Rahul S. Koti

Protection of the Liver by Ischemic Preconditioning: A Review of Mechanisms and Clinical Applications

Ischemic preconditioning refers to the endogenous mechanism of protection against a sustained ischemic insult following an initial, brief ischemic stimulus. Ischemia-reperfusion injury of the liver is a major cause of morbidity and mortality in liver surgery and transplantation and ischemic preconditioning is a promising strategy for improving the outcome of liver surgery. The preconditioning phenomenon was first described in a canine model of myocardial ischemia-reperfusion injury in 1986 and since then has been shown to exist in other organs including skeletal muscle, brain, kidneys, retina and liver. In the liver, the preconditioning effect has been demonstrated in rodents and a recent study has demonstrated human clinical benefits of preconditioning during hemihepatectomies. Ischemic preconditioning has been described as an adaptive response and although the precise mechanism of hepatoprotection from preconditioning is unknown it is likely to be a receptor-mediated process. Several hypotheses have been proposed and this review assesses possible mechanisms of ischemic preconditioning and its role in hepatic surgery and liver transplantation. The future lies in defining the mechanisms of the ischemic preconditioning effect to allow drug targeting to induce the preconditioning response.

Meta-analysis of randomized controlled trials on the effectiveness of somatostatin analogues for pancreatic surgery: a Cochrane review

BACKGROUND The use of synthetic analogues of somatostatin following pancreatic surgery is controversial. The aim of this meta-analysis is to determine whether prophylactic somatostatin analogues (SAs) should be used routinely in pancreatic surgery. METHODS Randomized controlled trials were identified from the Cochrane Library Trials Register, MEDLINE, EMBASE, Science Citation Index Expanded and reference lists. Data were extracted from these trials by two independent reviewers. The risk ratio (RR), mean difference (MD) and standardized mean difference (SMD) were calculated with 95% confidence intervals (95% CIs) based on intention-to-treat or available case analysis. RESULTS Seventeen trials involving 2143 patients were identified. The overall number of patients with postoperative complications was lower in the SA group (RR 0.71, 95% CI 0.62-0.82), but there was no difference between the groups in perioperative mortality (RR 1.04, 95% CI 0.68-1.59), re-operation rate (RR 1.15, 95% CI 0.56-2.36) or hospital stay (MD -1.04 days, 95% CI -2.54 to 0.46). The incidence of pancreatic fistula was lower in the SA group (RR 0.64, 95% CI 0.53-0.78). The proportion of these fistulas that were clinically significant is not clear. Analysis of results of trials that clearly distinguished clinically significant fistulas revealed no difference between the two groups (RR 0.69, 95% CI 0.34-1.41). Subgroup analysis revealed a shorter hospital stay in the SA group than among controls for patients with malignant aetiology (MD -7.57 days, 95% CI -11.29 to -3.84). CONCLUSIONS Somatostatin analogues reduce perioperative complications but do not reduce perioperative mortality. However, they do shorten hospital stay in patients undergoing pancreatic surgery for malignancy. Further adequately powered trials of low risk of bias are necessary.

The relationship of hepatic tissue oxygenation with nitric oxide metabolism in ischemic preconditioning of the liver

Ischemic preconditioning (IPC) may increase the hepatic tolerance of ischemic injury during liver surgery and transplantation via nitric oxide (NO) formation. This study investigates the effect of IPC on hepatic tissue oxygenation and the role of NO stimulation and inhibition on the preconditioning effect in the rat liver. Study groups had 1) sham laparotomy; 2) 45‐min lobar liver ischemia and 2‐h reperfusion (IR); 3) IPC with 5‐min ischemia and 10‐min reperfusion before IR; 4) L‐arginine before IR; and 5) Nω‐Nitro‐L‐arginine methyl ester (L‐NAME) + IPC before IR. Hepatic tissue oxygenation was monitored by near‐infrared spectroscopy. Plasma alanine aminotransferase and plasma nitrite/nitrate were measured. Following IR there was significant decrease in oxyhemoglobin and cytochrome oxidase and an increase in deoxyhemoglobin (P<0.05 vs. Sham). IPC produced a significant increase in intracellular oxygenation at the end of the reperfusion period (cytochrome oxidase CuA redox state, P<0.05 vs IR). NO stimulation with L‐arginine did not attenuate the impairment in hepatic tissue oxygenation after IR (P>0.05 vs IR). In contrast, inhibition of NO synthesis blocked the effect of IPC and further impaired tissue oxygenation (decreased cytochrome oxidase CuA redox state and increased deoxyhemoglobin, both P<0.05 vs IR), suggesting an aggravation of ischemia reperfusion injury. Hepatocellular injury was reduced by IPC and L‐arginine and increased by NO blockade with L‐NAME (Plasma ALT, all P< 0.05 vs IR). Hepatic tissue oxygenation correlated significantly with ALT and plasma nitrite/nitrate. Ischemic preconditioning significantly improved hepatic intra cellular oxygenation and reduced hepatocellular injury. NO stimulation reduced hepatocellular injury, whereas inhibition of nitric oxide synthesis blocked the effect of IPC and reduced tissue oxygenation and increased hepatocellular injury.

Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver.

This study was undertaken to identify nitric oxide synthase (NOS) isoforms responsible for the generation of cytoprotective NO during liver ischemic preconditioning (IPC). Sprague‐Dawley rats were subjected to 45 min lobar ischemia followed by 2 h reperfusion. l‐arginine or Nω‐nitro‐l‐arginine methyl ester (L‐NAME) was administered to stimulate or block NO synthesis. Study groups (n=6) had 1) sham laparotomy, 2) ischemia reperfusion (IR), 3) IPC with 5 min ischemia and 10 min reperfusion before IR, 4) l‐arginine before IR, or 5) L‐NAME + IPC before IR. Liver function tests, nitrite + nitrate (NOx) and plasma amino acids were analyzed. The endothelial cell and inducible isoforms of NOS (eNOS and iNOS) were identified using immunohistochemistry and Western blotting. Both IPC and l‐arginine treatment increased NOx (P<0.05) and improved serum liver enzymes (P<0.05) when compared with IR. These effects were prevented by L‐NAME. Hepatic vein NOx was significantly higher than circulating NOx. iNOS expression was absent within the groups. The preconditioned livers were associated with up‐regulation of eNOS expression and also increased l‐arginine levels. The effects of l‐arginine administration were similar to those evident following IPC. Thus, cytoprotective NO generation during IPC of the liver was a result of increased eNOS expression and increased l‐arginine substrate availability.

Continuous infusion of N-acetylcysteine reduces liver warm ischaemia-reperfusion injury.

N‐acetylcysteine (NAC) may modulate the initial phase (less than 2 h) of liver warm ischaemia–reperfusion (IR) injury but its effect on the late phase remains unclear. The present study investigated the role of NAC during the early and late phases in a rabbit lobar IR model.

The Role of Thiols in Liver Ischemia-Reperfusion Injury

Thiol-containing compounds have an essential role in many biochemical reactions due to their ability to be easily oxidised and then quickly regenerated. Main representatives are glutathione, lipoic acid and thioredoxin which are synthesised de novo in mammalian cells. N-acetylcysteine and Bucillamine are synthetic thiols which have been administered in experimental and clinical studies for treatment of conditions associated with oxidative stress. Ischemia and reperfusion (I/R) injury is characterised by significant oxidative stress, characteristic changes in the antioxidant system and organ injury leading to significant morbidity and mortality. I/R occurs in a variety of clinical settings such as liver resection, organ transplantation, haemorrhagic shock with fluid resuscitation, heart surgery, myocardial infarction followed by reperfusion and laparoscopic surgery. In these circumstances, the administration of antioxidant agents such as thiols, could provide protection from the harmful effects of I/R injury. However, the ability of thiol compounds to reduce free radicals is associated with the formation of thiyl radicals and the rate and efficiency of removal of thiyl radicals has a critical effect on antioxidant or prooxidant actions of thiols in the cells. The aim of this review is to present the mechanisms by which thiols act as antioxidants and signalling molecules and the experimental and clinical evidence regarding their role in I/R injury with a particular emphasis on liver I/R. The current evidence suggests that thiols ameliorate I/R injury and that their clinical significance should be further evaluated in large scale randomised clinical trials.

Effect of ischaemic preconditioning on hepatic oxygenation, microcirculation and function in a rat model of moderate hepatic steatosis.

IPC (ischaemic preconditioning) may protect the steatotic liver, which is particularly susceptible to I/R (ischaemia/reperfusion) injury. Hepatic steatosis was induced in Sprague-Dawley rats with a high-cholesterol (2%) diet for 12 weeks after which rats were subjected to I/R (ischaemia/reperfusion; 45 min of lobar ischaemia followed by 2 h of reperfusion). Rats were divided into three study groups (n=6 each) receiving: (i) sham laparotomy alone, (ii) I/R, and (iii) IPC (5 min of ischaemia, followed by 10 min of reperfusion) before I/R. Hepatic extra- and intra-cellular oxygenation and HM (hepatic microcirculation) were measured with near-infrared spectroscopy and laser Doppler flowmetry respectively. Plasma liver enzymes and hepatic tissue ATP were measured as markers of liver injury. Histology showed moderate-grade steatosis in the livers. At the end of 2 h of reperfusion, I/R significantly decreased extra- and intra-cellular oxygenation concomitant with a failure of recovery of HM (21.1+/-14.4% of baseline; P<0.001 compared with sham animals). IPC increased intracellular oxygenation (redox state of the copper centre of cytochrome oxidase; P<0.05 compared with rats receiving I/R alone) and flow in HM (70.9+/-17.1% of baseline; P<0.001 compared with rats receiving I/R alone). Hepatocellular injury was significantly reduced with IPC compared with I/R injury alone (alanine aminotransferase, 474.8+/-122.3 compared with 5436.3+/-984.7 units/l respectively; P<0.01; aspartate aminotransferase, 630.8+/-76.9 compared with 3166.3+/-379.6 units/l respectively; P<0.01]. In conclusion, IPC has a hepatoprotective effect against I/R injury in livers with moderate steatosis. These data may have important clinical implications in liver surgery and transplantation.

Inflammatory pseudotumour of the liver: the residuum of a biliary cystadenoma?

Inflammatory pseudotumour is a rare form of a liver mass. We report the case of a 28-year-old man presenting with obstructive jaundice, in whom an inflammatory pseudotumour arose with the resolution of a mucus secreting cystic liver lesion. The initial features suggested an intrahepatic cystadenoma or cystadenocarcinoma, which on its involution left a solid mass. Histopathology showed an inflammatory pseudotumour with no evidence of malignancy. A similar case has been reported recently, with the development of an inflammatory pseudotumour following collapse of a liver cyst seen on imaging. These two cases may shed some light on the origins of these rare liver lesions.

Arterialization of the portal vein improves hepatic microcirculation and tissue oxygenation in experimental cirrhosis

Arterialization of the portal vein (APV) has shown beneficial effects on liver regeneration and function in selected patients undergoing liver resection and transplantation. Whether APV improves liver perfusion and function in cirrhosis is unclear. This study investigated the effect of APV on hepatic haemodynamics and liver function in a rat model of cirrhosis.

Long-term survival with repeated resections of recurrent hepatocellular carcinoma in a non-cirrhotic liver: case report and brief review of the literature.

A healthy and asymptomatic 55-year-old woman underwent a complete (R0) non-anatomical resection of an incidentally detected solitary hepatocellular carcinoma (HCC) in a non-cirrhotic liver. Six years following the initial R0 non-anatomical resection, intrahepatic recurrence was diagnosed and the patient underwent a second R0 non-anatomical resection. At 12.5 years following the initial resection, a further intrahepatic recurrence was diagnosed, which was once again completely resected by left lateral hepatectomy. This represents one of the longest reported periods between initial resection and HCC recurrence, following repeated R0 resections in the absence of cirrhosis. The appropriate surveillance period and genetic testing protocol for such cases remains to be established.