients anticoagulation was initiated (27 warfarin, 3 enoxaparin) prior to OLT for median duration of 9 months (IQR 5 17). The median time to demonstrated improvement or resolution of PVT was 5 months (IQR 37.2). 19/30(63%) of anticoagulated patients achieved partial to full PVT resolution at time of OLT compared to 8/14 patients (57%) in whom no anticoagulation was initiated. 3 patients with partial or full resolution of PVT had recurrent thrombosis post OLT. 3 patients required jump grafts due to thrombosis. In the entire PVT cohort, there were 5 deaths post OLT (2 no anticoagulation, 1 warfarin, 2 enoxaparin). 1 month survival (no anti-coagulation 86% ;warfarin 100%;enoxaparin 67%), 6 month survival (no anti-coagulation 86% ;warfarin 96%%;enoxaparin 33%)and 1 year survival (no anti-coagulation 85% ;warfarin 94%;enoxaparin 0%) were superior in the warfarin treated group compared to enoxaparin or no anticoagulation (p<0.05). Bleeding complications were rare with no difference noted between the anticoagulated and non-anticoagulated groups. Conclusion: Anticoagulation for PVT prior to OLT is safe, and lead to partial or complete resolution in 19/30 patients. Improved survival was noted in the PVT cohort who received anticoagulation with warfarin prior to OLT. Data collection is ongoing to better refine which PVT patients derive benefit with this strategy.

Prevalence and Morbidity Associated With Muscle Cramps in Patients With Cirrhosis

PURPOSE: Patients with cirrhosis often experience muscle cramps with varying severity. We investigated the factors associated with the prevalence and morbidity associated with muscle cramps. METHODS: A total of 150 adult patients with cirrhosis were enrolled consecutively. Cramp questionnaire with visual analogue scale for pain, Chronic Liver Disease Questionnaire (CLDQ), and blood for measurement of 25-(OH) vitamin D levels were obtained after informed consent. RESULTS: A total of 101 patients (67%) reported muscle cramps in the preceding 3 months. Patients with cramps had significantly lower serum albumin (3.10.6 g/dL vs 3.30.7 g/dL, P.04) and CLDQ scores (10737 vs 13734, P.0001) compared with those without cramps. The median composite symptom score, defined as product of frequency and severity of cramps, in the study cohort was 12 with a range of 0.3 to 200. There were no clinical or biochemical predictors for occurrence of any cramps or severe cramps (composite symptom score12). Muscle cramps (P.001) and hepatic encephalopathy (P.009) were associated independently with decreased CLDQ scores. Vitamin D deficiency was seen in 66% of the study cohort, but the serum 25-(OH) vitamin D levels were not significantly different between patients with and without cramps (18.08.9 ng/mL vs 19.69.5 ng/mL, P.49). CONCLUSIONS: Muscle cramps are associated with significantly diminished quality of life in patients with cirrhosis. More research is needed to better understand their mechanism to develop effective treatment.

M1023 Pre-Transplant Factors Influencing Indication for Simultaneous Liver-Kidney Transplantation

The hepatic peptide is a critical regulator of iron metabolism and inflammation. In this (first) study of post-operative hepcidin levels in patients undergoing liver transplantation we show that post-operative serum hepcidin levels identify patients with severe preservation/reperfusion injury and predict early graft dysfunction following liver transplantation. Methods: Serial serum hepcidin levels were measured daily by SELDI-TOFmass spectrometry (using stable isotope labelled hepcidin as internal standard) in 11 patients after liver transplantation. Liver biopsies (T0) were taken at the time of operation in 9/11 patients. Patient outcomes were correlated with clinicopathological results. Results: Five (5/11) patients had poor graft function after transplantation (graft cholestasis, elevated PT time and AST); these patients were more likely to have moderate/severe preservation injury on TO biopsy than patients with normal graft function and more likely to have received a liver from a nonheart beating than a heart-beating donor (3/5 vs 1/7). One patient with graft dysfunction was not biopsied. Whilst there was no difference in hepcidin values between the 2 groups at the time of transplantation (90 vs 76ng/ml p=0.68), the 5 patients with poor graft function had significantly higher hepcidin levels on the third day 3 post-transplantation compared to the 6 patients with mild preservation/reperfusion injury (Mean 135 (91-179) vs.39 (1761) ng/ml, p<0.01 ANOVA). Hepcidin rose by 39% between day 1 and 3 in the poor graft function group but fell by 49% in the group with normal function. Day 3 hepcidin rise anticipated graft cholestasis in those with severe preservation injury and did not correlate with AST or CRP. There was no difference in the two groups regarding age, cold ischaemic time, mean length of ITU stay or rate of septic complications. Conclusion: Serum hepcidin may be a better determinant of graft dysfunction post liver transplant than AST or CRP.

S1004 Month 4 Post-OLT Liver Biopsy Accurately Predicts Subsequent Fibrosis in Those Undergoing Orthotopic Liver Transplantation for HCV-Related Cirrhosis

HCVrelated end stage liver disease is the most common indication for OLT in the US. There is evidence that HCV-related fibrosis is accelerated post OLT leading to poorer survival compared to other etiologies. Our AIM was to identify factors in hepatitis C patients undergoing OLT that predict accelerated fibrosis 1 year post OLT. METHODS: Retrospective single center review of patients undergoing OLT due to HCVrelated cirrhosis from 2001 to 2008. Donor variables included age,gender,BMI,race,ETOH use,positive toxicology screen,presence of anti-HCV or anti-HBV, graft steatosis/fibrosis,CMV status,perfusion solution,organ procurement location, cold and warm ischemia time,sodium,creatinine,total bilirubin,aminotransferase levels. Recipient variables included age,race,gender,BMI,post OLT ICU duration,MELD score,prior ETOH abuse, presence of HCC,immunosuppression regimen,HCV genotype/viral load,lack of SVR,CMV status,pre-OLT TIPS,pre-OLT encephalopathy stage III-IV, pre-OLT ascites, post-OLT prolonged mechanical ventilation, post-OLT hypotension requiring pressors,ALT,Alk Phos,TB, ERCP post OLT,hyperglycemia post OLT,creatinine post OLT, rejection episodes, tacrolimus levels, and liver biopsy fibrosis stage scored by Metavir at month 4,and years 1-4 post OLT. Data were analyzed using Chi Square test, Fishers Exact test and t-tests. The probit-normal model for correlated data and ordinal outcome was used to analyze repeated measures of fibrosis stage as the dependent variable with patient as a random effect. In both sets of analyses, adjustment for year 1 through 4 was also performed and year effect was evaluated.RESULTS: 114 HCV patients (mean ± SEM) age 52 ± 0.3 yrs, BMI 28 ± 0.5, MELD 16 ± 1, 77% male, 87% Caucasian underwent OLT with follow up liver biopsies available for review. Immunosuppression: ATG induction and tacrolimus monotherapy. Only the presence of month 4 fibrosis predicted fibrosis progression during years 1-4 post OLT by probit-normal (estimate 0.911 fibrosis units; p=0.004) and cumulative ordinal logistic regression (estimate 0.864 fibrosis units; p= 0.002). Specific year post OLT was not a predictor of later fibrosis. The interaction between month 4 fibrosis and year fibrosis was not significant. Conclusions:In HCV patients undergoing OLT, month 4 liver biopsy fibrosis level accurately predicts subsequent fibrosis. Those with stage 1-2 fibrosis at month 4 may be candidates for treatment of HCV to prevent further fibrosis progression.