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degree of allograft steatosis at 12 months in the HCV group. Degree of allograft ... with HCV-related liver disease undergoing first LT at Mayo. Clinic Transplant ...

Hepatitis C Recurrence Is Not Associated With Allograft Steatosis Within the First Year After Liver Transplantation Victor I. Machicao,1 Murli Krishna,2 Hugo Bonatti,3 Bashar A. Aqel,1 Justin H. Nguyen,3 Stephen D. Weigand,4 Barry G. Rosser,1 Christopher Hughes,3 and Rolland C. Dickson1 The natural history of allograft steatosis in hepatitis C (HCV)-infected patients after liver transplantation (LT) is poorly understood. The aim of our study was to determine the relationship of allograft steatosis to HCV recurrence after LT. All patients undergoing LT at our center from March 1998 to December 2001 were included in the study. Explanted liver tissue and liver biopsies performed at 1 week, 4 months, and 12 months were scored for degree of allograft steatosis (0 – 4), fibrosis (0 – 6), and modified histological activity index (0 – 18). One hundred sixty-seven HCV and 235 non – HCV-infected patients (control group) underwent LT. Of these patients, 122 HCV and 154 non-HCV patients had a viable graft at 1 year and were analyzed. Allograft steatosis was present in 40% of HCV patients at 4 months and 36% at 1 year. The incidence of allograft steatosis after LT was similar in HCV-infected and non – HCV-infected patients (P not significant). Age of the donor (P ⴝ .041), or higher recipient body mass index (BMI) at the time of LT (P ⴝ .015) or at 12 months after LT (P ⴝ .041) predicted a higher degree of allograft steatosis at 12 months in the HCV group. Degree of allograft steatosis was not associated with higher fibrosis or necroinflammatory score. In conclusion, there is a similar high incidence of allograft steatosis in HCV and non – HCV-infected patients after LT. A high BMI of the HCV-infected recipient is the best predictor for high degree of allograft steatosis after LT. Allograft steatosis does not predict the severity of HCV recurrence in the first 12 months after LT. (Liver Transpl 2004;10:599–606.)

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epatic steatosis is associated with chronic hepatitis C virus (HCV) infection. It is present in 30% to 70% of biopsy specimens of chronic HCV patients.1 – 3 Experiments in transgenic mice have suggested that HCV core protein may be involved in the pathogenesis of lipid accumulation in the hepatocyte.4 The strongest direct association between HCV infection and hepatic steatosis is within genotype 3a-infected patients.5 Host factors associated with nonalcoholic fatty liver (NAFL), such as obesity, are associated with the presence of hepatic steatosis in HCV-infected individuals.6 Hourigan et al. demonstrated that high body mass index (BMI), an indicator of obesity, was the strongest predictor of concomitant hepatic steatosis in patients with chronic HCV infection.7 Most importantly, sev-

eral cross-sectional studies of HCV-infected patients have identified an association between grade of hepatic steatosis and fibrosis progression.6 – 8 More recently, Caste´ra et al. identified that worsening of hepatic steatosis was associated with fibrosis progression in HCVinfected patients with paired biopsies.9 In contrast, the pathogenesis and clinical implications of allograft steatosis in HCV-infected patients following liver transplantation (LT) remains unknown. A single study has suggested that the presence of allograft steatosis is a specific marker of HCV recurrence.10 However, there is little data to define the natural history and risk factors associated with the development of allograft steatosis in the HCV-infected LT recipients, nor is there sufficient data to define the relation between allograft steatosis and severity of HCV recurrence. Therefore, the main objective of our study was to describe the natural history of allograft steatosis in HCV-infected patients undergoing LT in comparison with non – HCV-infected patients and to identify the relation between allograft steatosis and severity of HCV recurrence. The second objective was to elucidate the risk factors associated with the development of allograft steatosis in the HCV-infected patients after LT.

Abbreviations: HCV, hepatitis C virus; NAFL, nonalcoholic fatty liver; BMI, body mass index; LT, liver transplantation; antiHCV, serum hepatitis C virus antibodies; EIA-2, second-generation enzyme-linked immunosorbent assay; RT-PCR, reverse-transcriptase polymerase chain reaction; RIBA, recombinant immunoblot assay; HCC, hepatocellular carcinoma; ACR, acute cellular rejection; DM, diabetes mellitus; HAI, histological activity index. From the 1Divisions of Hepatology and Gastroenterology, 2Pathology, and 3Transplant Surgery, Mayo Clinic, Jacksonville, FL; and the 4Division of Biostatistics, Mayo Clinic, Rochester, MN. Address reprint requests to Rolland C. Dickson, MD, Division of Hepatology and Gastroenterology, Mayo Clinic, 4205 Belfort Rd., Suite 1100, Jacksonville, FL 32216. Telephone: 904-296-5876; FAX: 904296-5874; E-mail: [email protected] Copyright © 2004 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/lt.20107

Liver Transplantation, Vol 10, No 5 (May), 2004: pp 599 – 606

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Patients and Methods Study Design This was a longitudinal cohort study involving all patients with HCV-related liver disease undergoing first LT at Mayo Clinic Transplant Center (Jacksonville, FL) between March 1998 and December 2001. HCV-related liver disease was defined by the presence of serum hepatitis C antibodies (antiHCV) by second-generation enzyme-linked immunosorbent assay (EIA-2) plus the presence of detectable circulating HCV RNA in serum by reverse-transcriptase polymerase chain reaction (RT-PCR) or reactivity for anti-HCV by recombinant immunoblot assay (RIBA) before transplantation. Patients that did not have a viable allograft at 12 months after LT were excluded from the analysis. A cohort of non – HCV-infected patients undergoing first LT during the same study period was used as a control to compare the prevalence of allograft steatosis after LT.

HCV Detection Anti-HCV antibodies were detected using a commercially purchased assay (EIA-2.0; Abbott, Abbott Park, IL) and a 5-antigen RIBA (RIBA 3.0 SIA; Chiron, Emeryville, CA). Viral RNA was extracted from aliquots of 100 ␮L of sera using a chaotropic lysis protocol supplied in the Amplicor Hepatitis C Virus Version 2.0 Test Kit (Roche Diagnostics, Indianapolis, IN), as previously described.11 HCV RNA quantitation was expressed in IU/mL. Before May 2001, HCV RNA quantitation was performed using a branchedchain DNA assay (Quantiplex Version 2.0, Chiron) and expressed in viral equivalents/mL (vEq/mL). The lower limit of sensitivity of this assay was 0.2 ⫻ 106 vEq/mL. Since May 2001, HCV RNA quantitation was determined by VERSANT威 HCV RNA 3.0 Assay (bDNA) (Bayer Healthcare LLC, Terrytown, NY), a branched chain DNA assay, with a lower limit of detection of 615 IU/mL. A conversion factor of 158,730 was used to transform HCV RNA quantitation from vEq/mL to IU/mL for purposes of standardization.

Donor Procurement and Surgical Technique Organ procurement was carried out as described elsewhere with aortic and portal perfusion with University of Wisconsin solution.12 All transplantation procedures were performed using the piggyback technique, without venovenous bypass, as previously described.13 Patients with concomitant hepatocellular carcinoma (HCC) received pretransplantation chemoembolization according to protocol.14 LT was declined for HCC patients with extrahepatic involvement, documented tumor vascular invasion, or tumor size larger than 8 cm.

Immunosuppression and Cellular Rejection Initial immunosuppression involved 3 drugs: tacrolimus, prednisone, and mycophenolate mofetil or azathioprine. Target trough levels during tacrolimus induction were between 8

to 12 ng/mL during the first 4 months and 5 to 8 ng/mL thereafter. Prednisone was gradually tapered and discontinued during the first 4 months after LT. Mycophenolate mofetil or azathioprine were discontinued 4 months after LT. Acute cellular rejection (ACR) was defined by histologic assessment of liver tissue. ACR was graded as mild, moderate, or severe according to the criteria for global assessment proposed by Demetris et al.15 Patients with biopsy-documented moderate to severe ACR were treated with steroids. Initial treatment for ACR consisted of intravenous bolus of methylprednisolone (total dose: 1-3 g) divided into 3 alternate-day doses. Prednisone tapering followed a standard protocol, which was not modified in the presence of ACR. No single HCV-infected patient required muromonab-CD3 (OKT3) treatment for ACR.

Definition of Metabolic Derangements A diagnosis of diabetes mellitus (DM) pretransplantation was defined by the requirement of insulin and/or oral hypoglycemics, at least 2 serial fasting glucose levels above 126 mg/dL, or a random glucose of 200 mg/dL.16 Hypertriglyceridemia was defined as a total triglyceride level greater than or equal to 200 mg/dL. Hypercholesterolemia was defined as either a total cholesterol greater than or equal to 240 mg/dL or a low-density lipoprotein cholesterol greater than or equal to 160 mg/dL.17 The diagnosis of DM, hypertriglyceridemia, or hypercholesterolemia after LT were based on the same criteria used pretransplantation.

Histological Assessment Tissue from the native explanted liver was obtained for histological analysis in all subjects. Intraoperative wedge biopsy of the donor allograft was obtained during the first 2 hours after reperfusion. Percutaneous protocol liver biopsies were performed at 1 week, 4 months, and 12 months after LT, and yearly thereafter. Liver biopsies were also obtained when clinically indicated for elevated liver enzymes and 1 week after initiation of treatment for ACR. A liver pathologist (Krishna, M.) reviewed all explanted and biopsy specimens in a blinded fashion. Liver biopsy specimens were scored to evaluate the degree both of necroinflammatory activity and fibrosis, according to the modified histological activity index (HAI) and staging score (0 – 6) proposed by Ishak et al.18 Advanced fibrosis was defined as a fibrosis score greater than or equal to 3. For the quantification of hepatic steatosis, we used the previously validated scale described by Adinolfi et al.,8 which stratifies hepatic steatosis in 4 categories: grade 0 (no steatosis), grade 1 (1-10% steatosis), grade 2 (11-30% steatosis), grade 3 (31-60% steatosis), and grade 4 (⬎60% steatosis).

Statistical Analysis Clinical variables were tabulated using a Microsoft Excel database (Microsoft Corp., Redmond, WA) and analyzed using S-PLUS (MathSoft, Seattle, WA). Because the variables of interest were not normally distributed, we used nonparamet-

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Table 1. Demographic Characteristics of Patients With Viable Allografts at 12 Months Variable

HCV

Non-HCV

No. of patients No. of females (%) Median age of recipient in years (range) Median age of donor in years (range) Median BMI in kg/m2 (range) No. with BMI ⱕ 25.0 (%) No. with BMI 25.1 – 30.0 (%) No. with BMI 30.1 – 35.0 (%) No. with BMI ⱖ 35.1 (%) Median MELD score (range) Number with diabetes mellitus (%) Number with diagnosis of alcohol abuse (%)

122 37 (30%) 49 (32 – 70) 48 (5 – 85) 28 (19 – 51) 31 (25%) 52 (43%) 24 (20%) 15 (12%) 14 (6 – 43) 22 (18%) 39 (32%)

154 63 (41%)* 56 (16 – 71)† 46 (4 – 85)* 27 (16 – 51)† 53 (35%) 50 (33%) 28 (19%) 20 (13%) 14 (6 – 40)* 33 (21%)* 49 (32%)*

Abbreviations: BMI, body mass index; HCV, hepatitis C virus; MELD, model for end-stage liver disease. *P value not significant. †P ⬍ .05.

ric methods when appropriate. Nonparametric rank sum tests were used to evaluate whether average steatosis levels were the same in patients with and without metabolic derangements. Nonparametric rank correlations were calculated to assess the association between allograft steatosis and age, BMI, donor steatosis, modified HAI, and HCV levels. Choi’s test19 was used to compare dependent correlations. All tests were 2-sided and P values less than .05 were considered significant.

Results LT was performed in 167 HCV-infected patients at the Mayo Clinic, Jacksonville, FL during the study period. From the cohort of 167 HCV-infected patients, 159 of 167 had positive HCV-PCR before LT. The remaining 8 patients had positive RIBA test. Five HCV-infected individuals (3%) were coinfected with hepatitis B virus, and 52 (31%) had a concomitant diagnosis of alcohol abuse before LT. All patients with HCV recurrence had documented HCV viremia by HCV-PCR detection in serum after transplantation. All patients diagnosed with posttransplant HCV recurrence had HCV-PCR test detectable before transplantation. Retransplantation was required in 28 HCV-infected patients (17%) compared with 33 (14%) in the non – HCV-infected group. The proportion of patients requiring retransplantation due to HCV recurrence was 43% in the HCV-infected group. A total of 122 HCV-infected patients completed clinical and histological follow-up at 12 months after LT and were included in the analysis. Among these patients, the median follow-up was 669 days (range, 368-1611). During the same period, 235 non – HCV-

infected individuals (control group) underwent LT at our center. At 12 months, 154 subjects in the control group completed clinical and histological follow-up. The median follow-up for these patients was 846 days (range, 366-1633). The baseline characteristics of the HCV- and non – HCV-infected patients included in the analysis are presented in Table 1. Figure 1 shows the incidence of allograft steatosis during the first 12 months after LT in HCV-infected and non – HCV-infected patients; rates were comparable (P not significant). Figure 2 illustrates the degree of allograft steatosis at different time intervals during the first year after LT in the HCV-infected group of 122 patients. Forty-six percent received an allograft with

Figure 1. Prevalence of allograft steatosis in HCV and non-HCV patients at different time intervals after LT. NL, native liver; n, number of patients with an available allograft steatosis measurement; d, day.

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Figure 2. Distribution of degree of steatosis at different time intervals after LT in HCV-infected patients. NL, native liver; d, day; mo, months.

fatty infiltration, though in the majority of patients (74%) this was grade 2 or less. The type of steatosis in the donor organ was microvesicular in 37%, macrovescicular in 38%, and mixed in 25%. There was a significant resolution of allograft steatosis in the HCVinfected group during the first week after LT, with an incidence decrease from 46 to 10% (P ⬍ .001), as seen in Fig. 2. Complete resolution of steatosis at day-7 biopsy was present in 89% of patients with microvesicular type, 95% with macrovesicular type, and 67% with mixed type steatosis. After the initial resolution of allograft steatosis in the first week, it increased over the first 4 months (40%) but appeared to stabilize at 12 months (36%). The prevalence of grade 2-to-4 allograft steatosis at the same time points were 21% and 19%, respectively. The presence of a concomitant diagnosis of alcohol abuse before transplantation had no impact on the subsequent development of liver steatosis, as seen in Table 2 (P not significant). The potential donor and recipient factors contributing to allograft steatosis were assessed. BMI of the donor at the time of LT was not associated with the degree of allograft steatosis at 12 months after LT (P ⫽ .963). However, an elevated BMI of the recipient at the time of LT (P ⫽ .015, r ⫽ 0.25) or at 12 months after LT (P ⫽ .041, r ⫽ 0.21) predicted a higher degree of allograft steatosis at 12 months. Using Choi’s test19 we did not find evidence that either of these 2 predictors was superior to the other (P ⫽ .244). Change in body weight during the first 12 months (P ⫽ .546) or change in BMI during the same period (P ⫽ .565) did not predict degree of allograft steatosis at 12 months. Advanced age of the donor was associated with a higher degree of allograft steatosis at 12 months (P ⫽ .041, r ⫽ 0.21). The presence of DM, hypertriglyceridemia, or

hypercholesterolemia was not associated with higher degree of allograft steatosis during the first 12 months after LT (Table 3). The extent of steatosis in either the donor or the native liver at time of LT were not associated with fibrosis progression within the first 12 months after LT (Table 4). The extent of allograft steatosis at 1 week, 4 months, and 12 months after LT were not associated with a more rapid progression of fibrosis in the HCV transplant patients at 4 or 12 months. Table 4 shows there was a weak association between lower degree of allograft steatosis and higher modified HAI at 12 months after LT, although without reaching statistical significance (P ⫽ .053). The extent of allograft steatosis at different time points during the first 12 months after LT did not correlate with the serum HCV viral load as seen in Table 4.

Discussion LT represents a unique model for studying the natural history and contribution of allograft steatosis on the progression of HCV recurrence because HCV-related liver disease is the main indication for LT in the United States, has universal viral recurrence, and has an accelerated natural history. In addition, baseline histology is available at the time of viral exposure, and performance of serial protocol biopsies after LT allows the natural history of allograft steatosis to be studied. Although the natural history of allograft steatosis may have some similarities to the process seen in nontransplant patients, there exist certain characteristics that are unique to transplant patients including, but not restricted to, immunosuppresion. No previous study has assessed the relative contribution of the factors related to liver steatosis in nontransplant patients in a cohort of individuals who have undergone transplantation.

Table 2. Allograft Steatosis at 12 Months According to Alcohol Use Before Transplantation in HCV-Infected Patients Degree of Steatosis at 12 Months Category

0

1

2–4

Alcohol abuse 20 (67%) 6 (20%) 4 (13%) No alcohol abuse 42 (63%) 11 (16%) 14 (21%) All HCV 62 (63%) 17 (18%) 18 (19%)

Total 30 67 97

Abbreviation: HCV, hepatitis C virus. P ⫽ 0.66. P value based on chi-squared test with 2 degrees of freedom.

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Table 3. Association Between Recipient’s Metabolic Derangements and Allograft Steatosis at 12 Months After LT Degree of Steatosis at 12 Months Recipient Variable DM pre-LT (%) Yes No TGC ⬎ 200 mg/dL pre-LT (%) Yes No DM post-LT (%) Yes No TGC ⬎ 200 mg/dL post-LT (%) Yes No Hypercholesterolemia ⬎240 mg/dL post-LT (%) Yes No

0 (n ⫽ 62)

1 (n ⫽ 17)

2⫹ (n ⫽ 18)

12 (75%) 50 (62%)

2 (12.5%) 15 (19%)

2 (12.5%) 16 (20%)

.288

1 (33%) 61 (65%)

1 (33%) 16 (17%)

1 (33%) 17 (18%)

—*

26 (59%) 36 (68%)

12 (27%) 5 (9%)

6 (14%) 12 (23%)

.764

21 (58%) 41 (67%)

7 (19%) 10 (16%)

8 (22%) 10 (16%)

.333

6 (86%) 56 (62%)

0 17 (19%)

1 (14%) 17 (19%)

.264

P value

Abbreviations: DM, diabetes mellitus; TGC, triglycerides. *P value not reported due to insufficient data for the Yes group.

The first important finding from our study is the better understanding of the relationship between HCV infection and allograft steatosis. We identified a high incidence of allograft steatosis in HCV patients at 12 months after LT, occurring in up to 40% of individuals. This incidence rate is similar to the one identified in

nontransplant chronic HCV infected patients.1 – 3 However, our series reveals a similar incidence of allograft steatosis in non – HCV-infected patients after LT performed for other indications. Our results contrast with 2 previous case-control studies that reported a higher rate of steatosis in HCV-infected patients in

Table 4. Rank Correlation (P Value) Between Hepatic Steatosis and Study Variables Variable Age of recipient (y) Age of donor (y) BMI of donor (kg/m2) BMI of recipient at baseline (kg/m2) BMI of recipient at 12 mo (kg/m2) Steatosis of donor (0 – 4) Modified HAI 4 mo 12 mo HCV serum (log10 IU/mL) 4 mo 12 mo Fibrosis score (0 – 6) 4 mo 12 mo

7-Day Steatosis

4-Month Steatosis

12-Month Steatosis

0.00 (.963) ⫺0.09 (.309) ⫺0.02 (.824) ⫺0.03 (.706) —* 0.18 (.051)

⫺0.08 (.388) 0.10 (.272) ⫺0.05 (.612) 0.20 (.035) —* 0.02 (.851)

0.03 (.793) 0.21 (.041) 0.00 (.963) 0.25 (.015) 0.21 (.041) 0.05 (.593)

⫺0.03 (.741) 0.04 (.665)

0.17 (.066) ⫺0.18 (.075)

0.12 (.244) ⫺0.20 (.053)

0.01 (.939) ⫺0.03 (.805)

0.05 (.630) 0.00 (.981)

0.10 (.369) 0.03 (.747)

⫺0.07 (.452) 0.04 (.710)

0.13 (.157) 0.01 (.922)

⫺0.15 (.141) ⫺0.15 (.156)

Abbreviations: HAI, histological activity index; HCV serum, serum HCV viral load; BMI, body mass index. *Correlation between BMI of the recipient at 12 months and steatosis prior to 12 months are not reported because of temporal order of these variables.

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comparison with HCV-negative patients.10,20 Small sample size in both studies is the most likely explanation for the discrepancy. Therefore, our data suggest that allograft steatosis is a common occurrence after LT and is independent of concomitant HCV infection. Nonetheless, the high incidence of allograft steatosis identified in our study should lead to longer follow-up to ascertain its repercussions in long-term outcome. The relative contributions of donor, recipient, and viral factors in the development of allograft steatosis were also studied. A few studies have suggested hepatic steatosis is the morphological expression of a viral cytopathic effect in subjects infected with HCV genotype 3.20 In this group of patients, the level of viremia has been directly correlated with grade of hepatic steatosis.8,21 More recently, a study suggested hepatic steatosis and high HCV viral load act together in accelerating the progression of liver injury.22 In our series, in which there was a low incidence of genotype 3 patients, there was no relationship between degree of allograft steatosis and HCV viral load. In our patient population, which is comparable to other US centers, the presence of allograft steatosis in HCV-infected patients cannot be considered a reliable indicator of HCV recurrence as previously suggested by other authors.10 The incidence of hepatic steatosis in the explanted liver of HCV patients was minimal in our series. This contrasts with the relatively high incidence of hepatic steatosis described in HCV-infected individuals elsewhere.8,23 A potential explanation is that hepatic steatosis in the HCV-infected patient may regress once cirrhosis is established. Rubbia-Brandt et al. have previously described that moderate to severe hepatic steatosis (⬎30%) was less common in chronic HCVinfected patients with cirrhosis than in those without cirrhosis.21 Similarly, Caldwell et al. described minimal hepatic steatosis in the explanted liver of patients with “cryptogenic” cirrhosis who had NAFL as the likely cause for end-stage liver disease.24 Therefore, it appears that once end-stage liver disease arises, the degree of hepatic steatosis is modulated by the environment of a diseased liver. Severe steatosis in the donor organ at the time of LT has been shown to be an important risk factor for delayed nonfunction.25 However, recent studies have reported that adequate function is compatible with severe allograft steatosis of microvesicular type.26,27 The degree of steatosis in the donor organ at time of LT was not associated with the degree of allograft steatosis at 12 months after LT. This lack of correlation suggests donor factors make a relatively minor contribution to

the process of fat accumulation after LT in HCVinfected patients. A novel finding from our study is that the degree of allograft steatosis after LT varies with time in a given individual. This is characterized by significant resolution of allograft steatosis present in the donor organ at time of LT by day 7 and was independent of the type of steatosis (macrovesicular or microvesicular) and the reappearance of allograft steatosis in nearly 40% of HCV-infected individuals during the first year after LT. This dynamic process seen during the first year after LT represents a complex interaction between host, donor, and possibly viral factors. The BMI of the donor did not correlate with the degree of hepatic steatosis at 12 months after LT. In contrast to this observation, allograft steatosis at 12 months was significantly associated with baseline BMI of the recipient and the recipient’s BMI at 12 months after LT, although this was a weak association (r ⫽ 0.21). Our findings are similar to previously published series in nontransplant patients.6,7 However, baseline BMI of the recipient, measured just before LT, should be interpreted with caution since it was obtained in end-stage liver disease patients. Fluid excess is universal in subjects with advanced liver disease, in which case BMI can overestimate fat mass.28 BMI becomes a more reliable indicator of fat mass 12 months after LT. By that time most transplanted patients have a functional allograft without evidence of liver synthetic dysfunction or fluid retention. Therefore, our data suggest that elevated BMI of the recipient is the most important risk factor for the development of allograft steatosis in HCV-infected patients. A previous study in nontransplant subjects diagnosed with NAFL has shown regression of hepatic steatosis after gradual weight loss.29 Our findings emphasize the important role of nutrition and weight control in LT patients. Weight control after LT can be a potential mechanism to modify the natural history of allograft steatosis, requiring further evaluation. Nonetheless, based on our data we suggest that a similar pattern of rapid changes in steatosis level can be present in individuals affected by NAFL. Age of the donor appears to be weakly associated with a higher degree of allograft steatosis at 12 months after LT. This is not accounted for by increased steatosis in allografts from older donors because there were no differences in baseline steatosis between younger and older donors, and there was nearly complete resolution of steatosis in all recipients by day 7 after LT. If this finding is confirmed by other studies, further investigations should be done to determine whether there are metabolic derangements in older donor grafts leading

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to increased steatosis or worsened outcome related to recurrent HCV.30 Glucose intolerance and DM are present in 20 to 75% of individuals with hepatic steatosis.31 The incidence of DM following LT has been estimated to be 13 to 33% and is considered a predictive factor for poor outcome after LT.32 HCV infection has also been found to be an independent risk factor for DM, although this relationship is controversial.33,34 In our series, DM diagnosed either before or after LT has no role in the development of allograft steatosis. Our findings are congruent with other reports, which showed that DM was not associated with hepatic steatosis in nontransplant HCV-infected patients.6,35 Serum lipid abnormalities are associated with NAFL, with hypertriglyceridemia being the most commonly seen.36 In our series, neither hypertriglyceridemia nor hypercholesterolemia was related to the degree of allograft steatosis during the first year after LT. Our findings are also similar to a prior report in nontransplant chronic HCV patients.6 Finally, the most important contribution of our study is a better understanding of the relation between allograft steatosis and allograft fibrosis in HCV-infected patients after LT. Several studies in nontransplant HCV-infected patients identified an association between higher degree of hepatic steatosis and elevated fibrosis and necroinflammatory scores in the same liver biopsy specimen.6,7,9 Based on these studies, it has been suggested hepatic steatosis is a cofactor for worse outcome in HCV-infected patients. In our longitudinal study, the advanced degree of allograft steatosis present at 1 week, 4 months, and 12 months was not associated with worse fibrosis score at 4 or 12 months. Similarly, our data showed that an advanced degree of allograft steatosis was not associated with worse necroinflammatory activity. Therefore, a proinflammatory or profibrotic effect of allograft steatosis is not manifested in the first 12 months after LT. Based on our series, we conclude that the potential role of hepatic steatosis as a facilitator or stimulator of fibrosis remains undefined. Longer follow-up studies are necessary to clarify the effect of allograft steatosis in the natural history of HCV recurrence. In summary, our data confirms that there is a high incidence of allograft steatosis in HCV and non – HCV-infected patients after LT. The development of allograft steatosis is a dynamic process in which the degree of hepatic steatosis may increase or decrease over time in a given individual, depending on several factors. A high BMI of the HCV-infected recipient is the best

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predictor for high degree of allograft steatosis after LT. Allograft steatosis does not predict the severity of HCV recurrence in HCV-infected patients within the first 12 months after LT. Our study is the first step in the rational understanding of the association between allograft steatosis and HCV infection. Larger, multicenter studies are required to confirm the lack of association between HCV infection and allograft steatosis.

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