General anesthesia and hepatic circulation

This article describes hepatic circulatory disturbances associated with anesthesia and surgical intervention. The material is presented in three parts: part 1 describes the effects of general anesthetics on the hepatic circulation; part 2 deals with different factors related to surgical procedures and anesthesia; and part 3 analyzes the role of hepatic circulatory disturbances and hepatic oxygen deprivation in anesthesia-induced hepatotoxicity. The analysis of available data suggests that general anesthesia affects the splanchnic and hepatic circulation in various directions and to different degrees. The majority of anesthetics decreases portal blood flow in association with a decrease in cardiac output. However, hepatic arterial blood flow can be preserved, decreased, or increased. The increase in hepatic arterial blood flow, when it occurs, is usually not enough to compensate for a decrease in portal blood flow and therefore total hepatic blood flow is usually decreased during anesthesia. This decrease in total hepatic blood flow has certain pharmacokinetic implications, namely a decrease in clearance of endogenous and exogenous substances with a high hepatic extraction ratio. On the other hand, a reduction in the hepatic oxygen supply might play a certain role in liver dysfunction occurring perioperatively. Surgical procedures-preparations combined with anesthesia have a very complex effect on the splanchnic and hepatic circulation. Within this complex, the surgical procedure-preparation plays the main role in developing circulatory disturbances, while anesthesia plays only a modifying role. Hepatic oxygen deprivation may play an important role in anesthesia-induced hepatotoxicity in different experimental models.     

Effect of hepatic nerve stimulation on hepatic uptake of lidocaine in the cat

Hepatic blood flow and lidocaine uptake were measured using a hepatic venous long-circuit preparation in cats anesthetized with pentobarbital-Na. The processes involved with hepatic elimination of lidocaine were not affected by stimulation of the hepatic nerves. The lack of neural influence on hepatic extraction ratios of lidocaine supports the contention that nerve stimulation does not result in shunting or redistribution of blood to non-nutritive sites. In species which do not show complete vascular escape from neurogenic vasoconstriction, a reduced lidocaine elimination would be anticipated since it was shown that reduced hepatic blood flow results in reduced lidocaine elimination. In the intact rat one third of the lidocaine in the blood was extracted on each passage through the liver. This extraction ratio is not affected by arterial levels of lidocaine, by changes in blood flow or by activation of the hepatic nerves.     

Numerical investigation of non-Newtonian microcirculatory blood flow in hepatic lobule

The circulation in the liver is unique at macroscopic and microscopic levels. At the macroscopic level, there is an unusual presence of portal and arterial inputs rather than a single arterial input. At the microscopic level, a series of microenvironments in the acinar system is essential in controlling the functional characteristics of hepatic parenchymal cells. Since the hemodynamics is much less studied in the multifunctional liver, an attempt is made to study the hepatic hemodynamics in a segment of a hepatic lobular structure, that is made up of high-pressure oxygenated arteriole, low-pressure nutrient-rich portal venule, fenestrated sinusoidal space and hepatic venule. Our goal is to dispel some of the myths of this complex vascular bed by means of finite volume blood flow simulation. Flow features like high-velocity gradients near the fenestrations, flow reversal and Dean vortices in the sinusoidal space are analyzed within the non-Newtonian framework. Since no distinct exact or numerical solutions are available for this complex vascular bed, the present simulated results are compared with the available clinical observations. Results revealed that the pressure plays a key role in hepatic blood flow.     

The liver: a model of organ-specific lymphocyte recruitment

The liver is constantly exposed to gut-derived antigens that enter via the portal vein, and it must modulate immune responses so that harmful pathogens are cleared but necessary food antigens are ignored. The liver contains a large resident and migratory population of lymphocytes and macrophages that provide immune surveillance against foreign antigen. This population of cells can be rapidly expanded in response to infection or injury by recruiting leukocytes from the circulation, a process that is dependent on the ability of lymphocytes to recognise, bind to and migrate across the endothelial cells that line the vasculature. Lymphocytes can enter the liver at several sites: the vascular endothelium in the portal tracts (comprising the hepatic artery, portal vein and bile ductule), the sinusoids (through which the blood percolates past the hepatocytes) or the central hepatic veins (through which the blood exits). The requirements and physical conditions at each site vary and there is evidence that different combinations of adhesion proteins are involved at these different sites. This article discusses the expression and function of adhesion molecules within the liver and demonstrates how specific populations of effector lymphocytes can be selectively recruited to the liver.     

Melatonin and its protective role in attenuating warm or cold hepatic ischaemia/reperfusion injury

Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end‐stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti‐inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future.     

Management of hepatic injury.

Liver injuries may be due to either blunt or penetrating trauma to the thorax or abdomen. Specific treatment depends on the site and extent of hepatic injury. Following resuscitation with intravenous fluids and blood as needed, surgical therapy is directed to provide hemostasis, remove necrotic liver tissue and promote adequate external drainage in the postoperative period. While local measures are usually sufficient, complex hepatic wounds may require extensive resection and vascular ligature or repair.     

Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning

Ischemia-reperfusion injury is, at least in part, responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms that contribute to various degrees in the overall injury. Some of the topics discussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatory mediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatory response. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as a substrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection by ischemic preconditioning are discussed. On the basis of current knowledge, preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver surgery involving ischemic stress and reperfusion.     

Evaluation of serum uric acid changes in different forms of hepatic vascular inflow occlusion in human liver surgeries

Uric acid values in serum have been analyzed as one of the markers to predict cellular damage due to ischemia reperfusion injury in the field of organ transplantation. The present study was conducted to confirm that uric acid values in serum could be an efficient marker of ischemic injury of liver parenchyma following hepatic vascular occlusion in human liver surgery. The changes in serum uric acid values were analyzed at fixed intervals during different liver surgeries. Significant increases in serum uric acid values were observed in patients who received the Pringle's maneuver in which hepatic vascular inflow was manipulated with a repetition of 15 min occlusion and 5 min perfusion, whereas almost no changes in uric acid values were found in both groups of patients who received the hemilobal occlusion of the Glisson's triad in which the right or left vessels were manipulated with a repetition of 30 min occlusion and 5 min perfusion and the "control method" in which the hepatic vessels of the lesion side were previously cut before liver resection. Uric acid values in serum increased in patients of Pringle's maneuver compared to those of the hemilobal occlusion of the Glisson's triad and the control method though these procedures were used in larger hepatectomies rather than Pringle's maneuver. The results indicated that serum uric acid values do not always reflect the severity of ischemia of the liver parenchyma but reflect intestinal congestion because marked intestinal congestion was observed in patients of Pringle's maneuver but not in patients of the hemilobal occlusion of the Glisson's triad and the control method. The evaluation of the severity of the ischemic injury of the liver should be done with caution when uric acid is used as a marker in human liver surgery.     

Identification and preliminary validation of novel biomarkers of acute hepatic ischaemia/reperfusion injury using dual-platform proteomic/degradomic approaches

Hepatic ischaemia/reperfusion (I/R), a major cause of liver damage associated with multiple trauma, haemorrhagic and septic shock, and liver transplantation, contributes significantly to multiple organ failure. Development of novel sensitive biomarkers that detect early stages of liver damage is vital for effective management and treatment of ischaemic liver injury. By using high-throughput immunoblotting and cation–anion exchange chromatography/reversed-phase liquid chromatography-tandem mass-spectrometry, we identified several hepatic proteins, including argininosuccinate synthase (ASS) and estrogen sulfotransferase (EST-1), which were degraded in the liver and rapidly released into circulation during I/R injury. ASS accumulated in serum within 10 min, reached a steady state at 30 min, and persisted up until 3 h after reperfusion following 30 min of total hepatic ischaemia. EST-1 appeared rapidly in blood and attained maximum within 1 hour followed by a decline at 3 h of reperfusion. No ASS or EST-1 protein was detected in serum of control or sham operated rats. ASS and EST-1 exhibited greater sensitivity and specificity toward I/R liver injury as compared with alanine aminotransferase (ALT), an established marker of hepatocellular necrosis. In contrast, serum ASS and EST-1 were undetectable in rats with chronic alcoholic liver disease, while the levels of ALT protein were significantly increased. In addition, ASS, but not EST-1 or ALT accumulated in blood only 6 h after treatment with hepatotoxic combination of lipopolysaccharide and D-galactosamine. These data demonstrate the utility of ASS and EST-1 as novel sensitive and specific biomarkers of acute liver ischaemic injury for prospective clinical studies.     

Identification and preliminary validation of novel biomarkers of acute hepatic ischaemia/reperfusion injury using dual-platform proteomic/degradomic approaches

Hepatic ischaemia/reperfusion (I/R), a major cause of liver damage associated with multiple trauma, haemorrhagic and septic shock, and liver transplantation, contributes significantly to multiple organ failure. Development of novel sensitive biomarkers that detect early stages of liver damage is vital for effective management and treatment of ischaemic liver injury. By using high-throughput immunoblotting and cation-anion exchange chromatography/reversed-phase liquid chromatography-tandem mass-spectrometry, we identified several hepatic proteins, including argininosuccinate synthase (ASS) and estrogen sulfotransferase (EST-1), which were degraded in the liver and rapidly released into circulation during I/R injury. ASS accumulated in serum within 10 min, reached a steady state at 30 min, and persisted up until 3 h after reperfusion following 30 min of total hepatic ischaemia. EST-1 appeared rapidly in blood and attained maximum within 1 hour followed by a decline at 3 h of reperfusion. No ASS or EST-1 protein was detected in serum of control or sham operated rats. ASS and EST-1 exhibited greater sensitivity and specificity toward I/R liver injury as compared with alanine aminotransferase (ALT), an established marker of hepatocellular necrosis. In contrast, serum ASS and EST-1 were undetectable in rats with chronic alcoholic liver disease, while the levels of ALT protein were significantly increased. In addition, ASS, but not EST-1 or ALT accumulated in blood only 6 h after treatment with hepatotoxic combination of lipopolysaccharide and D-galactosamine. These data demonstrate the utility of ASS and EST-1 as novel sensitive and specific biomarkers of acute liver ischaemic injury for prospective clinical studies.     

The uncoordinated-5 homolog B receptor affects hepatic ischemia reperfusion injury

Recent evidence has demonstrated additional roles for the neuronal guidance protein receptor UNC5B outside the nervous system. Given the fact that ischemia reperfusion injury (IRI) of the liver is a common source of liver dysfunction and the role of UNC5B during an acute inflammatory response we investigated the role of UNC5B on acute hepatic IRI. We report here that UNC5B(+/-) mice display reduced hepatic IRI and neutrophil (PMN) infiltration compared to WT controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate- (AST) and alanine- (ALT) aminotransferase, the presence of PMN within ischemic hepatic tissue, and serum levels of inflammatory cytokines. Moreover, injection of an anti-UNC5B antibody resulted in a significant reduction of hepatic IR injury. This was associated with reduced parameters of liver injury (LDH, ALT, AST) and accumulation of PMN within the injured hepatic tissue. In conclusion our studies demonstrate a significant role for UNC5B in the development of hepatic IRI and identified UNC5B as a potential drug target to prevent liver dysfunction in the future.     

2,5-Anhydro-D-mannitol increases hepatocyte calcium: implications for a hepatic hunger stimulus

The fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), triggers feeding in rats via a mechanism linked to its ability to trap phosphate and deplete hepatic ATP. This metabolic inhibitor is particularly useful in the study of the role of the liver in initiation of feeding as its effects are preferentially localized to the liver, and its metabolic consequences have been extensively characterized. To determine whether changes in intracellular calcium may participate in a mechanism conveying information about hepatic energy status to the nervous system, we studied the effects of 2,5-AM on intracellular calcium in isolated hepatocytes using the ratiometric indicator, fura-2. 2,5-AM elicited a marked elevation of intracellular calcium within 2-3 min of exposure that returned to baseline upon removal of the agent. Removal of external calcium failed to prevent this response, while emptying intracellular stores prevented it. These data are consistent with the hypothesis that hepatic energy status may be conveyed to the nervous system via a calcium-mediated secretion event.     

Early effects of tribromoethanol, ketamine/xylazine, pentobarbitol, and isoflurane anesthesia on hepatic and lymphoid tissue in ICR mice

We investigated the effects of various anesthetic agents on hepatic and splenic injury in mice. Three and six hours after intraperitoneal injection of TBE, intramuscular injection of ketamine/xylazine combination (K/X), intraperitoneal injection of pentobarbital (PB), and inhalation of isoflurane (IF), or intraperitoneal and intramuscular injection of control saline, mice were exsanguinated and serum was obtained for measurement of hepatic aspartate transaminase (AST), alanine transaminase (ALT) and gamma-glutamyltransferase (GGT). The spleen and liver also were obtained, and sections were examined by use of routine light microscopy for pathologic changes and for apoptosis, as determined by use of the in situ terminal deoxynucleotidyl transferase-mediated dUPT nick-end-labeling (TUNEL) histochemical analysis. Three hours after TBE or K/X administration, AST activity increased three- to fourfold above that in untreated and saline-injected control animals, and remained high at six hours. Administration of PB did not effect AST activity at three hours, but there was a significant increase at six hours. Activity of ALT was non-significantly increased three hours after TBE and K/X, but not PB administration. Administration of IF had no effect on hepatic enzyme activities, and GGT was not increased after administration of any of the agents. Markedly increased apoptosis was observed in splenic follicles and in hepatic Kupffer and endothelial cells at three hours after TBE and K/X administration, but apoptosis decreased to control levels by six hours. Increased apoptosis was not observed after IF administration. Administration of TBE and K/X causes injury to lymphocytes and to hepatic Kupffer and endothelial cells within three hours, and PB administration induces changes within six hours. Thus, use of these anesthetic agents should be avoided when experiments are being designed to test short-term effects of an experimental intervention on the spleen and possibly on all lymphoid tissues. In addition, they also should be avoided in experiments testing effects on hepatic tissue.     

Nitric oxide-deficiency regulates hepatic heme oxygenase-1.

Nitric oxide plays a crucial role in the maintenance of liver function and integrity. During stress, the inducible heme oxygenase-1 protein and its reaction products, including carbon monoxide, also exert potent hepatoprotective effects. We investigated a potential relationship between endogenous nitric oxide synthesis and the hepatic regulation of heme oxygenase-1. Inhibition of nitric oxide synthesis in vivo by injection of l-NAME led to a dose-dependent induction of heme oxygenase-1 mRNA, protein and activity in the rat liver, whereas did not affect the expression of other heat shock proteins. The effect of l-NAME was demonstrated by hemodynamic changes within the liver circulation as measured by ultrasonic flow probes. Inhibition of nitric oxide synthase led to a decline in hepatic arterial and portal venous blood flow, and subsequently caused liver cell damage. In contrast, the combined administration of l-NAME and the nitric oxide-independent intestinal vasodilator dihydralazine completely restored portal venous flow, abolished the liver cell damage, and prevented the upregulation of heme oxygenase-1, despite inhibition of nitric oxide production. In conclusion, nitric oxide deficiency upregulates hepatic heme oxygenase-1, which is reversible by maintaining hepatic blood flow. This interdependence has important implications for the development of therapeutic strategies aimed at modulating the activity of these hepatoprotective mediator systems.     

Hepatic fibrosis--role of hepatic stellate cell activation

Hepatic fibrosis is a reversible wound healing response characterized by accumulation of extracellular matrix (ECM), or "scar," that follows chronic but not self-limited liver disease. The ECM components in fibrotic liver are similar regardless of the underlying cause. Activation of hepatic stellate cells is the central event in hepatic fibrosis. These perisinusoidal cells orchestrate an array of changes including degradation of the normal ECM of liver, deposition of scar molecules, vascular and organ contraction, and release of cytokines. Not only is hepatic fibrosis reversible, but it is also increasingly clear that cirrhosis may be reversible as well. The exact stage at which fibrosis/cirrhosis becomes truly irreversible is not known. Antifibrotic therapies will soon be a clinical reality. Emerging therapies will be targeted to those patients with reversible disease. The paradigm of stellate cell activation provides an important framework for defining therapeutic targets.     

Attenuation of acute and chronic liver injury in rats by iron-deficient diet

Oxidative stress due to iron deposition in hepatocytes or Kupffer cells contributes to the initiation and perpetuation of liver injury. The aim of this study was to clarify the association between dietary iron and liver injuries in rats. Liver injury was initiated by the administration of thioacetamide or ligation of the common bile duct in rats fed a control diet (CD) or iron-deficient diet (ID). In the acute liver injury model induced by thioacetamide, serum levels of aspartate aminotransferase and alanine aminotransferase, as well as hepatic levels of lipid peroxide and 4-hydroxynonenal, were significantly decreased in the ID group. The expression of 8-hydroxydeoxyguanosine and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling positivity showed a similar tendency. The expression of interleukin-1beta and monocyte chemotactic protein-1 mRNA was suppressed in the ID group. In liver fibrosis induced by an 8-wk thioacetamide administration, ID suppressed collagen deposition and smooth muscle alpha-actin expression. The expressions of collagen 1A2, transforming growth factor beta, and platelet-derived growth factor receptor beta mRNA were all significantly decreased in the ID group. Liver fibrosis was additionally suppressed in the bile-duct ligation model by ID. In culture experiments, deferoxamine attenuated the activation process of rat hepatic stellate cells, a dominant producer of collagen in the liver. In conclusion, reduced dietary iron is considered to be beneficial in improving acute and chronic liver injuries by reducing oxidative stress. The results obtained in this study support the clinical usefulness of an iron-reduced diet for the improvement of liver disorders induced by chronic hepatitis C and alcoholic/nonalcoholic steatohepatitis.     

Role of reactive oxygen and nitrogen species in the vascular responses to inflammation

Inflammation is a complex and potentially life-threatening condition that involves the participation of a variety of chemical mediators, signaling pathways, and cell types. The microcirculation, which is critical for the initiation and perpetuation of an inflammatory response, exhibits several characteristic functional and structural changes in response to inflammation. These include vasomotor dysfunction (impaired vessel dilation and constriction), the adhesion and transendothelial migration of leukocytes, endothelial barrier dysfunction (increased vascular permeability), blood vessel proliferation (angiogenesis), and enhanced thrombus formation. These diverse responses of the microvasculature largely reflect the endothelial cell dysfunction that accompanies inflammation and the central role of these cells in modulating processes as varied as blood flow regulation, angiogenesis, and thrombogenesis. The importance of endothelial cells in inflammation-induced vascular dysfunction is also predicated on the ability of these cells to produce and respond to reactive oxygen and nitrogen species. Inflammation seems to upset the balance between nitric oxide and superoxide within (and surrounding) endothelial cells, which is necessary for normal vessel function. This review is focused on defining the molecular targets in the vessel wall that interact with reactive oxygen species and nitric oxide to produce the characteristic functional and structural changes that occur in response to inflammation. This analysis of the literature is consistent with the view that reactive oxygen and nitrogen species contribute significantly to the diverse vascular responses in inflammation and supports efforts that are directed at targeting these highly reactive species to maintain normal vascular health in pathological conditions that are associated with acute or chronic inflammation.     

Effects induced hypothermia on hepatic portal circulation

Studies of the liver circulation in dogs during hypothermia, showed that portal blood flow is reduced with no significant changes of blood pressure and with important vascular resistance. These effects are probably due to the contraction of pre-capillaries sphincters.