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Inhibition of Pancreatitis-Associated Proteins Worsens Long Term Severity of Acute Pancreatitis in Rats
324
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
GASTROINTESTINAL AND NUTRITION 2: HEPATIC/PANCREATIC/BILIARY
Grant support: NIH grant DK02964-04, DK070784-02 to AH and DK 65131-01 to MG.
40.1. Transcriptional Regulation of Hepatic Genes by Hepatocyte Nuclear Factor OC1 Attenuates Liver Injury. A. Holterman,1 K. Wang,1 M. Wang,1 M. Gannon2; 1 Rush University Medical Center, Chicago, IL; 2Vanderbilt University Medical Center, Nashville, TN
40.2. Proximal Cholangiocarcinoma: Tumor Depth Predicts Outcome. M. Augustine, S. M. Hong, M. de Jong, M. Goggins, R. D. Schulick, C. L. Wolfgang, B. H. Edil, M. A. Choti, R. Anders, T. M. Pawlik; Johns Hopkins Hospital, Baltimore, MD
Background: Liver-enriched hepatocyte nuclear factors are key regulators of liver-specific gene expression and function. We test the hypothesis that the One-Cut transcription factor OC1 is critical to differentiated and adaptive hepatic function during liver injury by bile duct ligation (BDL). Methods: Gain of function of OC1 was done through GH administration (a known transcriptional activator of OC1) at the time of BDL to increase hepatic OC1 expression. Loss of OC1 function was assessed by conditional inactivation of OC1 in the liver of OC1-LKO mice by Alb-Cre Recombinase-mediated deletion of OC1 in OC1 LoxP mice. Serum biochemistries, the expression of OC1-regulated gene and protein expression were compared between PBS- or GH-treated OC1-LKO and WT mice liver following 1 week of Sham operation or BDL. OC1 binding to its target gene promoter site was confirmed by ChIP assays. Intergroup differences were evaluated by analysis of variance. P value 0.05 is significant Results: ChIP assays demonstrated significantly reduced promoter occupancy by OC1 for OC1 target genes in OC1-LKO liver (6-, 16- and 2.4 fold less for proliferative Cyclin D1, cholesterol converting enzyme cholesterol7a hydroxylase Cyp7A1 and organic anion bile acid transporter Oatp1 respectively). Baseline expression of OC1 and target genes Cyclin D1, Oatp1 and Cyp7A1 mRNA expression were significantly increased following GH treatment of WT liver (6-, 2.2-, 3-and 3-fold increases respectively vs PBS-treated liver) but diminished in OC1-LKO liver relative to WT liver (decreases of 180-, 2.4-, 2.3- and 3.8-fold respectively in OC1-LKO liver). During BDL, GH-mediated enhancement of OC1 and Cyclin D1, Cyp7A1 and Oatp1a1 gene expression in WT BDL mice were attenuated in OC1-LKO mice, with a corresponding impairment in OC1-LKO mice of GH-induced liver regeneration (liver mass of 8.4% þ/- 0.7 in PBS/BDL increasing to 10% þ/- 0.4 in GH/BDL for WT mice, p ¼ 0.001; vs 7.9% þ/- 0.7 BDL vs 8.3% þ/- 0.9 GHBDL for OC1-LKO mice, p ¼ 0.5), cholesterol clearance (cholesterol of 453 þ/147 mg/dL in PBS/BDL WT mice decreasing to 225 þ/- 95 mg/dL in GH/BDL WT mice, p ¼ 0.02; vs 560 þ/- 187 mg/dL in PBS/BDL and 462 þ/- 223 mg/dL GH/BDL in OC1-LKO, p ¼ 0.37) and GH-attenuation of cholestasis (Alkaline Phosphatase of 699 þ/- 199 U/L in PBS/ BDL WT mice decreasing to 415 þ/- 120 U/L GH/BDL WT mice, p ¼ 0.02; vs 634 þ/- 307 U/L PBS/BDL vs 611 þ/- 241 U/L GHBDL in OC1-LKO mice, p ¼ NS). Conclusion: BDL-induced hepatobiliary injury is alleviated by GH through enhancement of OC1-mediated transcriptional regulation of its target genes Cyclin D1, Cyp7A1 and Oatp1a1 to stimulate liver regeneration, cholesterol and bile acid turnover. This is compromised in OC1-LKO mice, demonstrating the broad role of OC1 transcription factor in hepatic survival and metabolic function through its downstream regulation of target genes which participate in the liver repair function, with the clinical implication of targeting OC1 function as potential hepatoprotective strategies.
Introduction: The current American Joint Committee on Cancer (AJCC) staging system for proximal cholangiocarcinoma may be inaccurate as the bile duct lacks discrete tissue boundaries. The objective of the current study was to examine the accuracy of the AJCC staging system for proximal cholangiocarcinoma. In turn, we sought to determine whether depth of tumor invasion was a more accurate predictor of prognosis in patients with resected proximal cholangiocarcinoma. Methods: Between 1987 and 2004, 297 patients who underwent surgical resection of cholangiocarcinoma were identified from a prospective, single-institution hepato-pancreato-biliary database. Of these 297 patients, 85 (27%) had a proximal cholangiocarcinoma and had pathologic slides available for re-review to measure depth of tumor invasion. Data on demographic, clinical, tumor-related and pathologic factors were collected and analyzed using univariate and multivariate models. Tumor depth was determined by measuring the distance between the basal lamina of the adjacent normal epithelium to the most deeply infiltrating tumor cells. Survival was calculated using the Kaplan-Meier estimate. Results: The mean age at surgery was 65 years and 47 patients (55%) were male. At time of operation, most patients had a bile duct resection (n ¼ 65, 76%) while 20 (24%) patients had a bile duct resection þ liver resection. Most tumors were moderately-differentiated (n ¼ 46, 54%), while fewer patients had either a well- (n ¼ 20, 24%) or poorly(n ¼ 19, 22%) differentiated tumor. On pathologic analysis, perineural invasion was present in 45 (53%) patients and vascular invasion was present in 11 (13%) patients. Invasion into the gallbladder or adjacent liver was present in 7% and 18% of patients, respectively. Thirty cases were classified as T1, 40 as T2, 15 as T3. The majority of patients (n ¼ 52, 62%) underwent an R0 resection. Overall survival was 57% at three years and 29% at five years with a median survival of 41 months. On univariate analyses, factors associated with survival included lymph node metastasis, tumor grade, and vascular invasion (all P < 0.05). Of note, the current AJCC T classification was not associated with prognosis. The T classification was unable to discriminate among T1, T2, and T3 lesions (median survival: T1, 29 mos vs. T2, 19 mos vs. T3, 18 mos; P ¼ 0.20). In contrast, depth of tumor invasion was able to stratify patients with regard to long-term survival (median survival: < 5 mm, 36 mos vs. 5 mm, 17 mos; P ¼ 0.005)(Figure). On multivariate analyses tumor depth remained associated with outcome with an increased depth of tumor invasion predictive of a higher risk of disease-specific death (< 5 mm, HR¼referent vs. 5 mm, HR ¼ 1.97; P ¼ 0.01). Conclusions: The current AJCC T classification for proximal cholangiocarcinoma may not accurately stratify patients with regard to prognosis. Depth of the bile duct carcinoma invasion may be a better alternative method and should be considered in the pathologic assessment of resected proximal cholangiocarcinoma. 40.3. Inhibition of Pancreatitis-Associated Proteins Worsens Long Term Severity of Acute Pancreatitis in Rats. N. A. Brown, E. Hassanain, C. Mueller, C. Huan, A. Stanek, M. E. Zenilman; SUNY Downstate Medical Center, Brooklyn, NY Introduction: Determinants of the devastating inflammatory response to acute pancreatitis (AP) are unknown. Pancreatitis-associated proteins (PAP 1, 2 and 3) are secretory proteins that are highly expressed in the pancreas during AP, but undetectable in healthy controls. We have previously demonstrated that targeted knockdown of all three isoforms in pancreas by antisense technology increased the inflammatory response at 24 hr; we now studied the effect at 7 days. Methods: Antisense oligodeoxyribonucleotides to all three PAP
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
325
ination revealed significantly increased leukocytic infiltration (Image 2) and edema (Image 3) compared to controls (p < 0.05 Student’s t-test). Conclusion: In mild, but not severe AP, endogenously produced PAPs are protective by reducing the inflammatory response. PAPs likely modulate local complications such as necrosis and infection, as well as the systemic inflammatory response to the insult. Differences in PAP expression, and severity of the original AP insult, ultimately determine the outcome. 40.4. Dose Variation of Hepatocyte Growth Factor and Its Effect in an Animal Model of TPN-Induced Liver Injury. M. S. Katz, K. A. Thatch, M. Z. Schwartz; St. Christopher’s Hospital for Children, Philadelphia, PA Introduction: Total parenteral nutrition (TPN) induced liver failure is the leading cause of liver failure leading to liver transplantation in the pediatric population in the United States. Our previous research has shown the benefit of intravenous hepatocyte growth factor (HGF) supplementation, in the amelioration of the TPN associated deleterious effects on the liver. While dose-response studies have been done to examine the growth factor effect of HGF, no previously published study has ascertained the ideal concentration of HGF for alleviating TPN-induced liver injury. Methods: Twenty adult female SpragueDawley rats underwent 70% mid-small bowel resection, followed by placement of jugular venous catheters connected to subcutaneously placed osmotic minipumps. The rats were divided into four groups based on the contents of the osmotic pump: Group 1 (control, n ¼ 5), normal saline; Group 2 (n ¼ 5), HGF 75 mcg/kg/d; Group 3 (n ¼ 5), HGF 150 mcg/kg/d; and Group 4 (n ¼ 5), HGF 250 mcg/kg/d. Each group underwent 14 days of intravenous TPN supplementation without enteral nutrition. On day 14 all animals were sacrificed and the liver was harvested. Hepatic inflammation was evaluated using immunoflourescent antibodies for TNF-a and IL-6. Apoptosis was evaluated using the terminal transferase dUTP nick end labeling (TUNEL) technique. Results: Increased concentrations of HGF at both 75 mcg/kg/day and 150 mcg/kg/day induced less IL-6 expression compared to liver-injury controls (p < 0.05 and p < 0.001, respectively). HGF also demonstrated increased efficacy with increased concentration up to 150 mcg/kg/day. Greater HGF concentration showed a trend, but was not significant over 150 mcg/kg/day (p < 0.09). TNFa expression inversely correlated with increased concentration of HGF at all concentrations in comparison to liver-injury controls (p < 0.02, p < 0.005 and p < 0.005, respectively). When comparing doses of HGF to its next higher concentration (i.e. 75 mcg/kg/day vs. 150 mcg/kg/day) the increasing concentration of HGF showed increased efficacy with the exception of 250 mcg/kg/day which showed decreased TNF-a expression over 150 mcg/kg/day but was not significant (p < 0.12). Apoptotic activity was decreased significantly for all concentrations with statistically significant increasing efficacy for all concentrations (p < 0.04,p < 0.0012 and p < 0.001, respectively). Conclusions: Increasing concentrations of HGF were directly correlated with increased modulation of the hepatic inflammatory response and apoptotic index in this animal model for TPN-induced liver injury, up to 150 mcg/kg/day. Increases in concentration above this level were suggestive of increased modulation, but were only statistically significant with respect to the apoptotic index. HGF may be useful to minimize the hepatic inflammation and fibrosis in children requiring longterm TPN.
isoforms (AS-PAPs) were synthesized and administered via direct intrapancreatic injections prior to the induction of mild and severe necrotizing AP in rats with 0.5% (n ¼ 14) and 4% Sodium Taurocholate (n ¼ 16), respectively. Animals were observed over a 7 day period and sacrificed. Results: NaT induced serum amylase, lipase, and Creactive protein levels in all groups. When compared to matched controls, AS-PAP animals showed no difference in survival over 7 days. In the 0.5% (Image 1) but not the 4% NaT group, histopathologic exam-
40.5. Improved Donor Insulin Resistance via Decreased Chronic ER Stress Is Not Hepatoprotective to Steatotic Livers Undergoing Liver Transplantation. C. D. Anderson, K. Conzen, G. Upadhya, J. Jia, S. Ramachandran, T. Mohanakumar, N. Davidson, W. C. Chapman; Washington University in St.Louis, St. Louis, MO Background: Obesity and the metabolic syndrome affect a growing number of liver donors via an increased incidence and severity of hepatic steatosis. Insulin resistance is an almost ubiquitous finding in
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
GASTROINTESTINAL AND NUTRITION 2: HEPATIC/PANCREATIC/BILIARY
Grant support: NIH grant DK02964-04, DK070784-02 to AH and DK 65131-01 to MG.
40.1. Transcriptional Regulation of Hepatic Genes by Hepatocyte Nuclear Factor OC1 Attenuates Liver Injury. A. Holterman,1 K. Wang,1 M. Wang,1 M. Gannon2; 1 Rush University Medical Center, Chicago, IL; 2Vanderbilt University Medical Center, Nashville, TN
40.2. Proximal Cholangiocarcinoma: Tumor Depth Predicts Outcome. M. Augustine, S. M. Hong, M. de Jong, M. Goggins, R. D. Schulick, C. L. Wolfgang, B. H. Edil, M. A. Choti, R. Anders, T. M. Pawlik; Johns Hopkins Hospital, Baltimore, MD
Background: Liver-enriched hepatocyte nuclear factors are key regulators of liver-specific gene expression and function. We test the hypothesis that the One-Cut transcription factor OC1 is critical to differentiated and adaptive hepatic function during liver injury by bile duct ligation (BDL). Methods: Gain of function of OC1 was done through GH administration (a known transcriptional activator of OC1) at the time of BDL to increase hepatic OC1 expression. Loss of OC1 function was assessed by conditional inactivation of OC1 in the liver of OC1-LKO mice by Alb-Cre Recombinase-mediated deletion of OC1 in OC1 LoxP mice. Serum biochemistries, the expression of OC1-regulated gene and protein expression were compared between PBS- or GH-treated OC1-LKO and WT mice liver following 1 week of Sham operation or BDL. OC1 binding to its target gene promoter site was confirmed by ChIP assays. Intergroup differences were evaluated by analysis of variance. P value 0.05 is significant Results: ChIP assays demonstrated significantly reduced promoter occupancy by OC1 for OC1 target genes in OC1-LKO liver (6-, 16- and 2.4 fold less for proliferative Cyclin D1, cholesterol converting enzyme cholesterol7a hydroxylase Cyp7A1 and organic anion bile acid transporter Oatp1 respectively). Baseline expression of OC1 and target genes Cyclin D1, Oatp1 and Cyp7A1 mRNA expression were significantly increased following GH treatment of WT liver (6-, 2.2-, 3-and 3-fold increases respectively vs PBS-treated liver) but diminished in OC1-LKO liver relative to WT liver (decreases of 180-, 2.4-, 2.3- and 3.8-fold respectively in OC1-LKO liver). During BDL, GH-mediated enhancement of OC1 and Cyclin D1, Cyp7A1 and Oatp1a1 gene expression in WT BDL mice were attenuated in OC1-LKO mice, with a corresponding impairment in OC1-LKO mice of GH-induced liver regeneration (liver mass of 8.4% þ/- 0.7 in PBS/BDL increasing to 10% þ/- 0.4 in GH/BDL for WT mice, p ¼ 0.001; vs 7.9% þ/- 0.7 BDL vs 8.3% þ/- 0.9 GHBDL for OC1-LKO mice, p ¼ 0.5), cholesterol clearance (cholesterol of 453 þ/147 mg/dL in PBS/BDL WT mice decreasing to 225 þ/- 95 mg/dL in GH/BDL WT mice, p ¼ 0.02; vs 560 þ/- 187 mg/dL in PBS/BDL and 462 þ/- 223 mg/dL GH/BDL in OC1-LKO, p ¼ 0.37) and GH-attenuation of cholestasis (Alkaline Phosphatase of 699 þ/- 199 U/L in PBS/ BDL WT mice decreasing to 415 þ/- 120 U/L GH/BDL WT mice, p ¼ 0.02; vs 634 þ/- 307 U/L PBS/BDL vs 611 þ/- 241 U/L GHBDL in OC1-LKO mice, p ¼ NS). Conclusion: BDL-induced hepatobiliary injury is alleviated by GH through enhancement of OC1-mediated transcriptional regulation of its target genes Cyclin D1, Cyp7A1 and Oatp1a1 to stimulate liver regeneration, cholesterol and bile acid turnover. This is compromised in OC1-LKO mice, demonstrating the broad role of OC1 transcription factor in hepatic survival and metabolic function through its downstream regulation of target genes which participate in the liver repair function, with the clinical implication of targeting OC1 function as potential hepatoprotective strategies.
Introduction: The current American Joint Committee on Cancer (AJCC) staging system for proximal cholangiocarcinoma may be inaccurate as the bile duct lacks discrete tissue boundaries. The objective of the current study was to examine the accuracy of the AJCC staging system for proximal cholangiocarcinoma. In turn, we sought to determine whether depth of tumor invasion was a more accurate predictor of prognosis in patients with resected proximal cholangiocarcinoma. Methods: Between 1987 and 2004, 297 patients who underwent surgical resection of cholangiocarcinoma were identified from a prospective, single-institution hepato-pancreato-biliary database. Of these 297 patients, 85 (27%) had a proximal cholangiocarcinoma and had pathologic slides available for re-review to measure depth of tumor invasion. Data on demographic, clinical, tumor-related and pathologic factors were collected and analyzed using univariate and multivariate models. Tumor depth was determined by measuring the distance between the basal lamina of the adjacent normal epithelium to the most deeply infiltrating tumor cells. Survival was calculated using the Kaplan-Meier estimate. Results: The mean age at surgery was 65 years and 47 patients (55%) were male. At time of operation, most patients had a bile duct resection (n ¼ 65, 76%) while 20 (24%) patients had a bile duct resection þ liver resection. Most tumors were moderately-differentiated (n ¼ 46, 54%), while fewer patients had either a well- (n ¼ 20, 24%) or poorly(n ¼ 19, 22%) differentiated tumor. On pathologic analysis, perineural invasion was present in 45 (53%) patients and vascular invasion was present in 11 (13%) patients. Invasion into the gallbladder or adjacent liver was present in 7% and 18% of patients, respectively. Thirty cases were classified as T1, 40 as T2, 15 as T3. The majority of patients (n ¼ 52, 62%) underwent an R0 resection. Overall survival was 57% at three years and 29% at five years with a median survival of 41 months. On univariate analyses, factors associated with survival included lymph node metastasis, tumor grade, and vascular invasion (all P < 0.05). Of note, the current AJCC T classification was not associated with prognosis. The T classification was unable to discriminate among T1, T2, and T3 lesions (median survival: T1, 29 mos vs. T2, 19 mos vs. T3, 18 mos; P ¼ 0.20). In contrast, depth of tumor invasion was able to stratify patients with regard to long-term survival (median survival: < 5 mm, 36 mos vs. 5 mm, 17 mos; P ¼ 0.005)(Figure). On multivariate analyses tumor depth remained associated with outcome with an increased depth of tumor invasion predictive of a higher risk of disease-specific death (< 5 mm, HR¼referent vs. 5 mm, HR ¼ 1.97; P ¼ 0.01). Conclusions: The current AJCC T classification for proximal cholangiocarcinoma may not accurately stratify patients with regard to prognosis. Depth of the bile duct carcinoma invasion may be a better alternative method and should be considered in the pathologic assessment of resected proximal cholangiocarcinoma. 40.3. Inhibition of Pancreatitis-Associated Proteins Worsens Long Term Severity of Acute Pancreatitis in Rats. N. A. Brown, E. Hassanain, C. Mueller, C. Huan, A. Stanek, M. E. Zenilman; SUNY Downstate Medical Center, Brooklyn, NY Introduction: Determinants of the devastating inflammatory response to acute pancreatitis (AP) are unknown. Pancreatitis-associated proteins (PAP 1, 2 and 3) are secretory proteins that are highly expressed in the pancreas during AP, but undetectable in healthy controls. We have previously demonstrated that targeted knockdown of all three isoforms in pancreas by antisense technology increased the inflammatory response at 24 hr; we now studied the effect at 7 days. Methods: Antisense oligodeoxyribonucleotides to all three PAP
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
325
ination revealed significantly increased leukocytic infiltration (Image 2) and edema (Image 3) compared to controls (p < 0.05 Student’s t-test). Conclusion: In mild, but not severe AP, endogenously produced PAPs are protective by reducing the inflammatory response. PAPs likely modulate local complications such as necrosis and infection, as well as the systemic inflammatory response to the insult. Differences in PAP expression, and severity of the original AP insult, ultimately determine the outcome. 40.4. Dose Variation of Hepatocyte Growth Factor and Its Effect in an Animal Model of TPN-Induced Liver Injury. M. S. Katz, K. A. Thatch, M. Z. Schwartz; St. Christopher’s Hospital for Children, Philadelphia, PA Introduction: Total parenteral nutrition (TPN) induced liver failure is the leading cause of liver failure leading to liver transplantation in the pediatric population in the United States. Our previous research has shown the benefit of intravenous hepatocyte growth factor (HGF) supplementation, in the amelioration of the TPN associated deleterious effects on the liver. While dose-response studies have been done to examine the growth factor effect of HGF, no previously published study has ascertained the ideal concentration of HGF for alleviating TPN-induced liver injury. Methods: Twenty adult female SpragueDawley rats underwent 70% mid-small bowel resection, followed by placement of jugular venous catheters connected to subcutaneously placed osmotic minipumps. The rats were divided into four groups based on the contents of the osmotic pump: Group 1 (control, n ¼ 5), normal saline; Group 2 (n ¼ 5), HGF 75 mcg/kg/d; Group 3 (n ¼ 5), HGF 150 mcg/kg/d; and Group 4 (n ¼ 5), HGF 250 mcg/kg/d. Each group underwent 14 days of intravenous TPN supplementation without enteral nutrition. On day 14 all animals were sacrificed and the liver was harvested. Hepatic inflammation was evaluated using immunoflourescent antibodies for TNF-a and IL-6. Apoptosis was evaluated using the terminal transferase dUTP nick end labeling (TUNEL) technique. Results: Increased concentrations of HGF at both 75 mcg/kg/day and 150 mcg/kg/day induced less IL-6 expression compared to liver-injury controls (p < 0.05 and p < 0.001, respectively). HGF also demonstrated increased efficacy with increased concentration up to 150 mcg/kg/day. Greater HGF concentration showed a trend, but was not significant over 150 mcg/kg/day (p < 0.09). TNFa expression inversely correlated with increased concentration of HGF at all concentrations in comparison to liver-injury controls (p < 0.02, p < 0.005 and p < 0.005, respectively). When comparing doses of HGF to its next higher concentration (i.e. 75 mcg/kg/day vs. 150 mcg/kg/day) the increasing concentration of HGF showed increased efficacy with the exception of 250 mcg/kg/day which showed decreased TNF-a expression over 150 mcg/kg/day but was not significant (p < 0.12). Apoptotic activity was decreased significantly for all concentrations with statistically significant increasing efficacy for all concentrations (p < 0.04,p < 0.0012 and p < 0.001, respectively). Conclusions: Increasing concentrations of HGF were directly correlated with increased modulation of the hepatic inflammatory response and apoptotic index in this animal model for TPN-induced liver injury, up to 150 mcg/kg/day. Increases in concentration above this level were suggestive of increased modulation, but were only statistically significant with respect to the apoptotic index. HGF may be useful to minimize the hepatic inflammation and fibrosis in children requiring longterm TPN.
isoforms (AS-PAPs) were synthesized and administered via direct intrapancreatic injections prior to the induction of mild and severe necrotizing AP in rats with 0.5% (n ¼ 14) and 4% Sodium Taurocholate (n ¼ 16), respectively. Animals were observed over a 7 day period and sacrificed. Results: NaT induced serum amylase, lipase, and Creactive protein levels in all groups. When compared to matched controls, AS-PAP animals showed no difference in survival over 7 days. In the 0.5% (Image 1) but not the 4% NaT group, histopathologic exam-
40.5. Improved Donor Insulin Resistance via Decreased Chronic ER Stress Is Not Hepatoprotective to Steatotic Livers Undergoing Liver Transplantation. C. D. Anderson, K. Conzen, G. Upadhya, J. Jia, S. Ramachandran, T. Mohanakumar, N. Davidson, W. C. Chapman; Washington University in St.Louis, St. Louis, MO Background: Obesity and the metabolic syndrome affect a growing number of liver donors via an increased incidence and severity of hepatic steatosis. Insulin resistance is an almost ubiquitous finding in