Sonal Asthana

Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database

The current model of liver graft allocation in place in the United States favors transplantation of patients with small hepatocellular carcinomas (HCCs) within the Milan criteria (a single tumor up to 5 cm in diameter or up to three lesions, none larger than 3 cm). Although several reports have suggested that these criteria could be extended, there is currently no agreement on new selection tools. In this study, we performed an overview of 6478 adult recipients of an isolated first liver transplant registered in the Scientific Registry of Transplant Recipients (SRTR) database. From March 2002 to January 2008, increasing numbers of patients outside Milan criteria (P ≤ 0.001) have been registered for a transplant, but they still represent less than 5% of the transplants performed for HCC. Of all the tested variables (tumor number, largest tumor size, and Milan and University of California San Francisco criteria), only total tumor volume (TTV; P ≤ 0.05) and alpha fetoprotein (AFP; P ≤ 0.001) could predict patient survival. While these two parameters demonstrated independent behaviors (no patient demonstrated an increase in both values), a composite score was defined, with patients with a TTV > 115 cm3 or an AFP > 400 ng/mL being outside criteria. The combined TTV/AFP score efficiently predicted posttransplant survival (hazard ratio = 2, 95% confidence interval = 1.7‐2.4, P ≤ 0.001); patients not meeting these criteria had a survival below 50% at 3 years. Conclusion: According to the present SRTR data, Milan criteria are too restrictive, and patients with larger TTV can enjoy satisfactory posttransplant survivals. A composite patient selection score combining TTV and AFP was the most effective of all tested staging criteria for the prediction of posttransplant patient survival for candidates with HCC. (HEPATOLOGY 2009.)

Donor risk index and MELD interactions in predicting long-term graft survival: a single-centre experience.

Introduction. Feng et al. described the donor risk index (DRI) in North American liver transplant recipients. We evaluated the effect of the DRI and model for end-stage liver disease (MELD) score on liver transplant recipients from a single center in the United Kingdom. Method. Prospectively, collected data of all patients transplanted at our center between January 1995 and December 2005 were included in the analysis (n=1090). Outcomes evaluated included patient-censored and death-censored graft survival. Outcomes of liver transplantation from “high” and “low” DRI groups (≥1.8 and <1.8, respectively) on patients categorized into low (<15), intermediate (15-30), and high (>30) MELD categories were analyzed. Results. MELD at transplant was the only significant predictor of patient survival. MELD at transplant and DRI more than 1.7 were associated with a poorer graft survival (P=0.03). There was a trend toward poorer graft survival in high DRI grafts transplanted in low and “intermediate” MELD categories (P=0.47 and 0.006, respectively). However, in the high MELD category, there was a similar graft survival for both high and low DRI grafts. Conclusion. Patients with low and intermediate MELDs at transplantation may be better served by a low DRI graft, whereas patients with high MELD may not be compromised by receiving a high DRI graft.

m-TOR inhibitors: what role in liver transplantation?

The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence.

Portal vein thrombosis in cirrhosis.

Portal vein thrombosis (PVT) is being increasingly recognized in patients with advanced cirrhosis and in those undergoing liver transplantation. Reduced flow in the portal vein is probably responsible for clotting in the spleno-porto-mesenteric venous system. There is also increasing evidence that hypercoagulability occurs in advanced liver disease and contributes to the risk of PVT. Ultrasound based studies have reported a prevalence of PVT in 10-25% of cirrhotic patients without hepatocellular carcinoma. Partial thrombosis of the portal vein is more common and may not have pathophysiological consequences. However, there is high risk of progression of partial PVT to complete PVT that may cause exacerbation of portal hypertension and progression of liver insufficiency. It is thus, essential to accurately diagnose and stage PVT in patients waiting for transplantation and consider anticoagulation therapy. Therapy with low molecular weight heparin and vitamin K antagonists has been shown to achieve complete and partial recanalization in 33-45% and 15-35% of cases respectively. There are however, no guidelines to help determine the dose and therapeutic efficacy of anticoagulation in patients with cirrhosis. Anticoagulation therapy related bleeding is the most feared complication but it appears that the risk of variceal bleeding is more likely to be dependent on portal pressure rather than solely related to coagulation status. TIPS has also been reported to restore patency of the portal vein. Patients with complete PVT currently do not form an absolute contraindication for liver transplantation. Thrombectomy or thromboendovenectomy is possible in more than 75% of patients followed by anatomical end-to-end portal anastomosis. When patency of the portal vein and/or superior mesenteric vein is not achieved, only non-anatomical techniques (reno-portal anastomosis or cavo-portal hemitransposition) can be performed. These techniques, which do not fully reverse portal hypertension, are associated with higher morbidity and mortality risks in the short term.

A score predicting survival after liver retransplantation for hepatitis C virus cirrhosis.

Background. Approximately one fourth of patients transplanted for hepatitis C virus (HCV)-induced liver failure progress to cirrhosis within 5 years, potentially requiring retransplantation. Although the relisting decision can be difficult in these patients, a score could help in selection of candidates with the best potential outcomes. Methods. A total of 1422 HCV-positive patients having undergone a retransplantation were included in this registry-based study. A multivariate Cox regression was performed, and an Akaike procedure was applied to design a score predicting survival after retransplantation and to allow an internal validation. Retained variables were donor age (DnAge), serum creatinine (Creat), International Normalized Ratio (INR), and serum albumin (Alb) at the second transplantation, recipient age (RecAge) at the first transplantation, and the interval between both transplantations (Int). Results. The score was designed as 0.23×DnAge+4.86×log Creat−2.45×log Int+2.69×INR+0.10×RecAge−3.27× Alb+40. The receiver operating characteristic area under curve was 0.643 at 3 years, and survivals were 71%, 56%, and 37% for scores <30, 30 to 40, and >40, respectively (log rank <0.0001). Conclusions. Overall, the proposed score is specifically designed for HCV-positive patients, accurately predicts survival after a liver retransplantation, and is helpful in the selection of candidates with the best potential outcomes.

Bloodstream infection after elective liver transplantation is associated with increased mortality in patients with cirrhosis

PURPOSE This study aims to investigate what factors predict the development of postoperative bloodstream infection (BSI) in patients transplanted electively for chronic liver disease and compare outcomes in infected transplant recipients (BCLD) with noninfected patients (CLD). METHODS A retrospective cohort study of 218 patients who had elective liver transplantation (LT) between January 2003 and July 2005 and admitted to a specialist intensive care unit (ICU) was done. RESULTS Fifteen patients had BSI post-LT (BCLD, 29 isolates) while in the ICU, and 203 patients did not (CLD). Thirty-eight percent of isolates were gram negatives; 55%, gram positives; and 7%, fungemia. Median time to first BSI post-LT was 11 days (range, 3-16 days). On admission post-LT to the ICU, patients with BCLD had higher Acute Physiology and Chronic Health Evaluation II scores (23 vs 10, P < .001). While in the ICU, patients with BCLD had greater requirements for renal replacement therapy (73% vs 8%) and days on mechanical ventilation (17 vs 2 days) and longer median ICU stay (21 vs 3 days, P < .001 for all). One-year survival was worse in the BCLD group (40% vs 94%, P < .001). On multivariate analysis, Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.36) post-LT was independently associated with subsequent BSI. Bloodstream infection (hazards ratio, 8.7) was independently associated with mortality. CONCLUSION Bloodstream infection post-LT was associated with increased severity of illness on admission, greater requirements for organ support, and increased mortality.

Arylacetamide deacetylase: A novel host factor with important roles in the lipolysis of cellular triacylglycerol stores, VLDL assembly and HCV production

BACKGROUND & AIMS Very low density lipoproteins (VLDLs) are triacylglycerol (TG)-rich lipoproteins produced by the human liver. VLDLs derive the majority of their TG cargo from the lipolysis of TG stored in hepatocellular lipid droplets (LDs). Important roles for LDs and the VLDL secretory pathway in the cell culture production of infectious hepatitis C virus (HCV) have been established. We hypothesized that TG lipolysis and VLDL production are impaired during HCV infection so that these cellular processes can be diverted towards HCV production. METHODS We used an HCV permissive cell culture system (JFH-1/HuH7.5 cells) to examine the relationship between TG lipolysis, VLDL assembly, and the HCV lifecycle using standard biochemical approaches. RESULTS Lipolysis of cellular TG and VLDL production were impaired in HCV infected cells during the early peak of viral infection. This was partially explained by an apparent deficiency of a putative TG lipase, arylacetamide deacetylase (AADAC). The re-introduction of AADAC to infected cells restored cellular TG lipolysis, indicating a role for HCV-mediated downregulation of AADAC in this process. Defective lipolysis of cellular TG stores and VLDL production were also observed in HuH7.5 cells stably expressing a short hairpin RNA targeting AADAC expression, proving AADAC deficiency contributes to these defective pathways. Finally, impaired production of HCV was observed with AADAC knockdown cells, demonstrating a role for AADAC in the HCV lifecycle. CONCLUSIONS This insight into the biology of HCV infection and possibly pathogenesis identifies AADAC as a novel and translationally relevant therapeutic target.

Impact of calcineurin inhibitors with or without interferon on hepatitis C virus titers in a chimeric mouse model of hepatitis C virus infection

Cyclosporine A (CSA) has potent effects against hepatitis C virus (HCV) in vitro, but its clinical efficacy after liver transplantation (LT) is uncertain. We evaluated the impact of CSA and tacrolimus (TAC) with or without concomitant interferon (IFN) therapy on serum HCV titers in a chimeric mouse model of HCV infection. Six groups of HCV‐infected mice received only the vehicle, IFN, CSA, CSA and IFN, TAC, or TAC and IFN for 4 weeks. The quantitative HCV polymerase chain reaction levels were determined after 1, 2, and 4 weeks of drug administration. There were no significant differences in the HCV titers after 4 weeks of treatment between the non–IFN‐treated groups (log HCV titers: 3.5 ± 0.3 for the vehicle group, 4.4 ± 0.6 for the CSA group, and 4.3 ± 0.4 for the TAC group, P = 0.3). Although IFN had a consistent effect of reducing HCV titers across the groups, there was no significant impact of CSA on HCV levels when it was used alone or in combination with IFN at any time point. The 4‐week HCV titers were as follows: 3.2 ± 0.3 for the IFN group, 4.7 ± 0.4 for the CSA/IFN group, and 4.0 ± 0.5 for the TAC/IFN group (P = 0.07). The CSA/IFN and TAC/IFN groups did not differ significantly (P = 0.6). Six of the 7 animals in the IFN group (85.7%) had an HCV titer decline ≥ 1 log, whereas in the test groups (CSA/IFN and TAC/IFN), 6 of 9 animals (66.7%) achieved a 1‐log decline in the HCV titer (P = 1). Using this animal model, we could find no evidence supporting the routine use of CSA after LT in HCV‐infected patients. Liver Transpl 18:38–44, 2012.

The impact of sirolimus on hepatocyte proliferation after living donor liver transplantation

Toso C, Patel S, Asthana S, Kawahara T, Girgis S, Kneteman NN, Shapiro AMJ, Bigam DL. The impact of sirolimus on hepatocyte proliferation after living donor liver transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01159.x
© 2009 John Wiley & Sons A/S.

Blood Cytokine, Chemokine and Gene Expression in Cholestasis Patients with Intractable Pruritus Treated with a Molecular Adsorbent Recirculating System: A Case Series

BACKGROUND The molecular adsorbent recirculating system (MARS) is an albumin-dialysis modality that has been investigated predominantly in patients with acute and acute-on-chronic liver failure. OBJECTIVES To report the clinical efficacy and safety of MARS therapy for intractable pruritus in cholestasis patients with stable chronic liver disease, characterizing the impact of MARS on cytokine levels and on the transcriptome in the blood compartment. METHODS MARS therapy was performed on three patients with cholestatic liver disease using 8 h runs for two consecutive days. The expression levels of 65 cytokines⁄chemokines and 24,000 genes were profiled by Luminex (Luminex Corporation, USA) and microarray, respectively. RESULTS A quality-of-life assessment demonstrated a marked improvement during therapy, which was sustained in two of three patients. No bleeding or infectious complications were observed. Bile acid levels were markedly reduced following MARS (mean [± SD] pretreatment 478.9±112.2 µmol⁄L versus post-treatment 89.7±68.8 µmol⁄L). Concordant decreases in cytokine⁄chemokine levels were noted for interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL-12 (p40), RANTES, tranforming growth factor-alpha, tumour necrosis factor-alpha and thrombopoietin following MARS. On microarray profiling, biologically relevant concordant changes among all patients were evident for 20 different genes (10 upregulated and 10 downregulated). The upregulation of several potentially immune suppressive⁄regulatory genes (eg, early growth response 3 [EGR-3], ephrin-A2 [EFNA2] and serum amyloid A1 [SAA1]), concurrent with downregulation of genes involved in innate immunity (eg, toll-like receptor 4 interactor with leucine-rich repeats [TRIL]) and inflammation (eg, ephrin receptor B1 [EPHB1]), was observed. CONCLUSIONS This investigative approach offers new insights into intractable pruritus and suggests future therapeutic targets. The clinical benefit of MARS in cholestasis patients with intractable pruritus may not exclusively result from filtration of pruritogens, but also from systemic changes in cytokine⁄chemokine levels and changes in gene expression of blood cells.