ORIGINAL ARTICLE. Hung-Tien Kuo, 1,2 Erik Lum, 1 Paul Martin, 3 and Suphamai Bunnapradist ORIGINAL ARTICLE

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1 ORIGINAL ARTICLE Effect of Diabetes and Acute Rejection on Liver Transplant Outcomes: An Analysis of the Organ rocurement and Transplantation Network/United Network for Organ Sharing Database Hung-Tien Kuo, 1,2 Erik Lum, 1 aul Martin, 3 and Suphamai Bunnapradist 1 1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; 2 Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 3 Division of Hepatology, Center for Liver Diseases, University of Miami School of Medicine, Miami, FL The effects of diabetic status and acute rejection (AR) on liver transplant outcomes are largely unknown. We studied 13,736 liver recipients from the United Network for Organ Sharing/Organ rocurement Transplant Network database who underwent transplantation between 2004 and 2007 with a functioning graft for greater than 1 year. The association of pretransplant diabetes mellitus (DM), new-onset diabetes after transplant (NODAT), and AR rates on allograft failure, all-cause mortality, and cardiovascular mortality were determined. To determine the differential and joint effects of diabetic status and AR on transplant outcomes, recipients were further stratified into 6 groups: neither (reference, n ); NODAT alone (n ); DM alone (n ); AR alone (n ); NODAT and AR (n 5 707); and DM and AR (n 5 513). An analysis with hepatitis C virus (HCV) serostatus was also performed (HCV recipients, n ; and non-hcv recipient, n ). The median follow-up was 2537 days. The prevalence of DM was 21.3%. At 1 year after transplant, the rates of NODAT and AR were 25.5% and 19.4%, respectively. Overall, DM, NODAT, and AR were associated with increased risks for graft failure (DM, hazard ratio [] , < 0.01; NODAT, , ; AR, , < 0.01). A multivariate Cox regression analysis of the 6 recipient groups demonstrated that NODAT alone was not significantly associated with any study outcomes. The presence of DM, AR, NODAT and AR, and DM and AR were associated with higher overall graft failure risk and mortality risk. The presence of DM was associated with higher cardiovascular mortality risk. The analyses in both HCVpositive and HCV-negative cohorts showed a similar trend as in the overall cohort. In conclusion, DM and AR, but not NODAT, is associated with increased mortality and liver allograft failure. Liver Transplantation AASLD. Received November 13, 2015; accepted January 29, Abbreviations: ADA, American Diabetes Association; AHN, acute hepatic necrosis; Alc, alcoholic; AR, acute rejection; BMI, body mass index; CIT, cold ischemia time; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CsA, cyclosporine A; D, donor; D/R, donor/recipient; DBD, donation after brain death; DCD, donation after cardiac death; DM, diabetes mellitus; ESLD, end-stage liver disease; HCV, hepatitis C virus; HCC, hepatocellular carcinoma;, hazard ratio; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; MA, mycophenolic acid; mtor, mammalian target of rapamycin; NODAT, new-onset diabetes after transplant; OTN, Organ rocurement and Transplantation Network; DM, pretransplant diabetes mellitus; R, recipient; SD, standard deviation; Tac, tacrolimus; UNOS, United Network for Organ Sharing. 796 ORIGINAL ARTICLE Diabetes mellitus (DM) is a common comorbidity among liver transplant recipients. In our previous study using the Organ rocurement and Transplantation Network (OTN)/United Network for Organ Sharing (UNOS) liver transplant database, we reported pretransplant diabetes mellitus (DM) in 21% of adult liver transplant recipients in the United States; furthermore, 26.4% of recipients developed new-onset diabetes after transplant (NODAT) in a mean follow-up time of 685 days. (1) However, information regarding the impact of recipient diabetic status on liver transplant outcomes is limited. reexisting diabetes has been reported to be

2 LIVER TRANSLANTATION, Vol. 22, No. 6, 2016 associated with inferior liver transplant outcomes, (2-4) whereas the association between NODAT and liver transplant outcomes is inconclusive. (5-7) Acute allograft rejection and hepatitis C virus (HCV) serostatus are 2 important conditions that may interact with recipient posttransplant diabetic status. Acute rejection (AR) was implicated in graft failure in liver transplantation in older studies. (8,9) Immunosuppressive agents, commonly used both to prevent and to treat AR, such as steroids and tacrolimus (Tac), are diabetogenic. (1,10) In our previous study in kidney transplant recipients analyzing the differential impact of DM status and AR on transplant outcomes, DM was the major predictor of all-cause and cardiovascular mortality, whereas AR was the major predictor of death-censored graft failure. An effect of NODAT on transplant outcomes could not be confirmed in the median follow-up time of 2.5 years following kidney transplantation. One of the most common indications for liver transplantation is cirrhosis caused by chronic HCV infection. retransplant HCV seropositivity is associated with an increased risk for both liver transplant failure and NODAT. In an analysis by Charlton and Seaberg, (11) the mortality risk was significantly increased for HCV-infected transplant recipients who developed early acute cellular rejection compared with HCVnegative transplant recipients. The presence of HCV could attenuate, or completely eliminate, any association between DM status and AR with liver transplant outcomes. In this study, we aimed to investigate the joint association of DM status and AR with liver transplant outcomes using the OTN/UNOS liver transplant database and whether pretransplant HCV serostatus attenuated or accentuated these results. Address reprint requests to Suphamai Bunnapradist, M.D., Department of Medicine, David Geffen School of Medicine, University of California, 1033 Gayley Avenue, Suite 208, Los Angeles, CA Telephone: ; FAX: ; bunnapradist@mednet.ucla.edu Copyright VC 2016 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt otential conflict of interest: Nothing to report. atients and Methods STUDY OULATION Adult recipients (age 18 years) who had received a primary liver transplant between July 1, 2004 and December 31, 2007 with at least 1 follow-up report with an unequivocal record of diabetic status during follow-up were identified in the OTN/UNOS database as of September 5, Multiorgan transplant recipients and recipients without clear reports of pretransplant diabetic status were excluded. A total of 13,736 recipients surviving with a functioning graft for at least 1 year posttransplant were selected for inclusion into the study population. The institutional review board of the University of California, Los Angeles approved the study protocol. VARIABLES OF INTEREST AND MEASUREMENT Definition of DM, NODAT, and AR The presence of DM was confirmed if DM was listed as a pretransplant comorbid condition by OTN/ UNOS. The presence of NODAT was identified in non-dm recipients with documentation on at least 1 occasion of DM after liver transplant. Onset of NODAT was assumed to be the date of the earliest report of DM after liver transplant. AR was defined in those who had at least 1 record of the indicated variables in the OTN/UNOS database: AR as contributory cause of graft failure, biopsy-confirmed AR, treated for rejection in 6 months, treated for rejection in 1 year, treated for rejection with steroids, or treated for rejection with antibodies. Definition of DM and AR atient Groups Initially, the liver recipients were stratified at 1 year after transplant by DM as a 3-level variable (DM [n ], NODAT [n ], or neither [n ]) and AR as a 2-level variable (AR [n ] and no AR [n 5 11,068]) for evaluation of the independent effects of each variable and interactions. Subsequently, the recipients were stratified into 6 groups according to their joint status of DM and AR at 1 year after transplant: group 1, neither (control), n ; group 2, NODAT alone (n ); group ORIGINAL ARTICLE 797

3 LIVER TRANSLANTATION, June 2016 FIG. 1. Flow diagram for stratification of recipients according to the status of DM and AR at 1 year after transplant. 3, DM alone (n ); group 4, AR alone (n ); group 5, NODAT and AR (n 5 707); group 6, DM and AR (n 5 513). The flow diagram for cohort assembly and recipient stratification is shown in Fig. 1. otential Confounding Factors Recipient-related confounding factors included sex, age, pretransplant body mass index (BMI), race, pretransplant hypertension, HCV infection, Model for End-Stage Liver Disease (MELD) score, cause of hepatic failure, and hepatocellular carcinoma (HCC) were recorded. Donor-related factors included sex, age, donor type (living or deceased), diabetic donor, donor/recipient cytomegalovirus (CMV) status, and induction were also recorded. Immunosuppressive factors including induction therapy; selection of calcineurin inhibitors (CNIs; Tac or cyclosporine A [CsA]); and mycophenolate mofetil (MMF)/mycophenolic acid (MA), mammalian target of rapamycin (mtor) inhibitors, and steroid use at discharge were retrieved. STATISTICAL ANALYSIS Recipient, donor, and transplant characteristics were described using means (6 standard deviation [SD]) or frequencies as appropriate. Continuous variables, including age and BMI, were categorized because their associations with the study outcomes were not linear. Comparisons among groups were made using the Wilcoxon rank sum test for continuous variables and chi-square test for categorical variables. Survival rates were estimated using the Kaplan-Meier product limit method. The log-rank test was used for comparison of the unadjusted survival curves. Multivariate Cox models were fitted to determine the relative risks for the outcomes of graft loss and all-cause mortality in those who survived with a functioning graft for at least 1 year following liver transplant. The independent association of diabetic status (DM, NODAT, DM-free) and AR (AR, AR-free) variables and their interactions for overall graft failure, all-cause mortality, and cardiovascular mortality were evaluated. The interactions between AR and DM status were tested with a global Wald test. To evaluate the joint association of DM and AR status with outcomes, the 6 patient groups and other potential confounding factors in the univariate analysis ( < 0.10) were analyzed by multivariate analysis. The multivariate model was derived by backward stepwise elimination of covariates with 0.1 (the variables of 6 patient groups were forcibly kept in the analysis). All analyses were made for the overall cohort (n 5 13,736), HCV recipients (n ), and non-hcv recipients (n ). All values were 2-tailed, and a value < 0.05 was considered statistically significant. All analyses were performed using STATA Statistical Software, version 10 (StataCorp L, College Station, TX). Results BASELINE CHARACTERISTICS Among the study population of 13,736 adult primary liver recipients who survived with a functioning graft for at least 1 year after transplant, the prevalence of DM was 21.3% (n ). NODAT was identified 798 ORIGINAL ARTICLE

4 LIVER TRANSLANTATION, Vol. 22, No. 6, 2016 during the first year after transplantation in 25.5% of the 10,809 non-dm recipients (n ), corresponding to 20.1% of all study patients (Fig. 1). atient baseline demographic characteristics, according to diabetic status, are listed in Table 1. AR was reported in 19.4% of recipients at 1 year after transplant in the overall study cohort. The percentage of recipients with AR at 1 year after transplant in the DM-free, DM, and NODAT group was 18%, 17.5%, and 25.6%, respectively. In the study cohort, 6384 recipients were positive for HCV, and 5934 recipients were HCV negative before liver transplant. The status of HCV was unclear in 1418 recipients. ASSOCIATION OF DIABETIC (DM, NODAT, DM-FREE) AND AR STATUS (AR, AR-FREE) WITH TRANSLANT OUTCOMES During the median follow-up period of 2537 days after transplant (interquartile range, days), there were 3686 recipients with graft failures, 3285 all-cause mortalities, and 252 cardiovascular mortalities. The graft failure rate in the DM-free, DM, and NODAT group was 24.4%, 31.7%, and 28.8%, respectively ( < 0.001). The mortality rate in the DM-free, DM, and NODAT group was 21.4%, 29.6%, and 25.3%, respectively ( < 0.001). The cardiovascular mortality rate in the DM-free, DM, and NODAT group was 1.4%, 3.5%, and 1.5%, respectively ( < 0.001). Results of Cox regression analysis are shown in Table 2. In the unadjusted analysis, DM, NODAT (compared to DM-free), and AR were all associated with an increased risk for liver transplant graft failure and overall mortality. Cardiovascular mortality was only associated with the presence of DM (hazard ratio [] ). In the multivariate adjustment, the association between NODAT and overall mortality was negated ( , ). The association between NODAT and liver graft failure was reduced ( , ). The association between DM and AR on reduced liver graft survival and mortality persisted in the multivariate analysis. The presence of DM at the time of liver transplant was associated with an increased risk for graft failure ( , <0.001) and overall mortality ( , <0.001). The association between DM and cardiovascular mortality remained ( , <0.001) in the multivariate analysis. A documented AR episode was also associated with an increase in liver graft failure and overall mortality ( , <0.001; and 1.20, <0.001; respectively). Analysis using pretransplant HCV serostatus showed similar levels of associations in unadjusted and adjusted analyses when compared to the overall cohort. The Wald test demonstrated an interaction between AR and DM (DM, NODAT) and the outcome of overall graft failure ( < 0.001) and all-cause mortality ( < 0.001) in the overall cohort, HCV-positive recipients, and HCV-negative recipients. JOINT ASSOCIATION OF DM AND AR STATUS WITH TRANSLANT OUTCOMES In order to determine the interaction between DM, NODAT, and AR, the cohort was subsequently divided into 6 groups based on the presence or absence of each condition, with the reference group being patients with neither condition. Kaplan-Meier survival curves for overall graft survivals after 1 year after transplant are shown in Fig. 2A. There were significant differences in overall graft survival between the 6 patient groups (unadjusted log-rank test, < 0.001). Results of Cox regression analysis are shown in Table 3. In the overall cohort, groups 3-6 were associated with an increased risk for graft failure, when compared to group 1 in the multivariate analysis. Group 2 (NODAT alone) was associated with an increased risk in the univariate analysis, but the association disappeared after adjusting for major donor- and recipientassociated confounding factors. Kaplan-Meier survival curves for patient survival after 1 year after transplant are shown in Fig. 2B. There was significant difference in patient survival among the 6 patient groups (unadjusted log-rank test, < 0.001). Results of the Cox regression analysis are shown in Table 3. In the multivariate analysis using group 1 as control, groups 3-6 were associated with an increased risk for all-cause mortality. Group 2 (NODAT alone) was associated with an increased risk for all-cause mortality in the univariate analysis but not in the multivariate analysis. Kaplan-Meier survival curves for patients free of cardiovascular mortality after 1 year after transplant are shown in Fig. 2C. There was a significant difference in patient survival among the 6 patient groups (unadjusted log-rank test, < 0.001). Results of the Cox regression analysis are shown in Table 3. Only the 2 groups with DM (group 3 and group 6) had an increased risk for cardiovascular mortality in the ORIGINAL ARTICLE 799

5 LIVER TRANSLANTATION, June 2016 TABLE 1. Baseline Characteristics DM-free (n 5 8,048) DM (n 5 2,927) NODAT (n 5 2,761) Rejection in 1 year, yes <0.001 Recipient factors Sex, male <0.001 Age <0.001 Mean 6 SD years years >60 years BMI, kg/m 2 <0.001 Mean 6 SD < Race Caucasian <0.001 African American Hispanic Asian/Others Cause of ESLD AHN <0.001 Cirrhosis, non-alc Cirrhosis, Alc Others HCC, yes <0.001 Hypertension, yes <0.001 HCV, yes <0.001 MELD at transplant <0.001 < Status 1A, yes <0.001 D/R CMV D1/R D /R D1/R D /R Donor factors Sex, male Age <40 years < years years Donor type Living <0.001 DBD DCD DM, yes CIT <6 hours hours hours Induction/immunosuppression at discharge Induction, yes <0.001 CNI Tac CsA None MMF/MA, yes mtor inhibitors, yes Steroid, yes <0.001 NOTE: Data are given as a percentage unless otherwise noted. 800 ORIGINAL ARTICLE

6 LIVER TRANSLANTATION, Vol. 22, No. 6, 2016 TABLE 2. Association of DM (DM, NODAT, DM-Free) and AR Status (AR, AR-Free) With Graft Failure HCV-Negative (n ) HCV-ositive (n ) All (n 5 13,736) Group Reference Overall Graft Failure DM DM-free < < < < < <0.001 NODAT < AR No AR < < < < < All-cause mortality DM DM-free < < < < < <0.001 NODAT < AR No AR < < < < <0.001 Cardiovascular mortality DM DM-free < < < < < <0.001 NODAT AR No AR NOTE: The multivariate model was derived by backward stepwise elimination of covariates with < 0.1 (the variables of DM, NODAT, and AR were forcedly kept in the analysis). FIG. 2. Kaplan-Meier survival curves for (A) overall graft survival, (B) patient survival, and (C) cardiovascular survival, according to the status of DM and AR at 1 year after transplant. multivariate analysis. The cardiovascular mortality was highest in the DM and AR group ( ; < 0.001) The analyses in both HCV-positive and HCVnegative cohorts showed a similar trend and impact as in the overall cohort (Table 3). NODAT alone was not significantly associated with inferior transplant outcomes in the multivariate analysis. The 2 groups with DM (group 3 and group 6) had a higher risk of cardiovascular mortality when compared with the control group. ORIGINAL ARTICLE 801

7 LIVER TRANSLANTATION, June 2016 TABLE 3. Joint Association of DM and AR Status With Graft Failure All (n 5 13,736) HCV-ositive (n ) HCV-Negative (n ) Group Reference Overall graft failure 2. NODAT alone 1. neither DM alone < < < < < AR alone < < NODAT & AR < < < < < < DM and AR < < < All-cause mortality 2. NODAT alone 1. neither DM alone < < < < < < AR alone NODAT and AR < < < < < < DM and AR < < < < <0.001 Cardiovascular mortality 2. NODAT alone 1. neither DM alone < < < < < AR alone NODAT and AR DM and AR < < < <0.001 NOTE: The multivariate model was derived by backward stepwise elimination of covariates with < 0.1 (the variables of 6 patient groups were forcedly kept in the analysis). 802 ORIGINAL ARTICLE

8 LIVER TRANSLANTATION, Vol. 22, No. 6, 2016 Discussion New-onset DM is a common complication after solid organ transplantation. It has been implicated in an increased risk of graft failure, death-censored graft failure, and mortality in kidney transplant recipients. (12) However, information concerning the association between NODAT and liver transplant outcomes is limited and inconsistent. In a retrospective review by Trail et al., (7) NODAT was diagnosed in 5.2% of 497 recipients ( ) within 1 month of liver transplant, but it did not have a significant impact on graft survival in the first year after transplant. John et al. (6) compared transplant outcomes of 46 liver recipients with NODAT and 92 controls without NODAT. NODAT patients had higher incidence of cardiac complication, infections, neurological, and neuropsychiatric complications. However, there was no difference in patient survival at 1 year, 2 years, and 5 years after transplant. In an analysis by Moon et al. (5) in 778 liver transplant recipients ( ) for whom median follow-up was 57.2 months, those with sustained NODAT had inferior patient and graft survivals, as well as a significantly higher rate of death due to infection, graft failure due to chronic rejection, and late-onset hepatic artery thrombosis. These studies were limited by relatively small patient numbers, and rejection was not included in the analysis. In the current study, we analyzed the differential impacts of AR, DM, and NODAT on graft and patient survivals in liver recipients transplanted between 2004 and 2007 who survived with a functioning graft for at least 1 year in the United States. When analyzing the entire cohort, DM and AR were associated with modestly increased liver graft failure risk (DM, , < 0.001; AR, , < 0.001), whereas NODAT impacted graft survival to a lesser degree ( , ). DM was the major predictor of all-cause ( , < 0.001) and cardiovascular mortality ( , < 0.001), whereas AR impacted patient survival to a lesser degree ( , < 0.001). Neither NODAT nor AR were associated with cardiovascular mortality. In our study cohort, recipients with NODAT in the first year had the highest reported rate of AR at 1 year (NODAT, 25.6%; DM-free, 18%; DM, 17.5%; < 0.001). The Wald test further shows the significant interactions between AR and DM and the transplant outcomes. There is potential interaction between DM and rejection. Steroid and Tac, commonly used to both prevent and treat AR, are diabetogenic. The high-dose steroid and Tac treatment may contribute to the development of NODAT, as well as the difficulty in diabetic control. On the other hand, the dosage strategy of steroid and Tac may also be influenced by pretransplant diabetic status. However, the information of medication dosage is not available in the UNOS database. Hence, the joint associations of DM and AR with each outcome were further analyzed in our study. In the multivariate Cox regression analysis, the presence of NODAT alone was not associated with an increased risk in any of the study outcomes. Only patients with NODAT in combination with AR (group 5) demonstrated an increased risk for graft failure and mortality ( , < 0.001; and , < 0.001; respectively). atients with DM or AR alone had an increased risk for graft failure and mortality, which was increased when the 2 occurred in combination. End-stage liver disease (ESLD) related to HCV is the leading indication for liver transplantation, (13) and graft reinfection with HCV is associated with inferior liver transplant outcomes after transplantation. (14) HCV may induce insulin resistance (15) and is associated with an increased prevalence of type 2 DM in the nontransplant population. (16) In our previous study, HCV was independently associated with an increased risk for NODAT in liver transplant recipients in the United States. (1) To address the potential interaction of HCV with NODAT on liver transplant outcomes, we made separate analyses in HCV-positive and HCV-negative recipients. NODAT alone was not significantly associated with inferior transplant outcomes, regardless of recipient HCV status. Only those with DM had a higher risk of cardiovascular mortality. There are certain limitations in our study. This retrospective analysis is subject to flaws inherent in the nature of the registry database, such as reporting bias or error. In our current study, the diagnosis of NODAT was based on the diagnosis reported on the UNOS form by the transplant physicians and may not have captured some patients who may have fulfilled the more rigorous criteria of DM as defined by the World Health Organization/American Diabetes Association (ADA). It is possible that the UNOS data may have underreported the incidence of NODAT, although these patients would fall in the milder category of hyperglycemia. In addition, the information concerning medication dosage is not available in the OTN/UNOS database; therefore, the effects of immunosuppression dosage on study outcomes cannot be analyzed. In conclusion, DM and AR were associated with a 20%-40% increased risk for graft failure and mortality, ORIGINAL ARTICLE 803

9 LIVER TRANSLANTATION, June 2016 regardless of HCV serostatus at the time of transplantation. The effect is increased to 50%-60% when both occur or when AR is accompanied by NODAT. NODAT alone was not associated with an increased risk of graft failure, mortality, or cardiovascular mortality. DM was the only factor associated with cardiovascular mortality after 1 year after transplant. REFERENCES 1) Kuo HT, Sampaio MS, Ye X, Reddy, Martin, Bunnapradist S. Risk factors for new-onset diabetes mellitus in adult liver transplant recipients, an analysis of the Organ rocurement and Transplant Network/United Network for Organ Sharing database. Transplantation 2010;89: ) Yoo HY, Thuluvath J. The effect of insulin-dependent diabetes mellitus on outcome of liver transplantation. Transplantation 2002;74: ) Shields L, Tang H, Neuberger JM, Gunson BK, McMaster, irenne J. oor outcome in patients with diabetes mellitus undergoing liver transplantation. Transplantation 1999;68: ) John R, Thuluvath J. Outcome of liver transplantation in patients with diabetes mellitus: a case-control study. Hepatology 2001;34: ) Moon JI, Barbeito R, Faradji RN, Gaynor JJ, Tzakis AG. Negative impact of new-onset diabetes mellitus on patient and graft survival after liver transplantation: Long-term follow up. Transplantation 2006;82: ) John R, Thuluvath J. Outcome of patients with new-onset diabetes mellitus after liver transplantation compared with those without diabetes mellitus. Liver Transpl 2002;8: ) Trail KC, McCashland TM, Larsen JL, Heffron TG, Stratta RJ, Langnas AN, et al. Morbidity in patients with posttransplant diabetes mellitus following orthotopic liver transplantation. Liver Transpl Surg 1996;2: ) Wiesner RH, Ludwig J, van Hoek B, Krom RA. Current concepts in cell-mediated hepatic allograft rejection leading to ductopenia and liver failure. Hepatology 1991;14(pt 1): ) Klintmalm GB, Nery JR, Husberg BS, Gonwa TA, Tillery GW. Rejection in liver transplantation. Hepatology 1989;10: ) Jindal RM, opescu I, Schwartz ME, Emre S, Boccagni, Miller CM. Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients. Transplantation 1994;58: ) Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Liver Transpl Surg 1999;5 (suppl 1): S107-S ) Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3: ) Wiesner RH, Sorrell M, Villamil F; for International Liver Transplantation Society Expert anel. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003;9:S1-S9. 14) Grassi A, Ballardini G. ost-liver transplant hepatitis C virus recurrence: an unresolved thorny problem. World J Gastroenterol 2014;20:11,095-11, ) Hui JM, Sud A, Farrell GC, Bandara, Byth K, Kench JG, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003;125: ) Allison ME, Wreghitt T, almer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 1994;21: ORIGINAL ARTICLE