Metabolic pathways and abnormalities

Metabolism describes the series of chemical reactions which are concerned with the provision of energy to biological systems. They may be divided into reactions involved in energy yield (catabolism: demand exceeds supply), and energy storage (anabolism: supply exceeds demand). Regulation of these pathways is critical for homoeostasis, and derangements in metabolism are seen in a wide variety of pathological processes. Understanding metabolism is key to the treatment of many diseases, notably diabetes, as well as underpinning clinical nutritional support.     

Human metabolism: pathways and clinical aspects

Metabolism describes the series of chemical reactions that are concerned with the provision of energy to biological systems. They may be divided into reactions involved in energy yield (catabolism: demand exceeds supply), and energy storage (anabolism: supply exceeds demand). Regulation of these pathways is critical for homeostasis, and derangements in metabolism are seen in a wide variety of pathological processes. Understanding metabolism is key to the treatment of many diseases, notably diabetes, as well as underpinning clinical nutritional support.     

Fatty acid lessens halothane's inhibition of energy metabolism in isolated hepatocytes

This study has examined whether adverse halothane effects on liver-cell energy metabolism are influenced by the availability of alternate substrates for energy-generating reactions. Halogenated volatile anesthetics affect both energy supply and energy demand in tissues, and cellular energy deficits have been implicated in anesthetic hepatotoxicity. Using hepatocytes isolated from fed rats either pretreated with phenobarbital or not treated (+PB or -PB cells, respectively), we studied the cellular energetic effects of providing fatty acid (oleic acid) along with glucose as substrate(s) for energy metabolism, while exposing the cells to 0%-2% halothane. In -PB cells incubated with glucose alone, there were halothane dose-related decreases in the oxygen (O2) consumption rate (VO2) and in the balance between adenosine triphosphate (ATP) supply and demand (ATP/ADP ratio), but no effect on lactate metabolism (lactate consumption or production) over the 10-min incubation period. Adding oleate along with glucose (a) raised VO2 but lowered ATP/ADP in the absence of halothane; (b) eliminated the decreases in VO2 and ATP/ADP seen when halothane was introduced; and (c) increased lactate consumption in both the presence and absence of halothane. In +PB cells, VO2 was higher, ATP/ADP lower, and lactate consumption also lower than in -PB cells under comparable conditions. Halothane or oleate effects, or both, on energy metabolism were thus qualitatively similar in +PB and -PB cells, except that in +PB cells incubated without oleate, lactate formation developed as halothane was increased from 0% to 2%, reflecting activation of glycolysis due to insufficient mitochondrial ATP production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Does placental lactate production have a role in ephedrine-induced fetal metabolic acidosis?

Editor—Maternal ephedrine administration can cause fetalrespiratory acidosis during spinal anaesthesia for caesareansection. We consider this to be secondary to a beta-adrenergic-mediatedincrease in fetal carbon dioxide production.¹ Ephedrine canalso cause fetal metabolic acidosis. We have previously consideredthis to be secondary to ephedrine increasing fetal metabolicrate to the extent that oxygen demand exceeds its limited supply,thereby increasing anaerobic metabolism. However, observationsfrom an     

Klinische Relevanz des Energiestoffwechsels im Herzen

The heart requires aerobic energy metabolism to cover the high adenosine triphosphate (ATP) demands when ATP energy reserves are low. Depending on the circulatory supply, heart muscle can switch between the use of various substrates, such as fatty acids, glucose and lactate, hence avoiding substrate deprivation. A highly efficient feed forward control of metabolism and coronary blood flow guarantees the continuous supply with energy under physiological conditions; however, impairment of the energy supply can result from decreased perfusion (flow stop) or increased myocardial diffusion distances (myocardial hypertrophy). Under such conditions the choice of substrate gains importance for maintenance of cardiac energy metabolism. While the energy content of fatty acids is high, the energy efficiency is much lower than that of carbohydrates. The combination of fasting, stress, flow stop, and heparin supplementation during cardiac surgery creates an unfortunate condition for efficient myocardial energy metabolism, because plasma levels of fatty acids are typically enhanced. Metabolic interventions aim to lower fatty acid concentrations in plasma and to increase myocardial glucose uptake, e.?g. by normoglycemic insulin-glucose infusion. The aim is the optimization of energy metabolism to decrease perioperative mortality and the duration of intensive care treatment of patients undergoing cardiac surgery.     

Lung transplantation. Donor selection

The demand for donor lungs currently exceeds the supply of suitable grafts by a significant margin. Legal backgrounds and organizational and logistic issues are of major impact on the available donor pool. Re-evaluation of the donor criteria currently in use and new, innovative approaches such as living donor lung transplantation and non-heart-beating donation will hopefully contribute to improve this situation and reduce waiting time and waiting list mortality.     

Three good reasons for heart surgeons to understand cardiac metabolism

It is the principal goal of cardiac surgeons to improve or reinstate contractile function with, through or after a surgical procedure on the heart. Uninterrupted contractile function of the heart is irrevocably linked to the uninterrupted supply of energy in the form of ATP. Thus, it would appear natural that clinicians interested in myocardial contractile function are interested in the way the heart generates ATP, i.e. the processes generally referred to as energy metabolism. Yet, it may appear that the relevance of energy metabolism in cardiac surgery is limited to the area of cardioplegia, which is a declining research interest. It is the goal of this review to change this trend and to illustrate the role and the therapeutic potential of metabolism and metabolic interventions for management. We present three compelling reasons why cardiac metabolism is of direct, practical interest to the cardiac surgeon and why a better understanding of energy metabolism might indeed result in improved surgical outcomes:

(1) To understand cardioplegic arrest, ischemia and reperfusion, one needs a working knowledge of metabolism;

(2) hyperglycemia is an underestimated and modifiable risk factor;

(3) acute metabolic interventions can be effective in patients undergoing cardiac surgery.

乳酸穿梭在心肌缺血/再灌注损伤中保护作用研究进展

背景 在传统观念上,乳酸是葡萄糖无氧代谢的废弃物,然而最近研究表明乳酸可作为能源物质,在体内能量代谢中有重要意义.在组织和细胞间存在大量乳酸穿梭现象,此种现象为机体代谢提供了保障. 目的 结合国内外相关研究,就乳酸穿梭机制在心肌保护中的作用进行阐述. 内容 乳酸是葡萄糖酵解的产物.乳酸穿梭是指机体不同组织和细胞间存在乳酸互相穿梭供能的现象.细胞间的乳酸转运主要由单羧酸转运蛋白(monocarboxylate transporter,MCT)、黏附分子(CD147)、乳酸脱氢酶组成.在心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)中乳酸穿梭主要是通过优化能量代谢及对Ca2+浓度的影响来发挥对心肌的保护作用. 趋向 目前研究发现乳酸在能量代谢中有重要意义,乳酸穿梭是机体I/RI时重要的能量代谢调节途径.但关于乳酸穿梭具体的调控机制研究尚少.     

Preventing,Recognizing and Treating Postoperative Complications

Complications can occur after any operation, but are most likely after major surgery or in patients with significant cardiac or respiratory comorbidity. They range from distressing or inconvenient to life-threatening. Complications causing failure of a single body organ or system can lead to multiple system failure or even death. Investigating and treating complications (and litigation) cost the UK NHS billions of pounds every year. For example, a simple wound infection delays discharge from hospital by an average of 7 days, and costs an extra £1700.Surgery injures and kills cells, causing inflammatory mediators (e.g. cytokines, thromboxanes, leukotrienes, prostaglandins, nitric oxide) to be released. The inflammatory response prevents introduction of infection into the body and promotes healing. An uncomplicated recovery from surgery relies on the body being able to increase its metabolic rate to maintain its normal homeostatic mechanisms and mount an adequate inflammatory response.The normal source of energy for a cell is derived from adenosine triphosphate (ATP), created during the metabolism of glucose in the presence of oxygen. Aerobic respiration, utilizing the citric acid cycle and oxidative phosphorylation inside mitochondria, liberates sufficient energy to create 36 ATP molecules per glucose molecule. Without oxygen, only 2 ATP molecules and 2 pyruvate molecules are created per glucose molecule; pyruvate is converted to lactate. If oxygen or glucose is in short supply during or after surgery, cells switch to anaerobic metabolism, producing such small amounts of energy that membrane pumps fail. The cell swells and is eventually irreversibly damaged or ruptures. Cells with a high demand for oxygen (e.g. myocardial cells, neurons) are especially susceptible. Most postoperative complications develop when organs fail to function correctly because oxygen supply to their cells does not meet demand.The prevention of complications is paramount and, on a physiological level, can be thought of as providing cells with sufficient oxygen and glucose to meet their energy demands. This occurs when blood is oxygenated adequately and the heart can produce enough systolic pressure to perfuse the tissues. Patients must be assessed preoperatively to identify those at increased risk of postoperative hypoxaemia or organ hypoperfusion, so that their condition can be optimized and appropriate postoperative monitoring instituted (e.g. admission to an HDU). Prompt identification of postoperative hypoxaemia or organ hypoperfusion, followed by appropriate intervention, limits the severity of complications and prevents the spiral into multi-organ failure.This contribution discusses postoperative complications by reference to common scenarios.     

Nutritional Treatment of Hemodialysis and Peritoneal Dialysis Patients

Abstract: The success of hemodialysis and peritoneal dialysis therapy is essentially dependent on adequate nutrition. Malnutrition represents one of the main factors in morbidity and mortality of dialysis patients. The main causes of malnutrition are insufficient energy intake, insufficient protein supply, loss of amino acids by dialysis, the uremic state of metabolism, catabolic stress of underlying diseases, and endocrinological disorders. For successful long-term chronic dialysis therapy, it is very important that patients be in an anabolic nutritional state when entering the dialysis program. In this paper, the nutritional needs of dialysis and peritoneal dialysis patients (fluid restriction, protein intake, energy supply, electrolyte balance, vitamin intake) are discussed to prevent the catabolic state.     

Nutrient supply and intervertebral disc metabolism

The metabolic environment of disc cells is governed by the avascular nature of the tissue. Because cellular energy metabolism occurs mainly through glycolysis, the disc cells require glucose for survival and produce lactic acid at high rates. Oxygen is also necessary for cellular activity, although not for survival; its pathway of utilization is unclear. Because the tissues are avascular, disc cells depend on the blood supply at the margins of the discs for their nutrients. The nucleus and inner anulus of the disc are supplied by capillaries that arise in the vertebral bodies, penetrate the subchondral bone, and terminate at the bone-disc junction. Small molecules such as glucose and oxygen then reach the cells by diffusion under gradients established by the balance between the rate of transport through the tissue to the cells and the rate of cellular demand. Metabolites such as lactic acid are removed by the reverse pathway. The concentrations of nutrients farthest from the source of supply can thus be low; oxygen concentrations as low as 1% have been measured in the discs of healthy animals. Although gradients cannot be measured easily in humans, they can be calculated. Measured concentrations in surgical patients are in agreement with calculated values.     

Real-Time assessment of organ vitality during the transplantation procedure

Although organ transplantation has become well established as a treatment modality for many patients with organ failure, little attention has been given to the evaluation of organ quality during its various steps. A critical factor in the success of the actual engraftment procedure is the integrity of energy metabolism and oxygen balance (supply/demand) at the microvasculature and intracellular mitochondrial level. The supply of oxygen to the cells is dependent on the saturation of hemoglobin (HbO₂), tissue blood flow, and tissue oxygen partial pressure. The mitochondrial reduced nicotinamide adenine dinucleotide redox state represents oxygen balance in the tissue. Although these parameters can be monitored in all tissues of the body, demand for oxygen may be organ-specific. The various steps surrounding transplantation may require different techniques for the evaluation of tissue vitality. Assessment of blood flow or HbO₂ is not possible during preservation of the organ. On the other hand, because extracellular levels of potassium may represent the energy demand processes in many organs, monitoring of extracellular potassium as an indicator of ionic homeostasis may provide important information regarding the quality of the preservation techniques. Although a large number of relevant studies have been performed in small laboratory animals, real-time monitoring in patients needs more practical tools. We present here the principles of multiparametric monitoring by which tissue vitality may be measured in both experimental and clinical situations. Much of the relevant literature on the subject is limited to the monitoring of kidney and liver. There are also some data on the monitoring of skin flaps. We have reviewed the major published reports in which organ and tissue vitality and quality were assessed in real time and will describe tissue and organ oxygen balance, vitality principles, technologic features of the various monitoring techniques, the clinical or experimental tools available and the conceptual and technologic aspects of the multiparametric monitoring concept. We will also discuss both experimental results and preliminary clinical observations by using multiparametric monitoring.     

The immunology of corneal xenotransplantation: a review of the literature

As the worldwide demand for human donor corneas far exceeds supply, there is a need for a new source of corneas for clinical transplantation. Genetically engineered pigs may prove to be that new source, particularly as current evidence indicates that the anatomical and biomechanical properties of human and pig corneas are similar. Experience with clinical and experimental corneal xenotransplantation has been comprehensively reviewed and is summarized. Studies in small and large animal models have documented that both humoral and cellular immune responses play roles in xenograft rejection. Recent progress in the genetic manipulation of pigs has led to the prospect that clinical corneal xenotransplantation, in the absence of exogenous immunosuppressive therapy, may become successful in the foreseeable future.     

发挥优势,开展亲属肾移植

肾移植是救治终末期尿毒症的理想手段.随着每年新增的终末期肾衰竭例数的不断增加,以及肾源有限,肾移植的供需矛盾日益突出.亲属活体供肾移植因其具有排斥反应少、手术成功率高等优点,成为当前扩大供肾来源的有效手段.我院具有良好的肾移植基础,积极开展亲属活体供肾移植工作,并重视医学伦理审查,从2007年至2008年,成功完成了196例亲属活体供肾移植手术,获得了良好效果.     

Wieviel Blutfluß braucht das Myokard?

Objectives: The myocardium of the left ventricle exhibits spatial heterogeneity of blood flow under physiological conditions. This study was designed to investigate, whether oxygen supply is jeopardized in low flow areas (blood flow <50% of mean) under physiological conditions and whether areas of high flow (>150% of mean) exihibit perfusion in excess of demand (?luxury perfusion”). Methods: The study was performed in anesthetized and ventilated beagle dogs. Local blood flow was reduced by mechanically narrowing of the r. circumflexus of the left coronary artery; myocardial blood flow was measured by the tracer-microsphere technique, free concentrations cellular adenosin by the SAH-technique, regional metabolism of substrates by the desoxyglucose-technique. Results: Low flow areas exhibited normal oxygenation of the myocardium, while in high flow areas no luxury perfusion could be demonstrated. Conclusion: Myocardial blood flow and metabolism demonstrate significant spatial heterogeneity. There appears to be no absolute threshold of blood flow, where regional myocardial ischemia develops. Probably biochemical evidence of myocardial ischemia is determined by a local ratio of oxygen supply and demand.     

Phylogeny of Mammalian metabolism

Mammals are at the end of a gradual metabolic evolution in the course of which the step from anaerobic to aerobic cellular metabolism and the transition from water to land life formed the basis for an increase in metabolic rate (from brady- to tachymetabolism). The increased metabolic rate and the resulting endogenous heat production were the preconditions for enhanced long-term performance as well as for homeothermy which allowed mammals and birds to invade temperate zones. However, the underlying increase in membrane permeability also results in an increased energy demand (for membrane pump activity) which leads to the reduced hypoxia tolerance of mammals and requires a permanent substrate supply. As an adaptation to a seasonal discrepancy between increased thermoregulatory energy demand and decreased food supply, some small mammals apparently extended the newly evolved non-REM-sleep into hibernation. Mammalian hibernation is characterized by a profound metabolic reduction which is influenced by acidosis and limited to a tolerable degree by maintained thermoregulation. The lower limit of cooling seems to be determined by a critical minimal metabolic rate which is common to all mammals. The higher the normothermic metabolic rate, the lower is the temperature at which this minimal metabolic rate is reached. Since specific (i. e., weight-corrected) basal metabolic rate increases with decreasing body mass, small mammals exhibit a higher hypothermia tolerance than larger ones. On the other hand, the metabolic decrease to a uniform minimal level reflects an inactivation of the overall metabolic size relationship and, thus, forms a counterpart to the metabolic increase from a lower fetomaternal to the higher size-related level, occurring after birth. The postnatal metabolic increase which favours the onset of thermoregulation, parallels the increase in oxygen tension at the transition from fetal to adult circulation and, thus, probably enables mammalian neonates to readjust their metabolic needs in response to hypoxia. There is increasing evidence that, similar to the step from anaerobiosis to aerobiosis, the increase in metabolic rate resulting from any increase in oxygen supply is a general principle of evolution that, apart from its further adaptive benefits, protects tissues from oxygen excess and subsequent oxidative stress.     

Bone delivers its energy information to fat and islets through osteocalcin

Bone has emerged as a novel endocrine organ for its ability to produce hormones and involvement in several regulatory feedback loops. Osteocalcin (OCN) is released into bloodstream during bone resorption and has been demonstrated to exert endocrine regulation on islets, fat and male testis to form feedback loops. We hypothesize that bone delivers its energy metabolism signals to related energy-regulating organs through OCN based on the following evidence: First, OCN has close interactions with islets and fat, and it shows ability to stimulate islets and fat to secret insulin and adiponectin, respectively. Islets and fat are important organs involved in energy metabolism. Second, OCN undergoes physiological fluctuations during a lifetime. In children and adolescents, during the development of osteoporosis or after bone fracture, OCN level increases significantly. The elevated OCN at these stages represents enhanced bone turnover and metabolic activity, which require more energy supply. Therefore, the metabolic activity of bone and the energy-related organs like fat and islets are closely linked by circulating OCN. Through systemic release of OCN, bone delivers its energy-demanding information to other organs to satisfy its energy requirement.     

Hepatic amino-acid metabolism in liver cirrhosis and in the long-term course after liver transplantation

The aim of this study was to investigate the impact of orthotopic liver transplantation (OLT) on plasma levels and splanchnic turnover of key amino acids for muscular (branched-chain amino acids: BCAAs) and hepatic metabolism (aromatic amino acids (AAAs) and methionine) in 48 patients with cirrhosis, 14 patients after OLT, and 46 controls. Also, hepatic amino-acid supply and resting energy expenditure were measured. BCAA levels (no hepatic uptake) decreased in cirrhosis (P<0.001) and were improved, although not normalized, after OLT (P<0.001). AAA and methionine levels were raised in cirrhosis (P<0.001) and normalized after OLT (P<0.001). Hepatic supply of these amino acids increased in patients graded Child B and C and decreased significantly after OLT. Splanchnic uptake of AAAs and methionine increased significantly in Child-B and decreased in Child-C patients. After OLT, splanchnic extraction of AAAs and methionine was as in Child A. Circulating AAAs and methionine correlated with indocyanine-green half-life (r=0.71, P<0.001) and resting energy expenditure (r=0.50, P<0.001), indicating that levels of circulating AAAs and methionine in cirrhosis are determined by hepatic and extra-hepatic metabolic factors. This study demonstrates persistent changes in muscular metabolism of BCAAs after OLT, while the hepatic amino-acid metabolism is normalized due to (1) a significant reduction in the rate of peripheral proteolysis, and (2) improved liver function compared with that in patients with cirrhosis.     

Hypotension and myocardial metabolism

This study investigated the effect of hypotension produced by nitroprusside or halothane on haemodynamics and myocardial metabolism. It is postulated that halothane might influence the balance of supply and demand of oxygen to the heart more favourably than nitroprusside. The results in six open-chested dogs do not support this view. Despite the fact that the two drugs lowered the mean arterial pressure by radically different mechanisms, the reduction in demand for oxygen by the heart seemed to be matched by a similar reduction in supply with both drugs. No evidence of anaerobic metabolism or increased a-v O₂ content differences was found. It is concluded that the reduction in mean arterial pressure to these levels by either method is not likely to impair myocardial energetics in healthy hearts with normal coronary anatomy.     

Organ donation and management of the potential organ donor

Solid organs for transplantation are a scarce and valuable resource. For many patients transplant offers the hope of disease cure but unfortunately demand far exceeds supply and many will die before a suitable organ becomes available. It is important that potential donors are both identified and appropriately managed to ensure that their gift of donation benefits the maximum number of recipients.Both donation after brain death and cardiac death present significant challenges. The pathophysiological changes that accompany brainstem death can significantly reduce the quality of organs retrieved and must be carefully controlled. Donation after cardiac death requires careful coordination to ensure that organs are retrieved in a timely fashion.