Constantinos Nastos

Global Consequences of Liver Ischemia/Reperfusion Injury

Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organs post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion.

Closure of a persistent sphincterotomy-related duodenal perforation by placement of a covered self-expandable metallic biliary stent

Retroperitoneal duodenal perforation as a result of endoscopic biliary sphincterotomy is a rare complication, but it is associated with a relatively high mortality risk, if left untreated. Recently, several endoscopic techniques have been described to close a variety of perforations. In this case report, we describe the closure of a persistent sphincterotomy-related duodenal perforation by using a covered self-expandable metallic biliary (CEMB) stent. A 61-year-old Greek woman underwent an endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy for suspected choledocholithiasis, and a retroperitoneal duodenal perforation (sphincterotomy-related) occurred. Despite initial conservative management, the patient underwent a laparotomy and drainage of the retroperitoneal space. After that, a high volume duodenal fistula developed. Six weeks after the initial ERCP, the patient underwent a repeat endoscopy and placement of a CEMB stent with an indwelling nasobiliary drain. The fistula healed completely and the stent was removed two weeks later. We suggest the transient use of CEMB stents for the closure of sphincterotomy-related duodenal perforations. They can be placed either during the initial ERCP or even later if there is radiographic or clinical evidence that the leakage persists.

IRON CHELATION FOR AMELIORATION OF LIVER ISCHEMIA-REPERFUSION INJURY

Liver resections are frequently associated with significant ischemia-reperfusion (I-R) injury of the liver remnant. The aim of this study was to investigate whether deferoxamine (DFO) can ameliorate I-R injury during major hepatectomies performed under vascular exclusion of the liver in a porcine model. Twelve female domestic pigs were divided into control (n = 6) and DFO treatment (n = 6) groups and subjected to 150 min. liver ischemia followed by 70% hepatectomy and 24 hours reperfusion. Pigs in the DFO group received a continuous intravenous infusion of 100 mg/kg DFO. Liver remnant injury was evaluated by liver function tests, hepatic histology as well as serum and liver tissue malondialdehyde (MDA) concentrations. Deferoxamine-treated animals had reduced total bilirubin, γ-glutamyl transferase and ammonia levels as well as hepatocyte necrosis and oxidative injury. In a subsequent randomized clinical trial using DFO for I-R protection during major liver surgery, preliminary results revealed amelioration of hepatocellular damage, oxidative and inflammatory serum markers and apoptotic response in liver remnant biopsies.

An ongoing dispute in the management of severe pancreatic fistula: Pancreatospleenectomy or not?

The aim of this manuscript is to review controversies in managing severe pancreatic fistula after pancreatic surgery. Significant progress in surgical technique and perioperative care has reduced the mortality rate of pancreatic surgery. However, leakage of the pancreatic stump still accounts for the majority of surgical complications after pancreatic resection. Various strategies have been employed in order to manage pancreatic fistula. Nonetheless high grade pancreatic fistula evokes controversy in relation to the choice of treatment. A Medline search was performed, with regard to conservative treatment options versus completion pancreatectomy for the management of pancreatic fistula grade C. Pancreatic fistula rates remain unchanged with an incidence ranging from 5%-20% and this is considered as the most important cause of postoperative death. Many authors claim that completion pancreatectomy has probably lost its role in favour of interventional radiology procedures, while others believe that completion pancreatectomy continues to have a place in the management of patients with severe clinical deterioration after pancreatic fistula who do not respond to non-surgical interventions. There is no agreement on the best clinical management of severe pancreatic fistula after pancreatic surgery. Completion pancreatectomy is reserved for patients not improving with conventional measures.

Iron chelation prevents lung injury after major hepatectomy

Aim:  Oxidative stress has been implicated in lung injury following ischemia/reperfusion and resection of the liver. We tested whether alleviating oxidative stress with iron chelation could improve lung injury after extended hepatectomy.

Beyond Preconditioning: Postconditioning as an Alternative Technique in the Prevention of Liver Ischemia-Reperfusion Injury

Liver ischemia/reperfusion injury may significantly compromise hepatic postoperative function. Various hepatoprotective methods have been improvised, aiming at attenuating IR injury. With ischemic preconditioning (IPC), the liver is conditioned with a brief ischemic period followed by reperfusion, prior to sustained ischemia. Ischemic postconditioning (IPostC), consisting of intermittent sequential interruptions of blood flow in the early phase of reperfusion, seems to be a more feasible alternative than IPC, since the onset of reperfusion is more predictable. Regarding the potential mechanisms involved, it has been postulated that the slow intermittent oxygenation through controlled reperfusion decreases the burst production of oxygen free radicals, increases antioxidant activity, suppresses neutrophil accumulation, and modulates the apoptotic cascade. Additionally, favorable effects on mitochondrial ultrastructure and function, and upregulation of the cytoprotective properties of nitric oxide, leading to preservation of sinusoidal structure and maintenance of blood flow through the hepatic circulation could also underlie the protection afforded by postconditioning. Clinical studies are required to show whether biochemical and histological improvements afforded by the reperfusion/reocclusion cycles of postconditioning during early reperfusion can be translated to a substantial clinical benefit in liver resection and transplantation settings or to highlight more aspects of its molecular mechanisms.

Sildenafil Attenuates Hepatocellular Injury after Liver Ischemia Reperfusion in Rats: A Preliminary Study

We evaluated the role of sildenafil in a rat liver ischemia-reperfusion model. Forty male rats were randomly allocated in four groups. The sham group underwent midline laparotomy only. In the sildenafil group, sildenafil was administered intraperitoneally 60 minutes before sham laparotomy. In the ischemia-reperfusion (I/R) group, rats were subjected to 45 minutes of hepatic ischemia followed by 120 minutes of reperfusion, while in the sild+I/R group rats were subjected to a similar pattern of I/R after the administration of sildenafil, 60 minutes before ischemia. Two hours after reperfusion, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured and histopathological examination of the lobes subjected to ischemia as well as TUNEL staining for apoptotic bodies was performed. Additionally, myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) were analyzed. Serum markers of hepatocellular injury were significantly lower in the sild+I/R group, which also exhibited lower severity of histopathological lesions and fewer apoptotic bodies, as compared to the I/R group. The I/R group showed significantly higher MPO activity and higher expression of ICAM-1, as compared to the sild+I/R group. Use of sildenafil as a preconditioning agent in a rat model of liver I/R exerted a protective effect.

Desferrioxamine Attenuates Pancreatic Injury after Major Hepatectomy under Vascular Control of the Liver: Experimental Study in Pigs

Introduction. Pancreatic injury can manifest after major hepatectomy under vascular control. The main mechanism involved seems to be remote oxidative injury due to “spillage” of reactive oxygen species and cytokines from the liver. The aim of this study is to evaluate the role of desferrioxamine in the prevention of pancreatic injury following major hepatectomy. Methods. Twelve Landrace pigs were subjected to a combination of major hepatectomy (70–75%), using the Pringle maneuver for 150 minutes, after constructing a porta-caval side-to-side anastomosis. The duration of reperfusion was 24 hours. Animals were randomly divided into a control group (n = 6) and a desferrioxamine group (DFX, n = 6). DFX animals were treated with continuous IV infusion of desferrioxamine 100 mg/kg. Pancreatic tissue injury, c-peptide and amylase concentrations, and pancreatic tissue oxidative markers were evaluated. Results. Desferrioxamine-treated animals showed decreased c-peptide levels, decreased acinar cell necrosis, and decreased tissue malondialdehyde levels 24 hours after reperfusion compared with the control group. There was no difference in portal pressure or serum amylase levels between the groups. Conclusions. Desferrioxamine seems to attenuate pancreatic injury after major hepatectomy under vascular control possibly by preventing and reversing production and circulation of oxidative products.

Expression of Inflammatory and Regenerative Genes in a Model of Liver Ischemia/Reperfusion and Partial Hepatectomy

ABSTRACT Purpose/Aim: Hepatic ischemia/reperfusion (I/R) describes the paradox of additional tissue injury caused by reperfusion. The aim of this survey was to investigate the mRNA expression of genes exerting their inflammatory and regenerative reaction in a porcine model of I/R and extended hepatectomy. Material and methods: Twelve pigs were used, weighing 30–35 kg in average, which were allocated in two groups: the I/R group with eight pigs and the sham-operated (control) one with four pigs. The I/R group underwent portacaval anastomosis and Pringle maneuver followed by extended hepatectomy. The hepatoduodenal ligament was occluded for 150 min and the liver remnant was reperfused for 24 hours. Blood samples were steadily received throughout the surgical procedure, where hepatic biopsies were taken for pathological evaluation. Animals were sacrificed in 24 hours after the onset of reperfusion. Results: Between the two groups, statistically significant differences were noticed in serum values of AST, ALT, ALP, and total bilirubin in the early and late phase of reperfusion. The mRNA expression of iNOS, IL-1b, and TGF-a did not increase significantly in the I/R group. Conversely, the mRNA modification of IL-6, STAT-3, and E-selectin demonstrated significantly increased expression in I/R animals. Conclusions: In the present survey, a new I/R swine model was proposed and specific parameters were analyzed, revealing differences between the study groups.

Comparative Effects of Ischemic Preconditioning and Iron Chelation in Hepatectomy

ABSTRACT Purpose/Aim: Major hepatectomies can result in severe ischemia/reperfusion (I/R) injury of the liver. The aim of this survey is to comparatively evaluate the effects of a surgical and a pharmacological hepatoprotective modality on the liver remnant in a porcine model of hepatectomy. Material and Methods: Twenty-one Landrace pigs were randomly divided into three groups: a control group (CON) (n = 7), an Ischemic Preconditioning (PRE) group (n = 7) and a Desferoxamine (DFX) treated one (n = 7). Animals were subjected to 120 min of liver ischemia with subsequent 75% hepatectomy followed by 24-hr reperfusion. In all animals, continuous intracranial pressure (ICP) monitoring was employed. Blood samples were collected at t0, t6, t12, and t24 hrs after reperfusion. Liver remnant specimens were excised for histological examination. Results: In the PRE group, ICP was statistically lower at t6 time point compared to CON group and in comparison with t0. In addition, ICP was significantly lower at all-time points after reperfusion in the DFX group. Finally, with regard to DFX and PRE group correlation, ICP was significantly lower at t0, t12, and t24 time points after reperfusion in the DFX group. In the PRE group, NH3 levels were significantly lower at t12 after reperfusion compared to CON and DFX groups. Histological evaluation elucidated significantly less hepatocellular necrosis, apoptosis, and degeneration in the PRE and DFX groups correlated to CON group. Conclusions: Both hepatoprotective modalities including PRE and DFX administration are associated with lower ICP levels and correlated with attenuated liver remnant injury.