Liver Defatting: An Alternative Approach to Enable Steatotic Liver Transplantation
2012; Elsevier BV; Volume: 12; Issue: 12 Linguagem: Inglês
10.1111/j.1600-6143.2012.04288.x
ISSN1600-6143
AutoresNir I. Nativ, Timothy J. Maguire, Gabriel Yarmush, D L Brasaemle, Scot D. Henry, James V. Guarrera, François Berthiaume, Martin L. Yarmush,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoMacrovesicular steatosis in greater than 30% of hepatocytes is a significant risk factor for primary graft nonfunction due to increased sensitivity to ischemia reperfusion (I/R) injury. The growing prevalence of hepatic steatosis due to the obesity epidemic, in conjunction with an aging population, may negatively impact the availability of suitable deceased liver donors. Some have suggested that metabolic interventions could decrease the fat content of liver grafts prior to transplantation. This concept has been successfully tested through nutritional supplementation in a few living donors. Utilization of deceased donor livers, however, requires defatting of explanted organs. Animal studies suggest that this can be accomplished by ex vivo warm perfusion in a time scale of a few hours. We estimate that this approach could significantly boost the size of the donor pool by increasing the utilization of steatotic livers. Here we review current knowledge on the mechanisms whereby excessive lipid storage and macrosteatosis exacerbate hepatic I/R injury, and possible approaches to address this problem, including ex vivo perfusion methods as well as metabolically induced defatting. We also discuss the challenges ahead that need to be addressed for clinical implementation. Macrovesicular steatosis in greater than 30% of hepatocytes is a significant risk factor for primary graft nonfunction due to increased sensitivity to ischemia reperfusion (I/R) injury. The growing prevalence of hepatic steatosis due to the obesity epidemic, in conjunction with an aging population, may negatively impact the availability of suitable deceased liver donors. Some have suggested that metabolic interventions could decrease the fat content of liver grafts prior to transplantation. This concept has been successfully tested through nutritional supplementation in a few living donors. Utilization of deceased donor livers, however, requires defatting of explanted organs. Animal studies suggest that this can be accomplished by ex vivo warm perfusion in a time scale of a few hours. We estimate that this approach could significantly boost the size of the donor pool by increasing the utilization of steatotic livers. Here we review current knowledge on the mechanisms whereby excessive lipid storage and macrosteatosis exacerbate hepatic I/R injury, and possible approaches to address this problem, including ex vivo perfusion methods as well as metabolically induced defatting. We also discuss the challenges ahead that need to be addressed for clinical implementation. Liver steatosis (fatty liver) is an early- and mild-stage abnormality within a broad spectrum of conditions that fall under the umbrella of nonalcoholic fatty liver disease (NAFLD) (1Cohen JC Horton JD Hobbs HH Human fatty liver disease: Old questions and new insights.Science. 2011; 332: 1519-1523Crossref PubMed Scopus (1606) Google Scholar). It is a very common chronic liver-related abnormality in North America and is estimated to occur in more than 65% of individuals who are obese (defined as BMI >30) (2Fabbrini E Sullivan S Klein S Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications.Hepatology. 2010; 51: 679-689Crossref PubMed Scopus (1405) Google Scholar). Morphologically, steatosis is the accumulation of lipid droplets within hepatocytes. Microvesicular steatosis is defined as an accumulation of relatively small lipid droplets that do not displace the hepatocyte nuclei. Microsteatotic livers can be successfully transplanted even at high steatosis percentages (3de Graaf EL Kench J Dilworth P et al.Grade of deceased donor liver macrovesicular steatosis impacts graft and recipient outcomes more than the donor risk index.J Gastroenterol Hepatol. 2012; 27: 540-546Crossref PubMed Scopus (124) Google Scholar, 4Perez-Daga JA Santoyo J Suárez MA et al.Influence of degree of hepatic steatosis on graft function and postoperative complications of liver transplantation.Transplant Proc. 2006; 38: 2468-2470Crossref PubMed Scopus (64) Google Scholar, 5Spitzer AL Lao OB Dick AA et al.The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment.Liver Transplant. 2010; 16: 874-884Crossref PubMed Scopus (244) Google Scholar, 6Guarrera JV Karim NA Liver preservation: Is there anything new yet.Curr Opin Organ Transplant. 2008; 13: 148-154Crossref PubMed Scopus (42) Google Scholar). In contrast, macrovesicular steatosis, which is characterized by large lipid droplets that displace the nucleus to the cell periphery, is a significant risk factor for primary nonfunction posttransplantation in humans and is associated with increased morbidity and secondary injury, such as renal failure (3de Graaf EL Kench J Dilworth P et al.Grade of deceased donor liver macrovesicular steatosis impacts graft and recipient outcomes more than the donor risk index.J Gastroenterol Hepatol. 2012; 27: 540-546Crossref PubMed Scopus (124) Google Scholar, 4Perez-Daga JA Santoyo J Suárez MA et al.Influence of degree of hepatic steatosis on graft function and postoperative complications of liver transplantation.Transplant Proc. 2006; 38: 2468-2470Crossref PubMed Scopus (64) Google Scholar, 5Spitzer AL Lao OB Dick AA et al.The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment.Liver Transplant. 2010; 16: 874-884Crossref PubMed Scopus (244) Google Scholar, 6Guarrera JV Karim NA Liver preservation: Is there anything new yet.Curr Opin Organ Transplant. 2008; 13: 148-154Crossref PubMed Scopus (42) Google Scholar). A recent large-scale analysis suggests that macrovesicular steatosis in more than 30% of hepatocytes decreases 1-year survival posttransplant (5Spitzer AL Lao OB Dick AA et al.The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment.Liver Transplant. 2010; 16: 874-884Crossref PubMed Scopus (244) Google Scholar). Therefore, transplantation centers typically shy away from using procured livers exhibiting >30% macrovesicular steatosis for orthotropic liver transplantation. Macrosteatotic livers below this cutoff may be used, however, if transplantation can be performed after a static cold storage period not exceeding 6 h (3de Graaf EL Kench J Dilworth P et al.Grade of deceased donor liver macrovesicular steatosis impacts graft and recipient outcomes more than the donor risk index.J Gastroenterol Hepatol. 2012; 27: 540-546Crossref PubMed Scopus (124) Google Scholar, 4Perez-Daga JA Santoyo J Suárez MA et al.Influence of degree of hepatic steatosis on graft function and postoperative complications of liver transplantation.Transplant Proc. 2006; 38: 2468-2470Crossref PubMed Scopus (64) Google Scholar, 5Spitzer AL Lao OB Dick AA et al.The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment.Liver Transplant. 2010; 16: 874-884Crossref PubMed Scopus (244) Google Scholar, 6Guarrera JV Karim NA Liver preservation: Is there anything new yet.Curr Opin Organ Transplant. 2008; 13: 148-154Crossref PubMed Scopus (42) Google Scholar). On the other hand, in the presence of additional risk factors, such as increasing donor age, macrosteatotic livers are more likely to be discarded (5Spitzer AL Lao OB Dick AA et al.The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment.Liver Transplant. 2010; 16: 874-884Crossref PubMed Scopus (244) Google Scholar). Given that obesity in the United States has surged from 19.8% to 27.2% in the last decade (7Fryar CD Ogden CL Carroll MD Prevalence of overweight, obesity, and extreme obesity among adults: United States, Trends 1960–1962 through 2007–2008.. Centers for Disease Control and Prevention, Hyattsville, MD2010Google Scholar), it is expected that the proportion of macrosteatotic livers in the donor pool will increase. Another daunting trend is the increasing age of the general population, which will superpose on the effects of the obesity epidemic. As a result, without measures to salvage more macrosteatotic livers, we are facing a likely decrease in the number of eligible donors in the coming years. Evidence suggests that steatosis increases sensitivity of the liver to the stresses that are inherent to the liver transplantation procedure, more specifically cold ischemia and I/R-related events. In vivo and in vitro studies using animal models suggest that liver injury due to I/R is largely initiated within the liver parenchymal cells (8Selzner N Selzner M Jochum W Amann-Vesti B Graf R Clavien P-A Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.J Hepatol. 2006; 44: 694-701Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 9Berthiaume F Barbe L Mokuno Y MacDonald AD Jindal R Yarmush ML Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury.J Surg Res. 2009; 152: 54-60Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 10Taneja C Prescott L Koneru B Critical preservation injury in rat fatty liver is to hepatocytes, not sinusoidal lining cells 1.Transplantation. 1998; 65: 167-172Crossref PubMed Scopus (37) Google Scholar). Furthermore, there is evidence that the presence of excess lipids within hepatocytes exacerbates the I/R response. For example, one study has shown that microsteatotic hepatocytes in culture are more sensitive to I/R-mediated injury compared to their lean counterparts. The level of injury, measured by hepatic intracellular enzyme release as a cellular death marker, was correlated with the level of intracellular triglyceride (TG) content (9Berthiaume F Barbe L Mokuno Y MacDonald AD Jindal R Yarmush ML Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury.J Surg Res. 2009; 152: 54-60Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Furthermore, by comparing mouse models of microsteatosis and macrosteatosis, Selzner et al. showed that macrosteatotic livers are more susceptible to I/R-mediated injury than microsteatotic livers with a similar TG content, clearly suggesting that besides the amount of TG stored, the presence of macrodroplets also exacerbates I/R sensitivity (8Selzner N Selzner M Jochum W Amann-Vesti B Graf R Clavien P-A Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.J Hepatol. 2006; 44: 694-701Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). We must also be cognizant of the fact that in human livers, the presence of steatosis is a well-described response to hepatocyte injury and could also be a marker of one or several predisposing conditions that may contribute to the increased sensitivity to I/R. Nonetheless, as discussed further below, I/R sensitivity of steatotic hepatocytes can be reversed by reducing stored fat (9Berthiaume F Barbe L Mokuno Y MacDonald AD Jindal R Yarmush ML Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury.J Surg Res. 2009; 152: 54-60Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar), consistent with the notion that excess lipid storage is independently a major cause of I/R hypersensitivity. Several mechanisms have been proposed to explain the exacerbating effect of steatosis on I/R injury, although it should be pointed out that these studies do not generally attempt to distinguish between microsteatotic and macrosteatotic livers. Human as well as animal studies suggest that post-I/R, steatotic livers are subject to more lipid peroxidation (9Berthiaume F Barbe L Mokuno Y MacDonald AD Jindal R Yarmush ML Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury.J Surg Res. 2009; 152: 54-60Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,11Serafín A Roselló-Catafau J Prats N Xaus C Gelpí E Peralta C Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat.Am J Pathol. 2002; 161: 587-601Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 12Ben Mosbah I Roselló-Catafau J Alfany-Fernandez I et al.Addition of carvedilol to University Wisconsin solution improves rat steatotic and nonsteatotic liver preservation.Liver Transplant. 2010; 16: 163-171Crossref PubMed Scopus (35) Google Scholar, 13Vairetti M Ferrigno A Carlucci F et al.Subnormothermic machine perfusion protects steatotic livers against preservation injury: A potential for donor pool increase.Liver Transplant. 2009; 15: 20-29Crossref PubMed Scopus (95) Google Scholar) and more exuberant proinflammatory responses, including increased release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-α) (13Vairetti M Ferrigno A Carlucci F et al.Subnormothermic machine perfusion protects steatotic livers against preservation injury: A potential for donor pool increase.Liver Transplant. 2009; 15: 20-29Crossref PubMed Scopus (95) Google Scholar,14Selzner M Clavien P-A Fatty liver in liver transplantation and surgery.Semin Liver Dis. 2001; 21 (14): 105Crossref PubMed Scopus (374) Google Scholar), and increased neutrophil infiltration (15Nakano H Nagasaki H Barama A et al.The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.Hepatology. 1997; 26: 670-678PubMed Google Scholar). In addition, animal models have shown that the increased cellular volume of steatotic hepatocytes leads to narrowed and tortuous microvessels in steatotic livers, consistent with reduced hepatic and sinusoidal blood flow postinjury compared to lean livers (8Selzner N Selzner M Jochum W Amann-Vesti B Graf R Clavien P-A Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.J Hepatol. 2006; 44: 694-701Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,12Ben Mosbah I Roselló-Catafau J Alfany-Fernandez I et al.Addition of carvedilol to University Wisconsin solution improves rat steatotic and nonsteatotic liver preservation.Liver Transplant. 2010; 16: 163-171Crossref PubMed Scopus (35) Google Scholar,15Nakano H Nagasaki H Barama A et al.The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.Hepatology. 1997; 26: 670-678PubMed Google Scholar,16Sun C-K Zhang X-Y Zimmermann A Davis G Wheatley AM Effect of ischemia-reperfusion injury on the microcirculation of the steatotic liver of the Zucker Rat1.Transplantation. 2001; 72: 1625-1631Crossref PubMed Scopus (95) Google Scholar). The impaired sinusoidal blood flow is also consistent with reported hepatocyte mitochondrial dysfunction and decreased intrahepatic energy (adenosine triphosphate, ATP) levels in steatotic livers (9Berthiaume F Barbe L Mokuno Y MacDonald AD Jindal R Yarmush ML Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury.J Surg Res. 2009; 152: 54-60Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,12Ben Mosbah I Roselló-Catafau J Alfany-Fernandez I et al.Addition of carvedilol to University Wisconsin solution improves rat steatotic and nonsteatotic liver preservation.Liver Transplant. 2010; 16: 163-171Crossref PubMed Scopus (35) Google Scholar,16Sun C-K Zhang X-Y Zimmermann A Davis G Wheatley AM Effect of ischemia-reperfusion injury on the microcirculation of the steatotic liver of the Zucker Rat1.Transplantation. 2001; 72: 1625-1631Crossref PubMed Scopus (95) Google Scholar). Interestingly, an in vivo Zucker rat model of I/R suggests that livers containing micro- and macrosteatosis exhibit hepatocellular necrosis as the predominant form of cell death while lean livers mainly exhibit apoptosis (17Selzner M RüDiger HA Sindram D Madden J Clavien P-A Mechanisms of ischemic injury are different in the steatotic and normal rat liver.Hepatology. 2000; 32: 1280-1288Crossref PubMed Scopus (239) Google Scholar). It is possible that reduced ATP levels in steatotic livers favored necrosis versus apoptosis because the latter is an ATP-requiring pathway. It was reported that inhibiting apoptosis pathways in lean livers undergoing I/R is effective in reducing the extent of injury, but not effective in the case of steatotic livers due to the difference in cell death mechanisms (17Selzner M RüDiger HA Sindram D Madden J Clavien P-A Mechanisms of ischemic injury are different in the steatotic and normal rat liver.Hepatology. 2000; 32: 1280-1288Crossref PubMed Scopus (239) Google Scholar). A variety of techniques have been tested to address one or more of the putative mechanisms that predispose steatotic livers to I/R injury in experimental animals. These approaches generally consist of using pharmacological agents or preconditioning methods to turn on protective pathways before subjecting the liver to I/R stress. While many pharmacological agents have been tested in the context of liver transplantation, only few have been used on macrosteatotic livers (6Guarrera JV Karim NA Liver preservation: Is there anything new yet.Curr Opin Organ Transplant. 2008; 13: 148-154Crossref PubMed Scopus (42) Google Scholar). Some of these agents have been added to the cold storage preservation solution, and found to reduce I/R injury-related markers in reperfused Zucker rat steatotic livers (12Ben Mosbah I Roselló-Catafau J Alfany-Fernandez I et al.Addition of carvedilol to University Wisconsin solution improves rat steatotic and nonsteatotic liver preservation.Liver Transplant. 2010; 16: 163-171Crossref PubMed Scopus (35) Google Scholar). For example, carvedilol, a beta- and alpha-adrenergic blocker to treat ischemic heart, reduced hepatic death markers, vascular resistance and reactive oxygen species, as well as increased bile production and hepatic ATP levels postreperfusion (12Ben Mosbah I Roselló-Catafau J Alfany-Fernandez I et al.Addition of carvedilol to University Wisconsin solution improves rat steatotic and nonsteatotic liver preservation.Liver Transplant. 2010; 16: 163-171Crossref PubMed Scopus (35) Google Scholar). In a separate study aimed at reducing the increased levels of peroxidation observed in steatotic livers, obese Zucker rat livers containing micro and macrosteatosis were intravenously administered the antioxidant glutathione (GSH)-ester shortly prior to reperfusion in a surgically induced hepatic ischemia model. The treatment elevated intracellular levels of GSH and significantly reduced lipid peroxidation, I/R injury markers and hepatic death (11Serafín A Roselló-Catafau J Prats N Xaus C Gelpí E Peralta C Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat.Am J Pathol. 2002; 161: 587-601Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). In a similar animal model, Laurens et al. successfully reduced liver injury markers and enhanced the 15-day survival rate from 40% to 70% by increasing hepatic ATP content via intravenous administration of Tacrolimus 24 h prior to surgically induced I/R injury (18Laurens M Scozzari G Patrono D et al.Warm ischemia-reperfusion injury is decreased by tacrolimus in steatotic rat liver.Liver Transplant. 2006; 12: 217-225Crossref PubMed Scopus (17) Google Scholar). In a hypothermic I/R model where hepatic micro- and macrosteatosis were induced by feeding the rats a choline- and methionine-deficient diet (CMDD), administration of the GSH precursor N-acetylcysteine 15 min before liver recovering normalized GSH levels, reduced hepatic death markers and microcirculatory injury (15Nakano H Nagasaki H Barama A et al.The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.Hepatology. 1997; 26: 670-678PubMed Google Scholar). In the same study, it was also shown that pretreatment with an antibody to intercellular adhesion molecule-1 (ICAM-1) prior to subjecting the graft to 60 min of warm ischemia inhibited neutrophil infiltration and reduced hepatic death markers (15Nakano H Nagasaki H Barama A et al.The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.Hepatology. 1997; 26: 670-678PubMed Google Scholar). In sum, although a significant reduction of several I/R injury markers was generally reported in these studies, in most cases, the level of injury remained high above that of steatotic livers which did not undergo I/R injury, or lean livers (11Serafín A Roselló-Catafau J Prats N Xaus C Gelpí E Peralta C Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat.Am J Pathol. 2002; 161: 587-601Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar,12Ben Mosbah I Roselló-Catafau J Alfany-Fernandez I et al.Addition of carvedilol to University Wisconsin solution improves rat steatotic and nonsteatotic liver preservation.Liver Transplant. 2010; 16: 163-171Crossref PubMed Scopus (35) Google Scholar,18Laurens M Scozzari G Patrono D et al.Warm ischemia-reperfusion injury is decreased by tacrolimus in steatotic rat liver.Liver Transplant. 2006; 12: 217-225Crossref PubMed Scopus (17) Google Scholar). It is worth noting that none of these studies investigated the possibility of combining several pharmacological agents at once; therefore it is possible that doing so would lead to more dramatic decrease in sensitivity to I/R injury. A surgical method whereby the major blood vessels to the liver are clamped momentarily, known as "ischemic preconditioning", has been shown to reduce lipid peroxidation, hepatic microcirculation failure and neutrophil accumulation after subsequent I/R injury when applied to microsteatotic and macrosteatotic livers (8Selzner N Selzner M Jochum W Amann-Vesti B Graf R Clavien P-A Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.J Hepatol. 2006; 44: 694-701Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). This treatment restored microcirculatory parameters to those observed in lean livers for both micro- and macrosteatotic livers, but had a more mitigated benefit on cell death markers. While cell death markers in microsteatotic livers returned to levels found in lean livers, macrosteatotic livers remained above baseline (8Selzner N Selzner M Jochum W Amann-Vesti B Graf R Clavien P-A Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.J Hepatol. 2006; 44: 694-701Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The protective mechanism appears to involve nitric oxide (NO) (8Selzner N Selzner M Jochum W Amann-Vesti B Graf R Clavien P-A Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.J Hepatol. 2006; 44: 694-701Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,11Serafín A Roselló-Catafau J Prats N Xaus C Gelpí E Peralta C Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat.Am J Pathol. 2002; 161: 587-601Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). Ischemic preconditioning has been shown to protect human livers against a subsequent period of ischemia in patients undergoing hemihepatectomy. The analysis of a subgroup of patients with mild-to-moderate steatosis presented reduced serum levels of liver damage markers (aspartate/alanine aminotransferases) when preconditioned (19Pierre-Alain Clavien SY Sindram D Rex C.B. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans.Ann Surg. 2000; 232: 155-162Crossref PubMed Scopus (429) Google Scholar). Another experimental approach to alleviate I/R injury is heat shock preconditioning, which has been shown to preserve microcirculatory parameters (sinusoidal perfusion rate, sinusoidal diameter, minimal leukocyte-endothelial adhesion) and prevent microvascular perfusion failure after surgically induced I/R in livers from obese Zucker rats containing micro- and microsteatosis (20Yamagami K Enders G Schauer RJ et al.Heat-shock preconditioning protects fatty livers in genetically obese Zucker rats from microvascular perfusion failure after ischemia reperfusion.Transplant Int. 2003; 16: 456-463Crossref PubMed Google Scholar). This study reported decreased oxidative stress (as measured by the oxidized/reduced glutathione ratio) and liver damage markers such as hepatic intracellular enzyme release (20Yamagami K Enders G Schauer RJ et al.Heat-shock preconditioning protects fatty livers in genetically obese Zucker rats from microvascular perfusion failure after ischemia reperfusion.Transplant Int. 2003; 16: 456-463Crossref PubMed Google Scholar). Similarly, in a CMDD rat liver transplantation model containing micro- and macrosteatosis, heat shock preconditioning dramatically improved the recipient 1 week posttransplant survival rate to that of lean liver recipients (21Mokuno Y Berthiaume F Tompkins RG Balis UJ Yarmush ML Technique for expanding the donor liver pool: Heat shock preconditioning in a rat fatty liver model.Liver Transplant. 2004; 10: 264-272Crossref PubMed Scopus (33) Google Scholar). Interestingly, there was a time window of efficacy ranging from 6 h to 24 h postheat shock, which correlated with the dynamics of heat shock protein (HSP) expression in liver, in particular HSP72 and heme oxygenase-1 (HO-1) (20Yamagami K Enders G Schauer RJ et al.Heat-shock preconditioning protects fatty livers in genetically obese Zucker rats from microvascular perfusion failure after ischemia reperfusion.Transplant Int. 2003; 16: 456-463Crossref PubMed Google Scholar,21Mokuno Y Berthiaume F Tompkins RG Balis UJ Yarmush ML Technique for expanding the donor liver pool: Heat shock preconditioning in a rat fatty liver model.Liver Transplant. 2004; 10: 264-272Crossref PubMed Scopus (33) Google Scholar). The protective mechanisms of heat shock preconditioning are not fully understood, but the utility of this approach warrants further studies that would enable a rational design of heat shock preconditioning regimens to improve effectiveness and practicality. The methods described above focus on reducing one or more of the I/R injury-related events that are elevated in macrosteatotic livers. If excessive lipid storage is indeed a primary initiating event in the exacerbated response of macrosteatotic livers to I/R, a conceptually different approach would be to more directly address the initiating cause of I/R hypersensitivity in steatotic livers by 'defatting' livers prior to subjecting the grafts to I/R. The concept has been tested in humans, where a combination of a protein-rich (1000 kcal/day) diet, exercise (600 kcal/day) and fibrate drugs (bezafibrate 400 mg/day) for 2–8 weeks led to a threefold reduction in macrosteatosis (22Nakamuta M Morizono S Soejima Y et al.Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation.Transplantation. 2005; 80: 608-612Crossref PubMed Scopus (105) Google Scholar,23Clavien PA Oberkofler CE Raptis DA Lehmann K Rickenbacher A El-Badry AM What is critical for liver surgery and partial liver transplantation: Size or quality.Hepatology. 2010; 52: 715-729Crossref PubMed Scopus (92) Google Scholar). In a separate study, the consumption of omega-3 fatty acids for 1 month was used to decrease macrosteatosis in three candidates for living donor transplantation who had biopsy-proven hepatic macrosteatosis >30% prior to donation (22Nakamuta M Morizono S Soejima Y et al.Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation.Transplantation. 2005; 80: 608-612Crossref PubMed Scopus (105) Google Scholar,23Clavien PA Oberkofler CE Raptis DA Lehmann K Rickenbacher A El-Badry AM What is critical for liver surgery and partial liver transplantation: Size or quality.Hepatology. 2010; 52: 715-729Crossref PubMed Scopus (92) Google Scholar). In both studies, the 'defatting' process led to decreased hepatic macrosteatosis, normalized donor liver tests and successful transplantation (22Nakamuta M Morizono S Soejima Y et al.Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation.Transplantation. 2005; 80: 608-612Crossref PubMed Scopus (105) Google Scholar,23Clavien PA Oberkofler CE Raptis DA Lehmann K Rickenbacher A El-Badry AM What is critical for liver surgery and partial liver transplantation: Size or quality.Hepatology. 2010; 52: 715-729Crossref PubMed Scopus (92) Google Scholar). It should be pointed out that alterations in diet and exercise could have wider effects on the donor metabolic state; therefore, we cannot exclude the possibility that besides decreased steatosis, additional indirect effects may have impacted the performance of the donor livers. Animal studies in which diet was used to modulate liver fat content, and studies in cultured hepatocytes incubated with different medium compositions have clearly shown that when fatty hepatocytes or livers are cleared of intracellular lipids, they recover the normal response to I/R similar to that of their lean counterparts (9Berthiaume F Barbe L Mokuno Y MacDonald AD Jindal R Yarmush ML Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury.J Surg Res. 2009; 152: 54-60Abstract Full Text Full Text PDF PubMed Scopus (37) Google Sc
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