Hepatic Lactate Research Articles

Blood lactate and pyruvate levels in the perioperative period of liver resection with pringle maneuver

Bleeding during liver surgery is often routinely controlled by the Pringle maneuver consisting in the temporary clamping of hepatic artery, portal vein, and bile duct. This study aimed at investigating a possible influence of the Pringle maneuver on tissue hypoxia during liver resection. Twenty-five consecutive patients undergoing elective liver resection were prospectively randomized either to be treated with the Pringle maneuver (Pringle group, n = 14) or without clamping (Controls, n = 11). Blood lactate levels, pyruvate levels, and hepatic vein oxygen saturation were monitored perioperatively. Patients were comparable with respect to resection time, intraoperative blood loss, and duration of surgery. The Pringle maneuver induced a significant increase in arterial lactate levels during liver resection when compared to Controls (2.6 +/- 0.3 vs 1.8 +/- 0.2 mmol/l; p < 0.05). Further, the Pringle maneuver significantly increased hepatic venous lactate (3.3 +/- 0.3 vs 1.6 +/- 0.3 mmol/l; p < 0.05) and lactate/pyruvate ratio in hepatic venous blood (43 +/- 8 vs 21 +/- 5; p < 0.05) during surgery. This was paralleled by a temporal decrease in hepatic venous oxygen saturation in the Pringle group (61 +/- 4 vs 73 +/- 4%; p < 0.05). Our findings demonstrate that liver metabolism and tissue oxygenation were markedly affected by occlusion of the liver hilus. Restricting the use of the Pringle maneuver to cases with severe bleeding might therefore be beneficial in patients undergoing liver resection.

Hypotaurine is an Energy-Saving Hepatoprotective Compound against Ischemia-Reperfusion Injury of the Rat Liver

Metabolome analyses assisted by capillary electrophoresis-mass spectrometry (CE-MS) have allowed us to systematically grasp changes in small molecular metabolites under disease conditions. We applied CE-MS to mine out biomarkers in hepatic ischemia-reperfusion. Rat livers were exposed to ischemia by clamping of the portal inlet followed by reperfusion. Metabolomic profiling revealed that l contents of taurine in liver and plasma were significantly increased. Of interest is an elevation of hypotaurine, collectively suggesting significance of hypotaurine/taurine in post-ischemic responses. Considering the anti-oxidative capacity of hypotaurine, we examined if supplementation of the compound or its precursor amino acids could affect hepatocellular viability and contents of taurine in liver and plasma. Administration of hypotaurine, N-acetylcysteine or methionine upon reperfusion comparablly attenuated the post-ischemic hepatocellular injury but with different metabolomic profiling among groups: rats treated with methionine or N-acetylcysteine but not those treated with hypotaurine, exhibited significant elevation of hepatic lactate generation without notable recovery of the energy charge. Furthermore, the group treated with hypotaurine exhibited elevation of the plasma taurine, suggesting that the exogenously administered compound was utilized as an antioxidant. These results suggest that taurine serves as a surrogate marker for ischemia-reperfusion indicating effectiveness of hypotaurine as an energy-saving hepatoprotective amino acid.

The use of β-adrenergic drugs improves hepatic oxygen metabolism in cirrhotic patients undergoing liver resection

Hepatic resection is associated with hemodynamic and oxygen metabolism disturbances of the residual liver resulting from liver regeneration. In underlying liver disease, the remnant liver responds inadequately to increased energy demands leading to a less efficient recovery process. The aim of this study was to assess the effect of vasoactive drugs on hepatic oxygen metabolism and hemodynamics in cirrhotic patients that have undergone liver resection. Thirty patients were randomly allocated to receive peri-operatively low doses (4 microg/kg/min) of dopamine (DaG, n=10), dobutamine (DbG, n=10) or saline (CG, n=10). Hepatic hemodynamics, hepatic oxygen metabolism and lactate uptakes were evaluated before drug administration and at the time of abdominal closure. Post-operative liver function and outcome were recorded. The peri-operative use of vasoactive drugs preserved total hepatic blood flow and hepatic compliance, even increasing in patients who received Db, whereas those parameters decreased in CG after liver resection. At this time, oxygen delivery and consumption decreased in CG patients, but were unchanged when vasoactive drugs were used. In all groups, lactate uptake decreased sharply and only DbG showed positive lactate extraction capacity. The peak of post-operative bilirubin, which resumed baseline values more quickly in DbG, inversely correlated with intra-operative hepatic compliance and hepatic oxygen extraction. Low doses of vasoactive drugs, especially dobutamine, improved hepatic oxygen supply and uptake preserving immediate function of the remnant cirrhotic liver.

Effect of dietary cadmium level on the growth, body composition and several hepatic enzymatic activities of juvenile yellow catfish,Pelteobagrus fulvidraco

The present study was conducted to investigate the effect of dietary cadmium (Cd) level on the growth, body composition and several enzymatic activities of juvenile yellow catfish, Pelteobagrus fulvidraco. The experimental diets were formulated with CdCl2·2.5H2O at levels of 0, 0.01, 0.1 and 1.0 g kg−1 diet, resulting in four dietary Cd levels of 0.25 (control), 4.92, 48.57 and 474.7 mg Cd kg−1 diet respectively. They were fed to juvenile yellow catfish (mean initial weight: 3.26±0.07 g, mean±SD) for 4 weeks. Weight gain, specific growth rate, feed intake and protein efficiency ratio tended to decline with increasing dietary Cd levels (P 0.05). Hepatic alkaline phosphatase, glutathione peroxidase and lactate dehydrogenase activities increased (P 0.05). The present study provided for the first time the toxic assessment of dietborne Cd in yellow catfish, based on growth performance and the changes in hepatic enzymatic activities for the fish species.

Effects of Insulin on the Metabolic Control of Hepatic Gluconeogenesis In Vivo

OBJECTIVEInsulin represses the expression of gluconeogenic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were 1) to determine the maximal physiologic effect of insulin, 2) to determine the relative importance of its effects on gluconeogenic regulatory sites, and 3) to correlate those changes with alterations at the cellular level.RESEARCH DESIGN AND METHODSConscious 60-h fasted canines were studied at three insulin levels (near basal, 4×, or 16×) during a 5-h euglycemic clamp. Pancreatic hormones were controlled using somatostatin with portal insulin and glucagon infusions. Glucose metabolism was assessed using the arteriovenous difference technique, and molecular signals were assessed.RESULTSInsulin reduced gluconeogenic flux to glucose-6-phosphate (G6P) but only at the near-maximal physiological level (16× basal). The effect was modest compared with its inhibitory effect on net hepatic glycogenolysis, occurred within 30 min, and was associated with a marked decrease in hepatic fat oxidation, increased liver fructose 2,6-bisphosphate level, and reductions in lactate, glycerol, and amino acid extraction. No further diminution in gluconeogenic flux to G6P occurred over the remaining 4.5 h of the study, despite a marked decrease in PEPCK content, suggesting poor control strength for this enzyme in gluconeogenic regulation in canines.CONCLUSIONSGluconeogenic flux can be rapidly inhibited by high insulin levels in canines. Initially decreased hepatic lactate extraction is important, and later reduced gluconeogenic precursor availability plays a role. Changes in PEPCK appear to have little or no acute effect on gluconeogenic flux.

Traditional ‘rate‐limiting’ molecular indices of gluconeogenesis do not correlate with flux through the pathway in vivo

Hyperglycemia in type 2 diabetes is due, in part, to elevated gluconeogenesis (GNG). This has been attributed, based largely on in vitro models, to increased mRNA transcription of supposed rate‐limiting enzymes PEPCK and G6Pase. However, in vivo metabolic substrate analysis in man and dog indicate that GNG flux to G6P varies minimally within the physiological range of insulin. We propose that GNG mRNA and protein expression would be decreased during hyperinsulinemic (2.0 mU/kg/min), euglycemic conditions in 24 h fasted conscious dogs subjected to a pancreatic clamp, but that the time course of expression would not correlate with functional GNG flux to G6P. Arterial and hepatic sinusoidal insulin levels increased 8‐fold and glucagon was clamped at basal levels. At 0.5 h, GNG flux to G6P was decreased 50% due to the suppression of lipolysis and a switch from net hepatic lactate uptake to output. Liver FOXO1 phosphorylation was increased 1.9‐fold and GNG enzyme mRNA expression was decreased ~40‐50% at 0.5 h but PEPCK protein levels did not change. By 4 h, GNG mRNA expression was decreased ~80%, and PEPCK protein was reduced by 45%, but GNG flux to G6P had stabilized at near‐basal levels. Thus, while insulin can inhibit GNG gene transcription and protein expression in vivo, these changes do not result in functional changes in substrate flux in the GNG pathway, indicating PEPCK was not a rate‐limiting marker for GNG in vivo.

Tezosentan normalizes hepatomesenteric perfusion in a porcine model of cardiac tamponade

To investigate endothelin-1 (ET-1)-dependent hepatic and mesenteric vasoconstriction, and oxygen and lactate fluxes in an acute, fixed low cardiac output (CO) state. Sixteen anesthetized, mechanically ventilated pigs were studied. Cardiac tamponade was established to reduce portal venous blood flow (Q(PV)) to 2/3 of the baseline value. CO, hepatic artery blood flow (Q(HA)), Q(PV), hepatic laser-Doppler flow (LDF), hepatic venous and portal pressure, and hepatic and mesenteric oxygen and lactate fluxes were measured. Hepatic arterial (R(HA)), portal (R(HP)) and mesenteric (R(mes)) vascular resistances were calculated. The combined ET(A)-ET(B) receptor antagonist tezosentan (RO 61-0612) or normal saline vehicle was infused in the low CO state. Measurements were made at baseline, after 30, 60, 90 min of tamponade, and 30, 60, 90 min following the infusion of tesozentan at 1 mg/kg/h. Tamponade decreased CO, Q(PV), Q(HA), LDF, hepatic and mesenteric oxygen delivery, while hepatic and mesenteric oxygen extraction and lactate release increased. R(HA), R(HP) and R(mes) all increased. Ninety minutes after tesozentan, Q(PV), LDF and hepatic and mesenteric oxygen delivery and extraction increased approaching baseline values, but no effect was seen on CO or Q(HA). Hepatic and mesenteric handling of lactate converted to extraction. R(HA), R(HP) and R(mes) returned to baseline values. No changes were observed in these variables among control animals not receiving tesozentan. In a porcine model of acute splanchnic hypoperfusion, unselective ET-1 blockade restored hepatomesenteric perfusion and reversed lactate metabolism. These observations might be relevant when considering liver protection in low CO states.

Protective effect of Cassia glauca Linn. on the serum glucose and hepatic enzymes level in streptozotocin induced NIDDM in rats.

Objective:The objective of the present study was to investigate the hypoglycemic and hepatoprotective effect of Cassia glauca leaf extracts on normal and non insulin dependent diabetes mellitus (NIDDM) in rats. The study was further carried out to investigate the effect of different fractions of the active extract of Cassia glauca, on normal and NIDDM rats, and the effect of active fraction on the blood glucose and hepatic enzymes level.Methods:Diabetes was induced by streptozotocin (STZ) at a dose of 90mg/kg, i.p. in neonates. Different extracts of cassia glauca (100mg/kg, p.o.) were administered to the diabetic rats. Acetone extract was found to lower the serum glucose level significantly in diabetic rats. Further, the acetone extract was subjected to column chromatography and four fractions were obtained on the basis of TLC. All the four fractions (100mg/kg, p.o.) were administered to the diabetic rats. Fraction 1 (F1) caused the maximum reduction in the blood glucose level. The results of the test were compared with the standard antidiabetic drug glibenclamide (5mg/kg, p.o.).Results:Fraction 1 of acetone extract caused a significant reduction in the levels of hepatic enzyme Aspartate transaminase (AST), alanine transaminase (ALT), creatine kinase (CK), and lactate dehydrogenase (LDH) in STZ-induced diabetic rats.Conclusion:Improvement in the blood sugar level and normalization of liver functions by Cassia glauca indicates that the plant has hepatoprotective potential, along with antidiabetic activity, and it provides a scientific rationale for the use of Cassia glauca as an antidiabetic agent.

Unique Case of Giant Adult Paratesticular Spindle Cell Rhabdomyosarcoma

A 50-year-old unmarried rural man was referred for a giant painless scrotal lump which had developed over a period of about six years. At the admission physical examination disclosed a large swelling scrotum and palpable left supraclavicular lymph nodes. Blood counts, renal and hepatic function tests, lactate dehydrogenase, beta-HCG, and alpha-fetoprotein were normal. Computed tomographic scan of thorax and abdomen revealed supraclavicular, mediastinal, and retroperitoneal adenopathies. The patient underwent right-sided radical orchiectomy. The final pathological diagnosis was paratesticular spindle cell rhabdomyosarcoma. Unfortunately, few days after surgery, patient presented a clinical and laboratory picture of disseminated intravascular coagulation followed by exitus.

Human adrenomedullin combined with human adrenomedullin binding protein-1 is protective in gut ischemia and reperfusion injury in the rat

Previous studies have demonstrated that co-administration of rat adrenomedullin (AM) and human AM binding protein-1 (AMBP-1) has various beneficial effects following adverse circulatory conditions. In order to reduce rat proteins to elicit possible immune responses in humans, we determined the effect of human AM combined with human AMBP-1 after intestinal ischemia and reperfusion (I/R). Intestinal ischemia was induced in the rat by occluding the superior mesenteric artery for 90 min. At 60 min after the beginning of reperfusion, human AM/AMBP-1 at 3 different dosages was administered intravenously over 30 min. At 240 min after the treatment, blood and tissue samples were harvested and measured for pro-inflammatory cytokines (i.e., TNF-α and IL-6), myeloperoxidase activities in the gut and lungs, and cleaved caspase-3 expression in the lungs, as well as serum levels of hepatic enzymes and lactate. In additional groups of animals, a 10-day survival study was conducted. Results showed that administration of human AM/AMBP-1 reduced pro-inflammatory cytokines, attenuated organ injury, and improved the survival rate in a seemingly dose–response fashion. Co-administration of the highest dose of human AM/AMBP-1 in this study had the optimal therapeutic effect in the rat model of intestinal I/R.

Dichloroacetate stabilizes the intraoperative acid-base balance during liver transplantation

Lactic acidosis occurs during orthotopic liver transplantation (OLT), especially during the anhepatic and early postreperfusion phases. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase-1, indirectly activating mitochondrial pyruvate dehydrogenase. This, in turn, markedly reduces systemic lactate production and, to a lesser extent, increases hepatic lactate uptake. The result is moderation of lactic acidosis in many clinical conditions. This study evaluated the efficacy of DCA in controlling lactic acidosis during OLT and improving perioperative outcome from OLT. After informed consent, 250 patients for OLT received either intraoperative DCA or placebo. DCA (40 mg/kg intravenously) or placebo was administered after anesthesia induction and repeated 4 hours later. Intraoperative measures were arterial blood gases, lactate, and Na+ and utilization of blood products, CaCl2, and NaHCO3. Outcome measures were time to tracheal extubation, intensive care unit length of stay, hospital length of stay, requirement for postoperative plasma transfusion, retransplantation, and perioperative mortality. DCA reduced the arterial lactic acid concentration by an average of 44% (1.8 mmol L(-1), P < 0.001), stabilized the acid-base balance, and reduced NaHCO(3) administration by 80% (P < 0.001). Postoperatively, DCA-treated patients required 50% less postoperative plasma transfusion (2 versus 4 units, respectively, P = 0.016), but the incidence of transfusion was similar in both groups (62% versus 60%, P = 0.381). DCA did not alter time to extubation, intensive care unit length of stay, or hospital length of stay. In conclusion, DCA attenuated lactic acidosis during OLT, stabilizing the intraoperative acid-base balance and decreasing NaHCO3 use. DCA decreased postoperative plasma transfusion requirement but otherwise had no measurable effect on perioperative outcome parameters.

Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration

IntroductionLow blood pressure, inadequate tissue oxygen delivery and mitochondrial dysfunction have all been implicated in the development of sepsis-induced organ failure. This study evaluated the effect on liver mitochondrial function of using norepinephrine to increase blood pressure in experimental sepsis.MethodsThirteen anaesthetized pigs received endotoxin (Escherichia coli lipopolysaccharide B0111:B4; 0.4 μg/kg per hour) and were subsequently randomly assigned to norepinephrine treatment or placebo for 10 hours. Norepinephrine dose was adjusted at 2-hour intervals to achieve 15 mmHg increases in mean arterial blood pressure up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic (ultrasound Doppler) blood flow were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometry) were assessed.ResultsMean arterial pressure (mmHg) increased only in norepinephrine-treated animals (from 73 [median; range 69 to 81] to 63 [60 to 68] in controls [P = 0.09] and from 83 [69 to 93] to 96 [86 to 108] in norepinephrine-treated animals [P = 0.019]). Cardiac index and systemic oxygen delivery (DO2) increased in both groups, but significantly more in the norepinephrine group (P < 0.03 for both). Cardiac index (ml/min per·kg) increased from 99 (range: 72 to 112) to 117 (110 to 232) in controls (P = 0.002), and from 107 (84 to 132) to 161 (147 to 340) in norepinephrine-treated animals (P = 0.001). DO2 (ml/min per·kg) increased from 13 (range: 11 to 15) to 16 (15 to 24) in controls (P = 0.028), and from 16 (12 to 19) to 29 (25 to 52) in norepinephrine-treated animals (P = 0.018). Systemic oxygen consumption (systemic VO2) increased in both groups (P < 0.05), whereas hepatosplanchnic flows, DO2 and VO2 remained stable. The hepatic lactate extraction ratio decreased in both groups (P = 0.05). Liver mitochondria complex I-dependent and II-dependent respiratory control ratios were increased in the norepinephrine group (complex I: 3.5 [range: 2.1 to 5.7] in controls versus 5.8 [4.8 to 6.4] in norepinephrine-treated animals [P = 0.015]; complex II: 3.1 [2.3 to 3.8] in controls versus 3.7 [3.3 to 4.6] in norepinephrine-treated animals [P = 0.09]). No differences were observed in citrate synthase activity.ConclusionNorepinephrine treatment during endotoxaemia does not increase hepatosplanchnic flow, oxygen delivery or consumption, and does not improve the hepatic lactate extraction ratio. However, norepinephrine increases the liver mitochondria complex I-dependent and II-dependent respiratory control ratios. This effect was probably mediated by a direct effect of norepinephrine on liver cells.

Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease

More than 70% of alcohol is consumed by 10% of the population in the United States. Implicit in this statistic is that tremendous variation in the pattern of drinking (quantity, frequency, and duration) exists among alcohol consumers. Individuals who are binge or chronic drinkers will have different health outcomes than social drinkers. Therefore, knowing the pattern of drinking will shed light on how severely individuals are alcohol-dependent and on the extent of liver damage. Thus, these parameters assume particular relevance for the treatment-providing physician. Genetic factors contribute substantially to differences in alcohol metabolism. Variations in the activities of the alcohol-metabolizing enzymes, cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, in part determine blood alcohol concentration, thereby contributing to the predisposition to becoming alcohol-dependent and to susceptibility to alcohol-induced liver damage. Chronic alcohol consumption induces cytochrome P450 2E1, a microsomal enzyme that metabolizes alcohol at high concentrations and also metabolizes medications such as acetaminophen and protease inhibitors. Alcohol metabolism changes the redox state of the liver, which leads to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The quantity and frequency of alcohol consumption severely impact the liver in the presence of comorbid conditions such as infection with hepatitis B or C and/or human immunodeficiency virus, type 2 diabetes, hemochromatosis, or obesity and thus have implications with respect to the extent of injury and response to medications. Knowledge of the relationships between the quantity, frequency, and patterns of drinking and alcoholic liver disease is limited. A better understanding of these relationships will guide hepatologists in managing alcoholic liver disease.

Oxidative stress and matrix metalloproteinase-9 activity in the liver after hypoxia and reoxygenation with 21% or 100% oxygen in newborn piglets

We designed a randomized controlled study to identify and compare the liver tissue responses in systemic hypoxia and resuscitation with 21% and 100% oxygen using an animal model of neonatal hypoxia and reoxygenation. Twenty-seven piglets (1–3 days old, weight 1.5–2.0 kg) were acutely instrumented and mechanically ventilated. The animals underwent 2 h of normocapnic alveolar hypoxia (10–15% oxygen) then reoxygenation with 21% or 100% oxygen for 1 h, then 1 h with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. After 2 h of reoxygenation liver tissue samples were immediately processed for histological and biochemical analyses of markers of oxidative stress and tissue injury. Two hours of hypoxia caused a significant reduction in mean arterial pressure with cardiogenic shock and metabolic acidemia, with similar recovery upon resuscitation with 21% and 100% oxygen. After 2 h of reoxygenation, the hepatic GSSG:total glutathione ratio and matrix metalloproteninase-9 activity, which correlated with the portal venous oxygenation at 15 min of reoxygenation, were greater in the 100% group and hepatic lactate level was higher in the 21% group than the controls (all P<0.05). Both hypoxic-reoxygenated groups had similarly elevated hepatic Bcl-2 levels. Apart from more non-distinct mitochondria identified in the 100% group, hepatic tissue adenylate energy charge and plasma transaminases levels did not differ among groups. We concluded that in this acute model of neonatal hypoxia and reoxygenation, resuscitation using 21% oxygen avoids the excess oxidative stress and elevated matrix metalloproteninase-9 activity in the liver when 100% oxygen was used. The study supports the conservative use of oxygen in optimizing post-hypoxic hepatic recovery.

Effects of free fatty acids on carbohydrate metabolism and insulin signalling in perfused rat liver

Elevated circulating free fatty acids (FFAs) induce insulin resistance and play a crucial role in the development of type 2 diabetes, in which fasting hepatic glucose production (HGP) is increased. However, direct effects of FFAs on fasting HGP are still unclear because indirect endocrine and metabolic effects contribute to FFA action. Thus, we aimed to investigate acute direct effects of specific FFAs on fasting HGP, lactate uptake, and insulin signalling. Isolated livers obtained from 20 h fasted rats were perfused with albumin-bound palmitate or oleate (200 micromol L(-1) each) or vehicle (control) for 180 min (n = 5-7/group). Compared to control, hepatic lactate uptake was increased by palmitate and oleate (~+40%; P < 0.05), while HGP from lactate (~3 mmol L(-1)) and liver glycogen content were similar. Tyrosine phosphorylation (pY) of insulin-receptor-substrate-(IRS)-2 and p70S6-kinase phosphorylation were not affected by FFAs. Palmitate decreased insulin-receptor-beta pY, IRS-1 pY and phosphoinositol-3-kinase expression by 46 +/- 16%, 46 +/- 11% and 20 +/- 9%, respectively (P < 0.03), while oleate reduced Akt phosphorylation by 85 +/- 7% (P < 0.006). Isolated liver perfusion with saturated or unsaturated FFAs reduced insulin signalling protein phosphorylation at different sites and increased lactate uptake without affecting HGP or glycogen content. These results suggest that at fasting, both saturated and unsaturated FFAs increase hepatic glucose precursor uptake and may, independently of insulin's presence, accelerate protein dephosphorylation of the insulin signalling cascade at different sites.

Hepatic lactate uptake versus leg lactate output during exercise in humans

The exponential rise in blood lactate with exercise intensity may be influenced by hepatic lactate uptake. We compared muscle-derived lactate to the hepatic elimination during 2 h prolonged cycling (62 +/- 4% of maximal O(2) uptake, (.)Vo(2max)) followed by incremental exercise in seven healthy men. Hepatic blood flow was assessed by indocyanine green dye elimination and leg blood flow by thermodilution. During prolonged exercise, the hepatic glucose output was lower than the leg glucose uptake (3.8 +/- 0.5 vs. 6.5 +/- 0.6 mmol/min; mean +/- SE) and at an arterial lactate of 2.0 +/- 0.2 mM, the leg lactate output of 3.0 +/- 1.8 mmol/min was about fourfold higher than the hepatic lactate uptake (0.7 +/- 0.3 mmol/min). During incremental exercise, the hepatic glucose output was about one-third of the leg glucose uptake (2.0 +/- 0.4 vs. 6.2 +/- 1.3 mmol/min) and the arterial lactate reached 6.0 +/- 1.1 mM because the leg lactate output of 8.9 +/- 2.7 mmol/min was markedly higher than the lactate taken up by the liver (1.1 +/- 0.6 mmol/min). Compared with prolonged exercise, the hepatic lactate uptake increased during incremental exercise, but the relative hepatic lactate uptake decreased to about one-tenth of the lactate released by the legs. This drop in relative hepatic lactate extraction may contribute to the increase in arterial lactate during intense exercise.

Leishmania chagasi: Cytotoxic effect of infected macrophages on parenchymal liver cells

Leishmania ( Leishmania) chagasi, the ethiological agent of New World visceral leishmaniasis, causes morphological and functional injury to the liver. To investigate the role of macrophage-released leishmanicidal factors in hepatocyte damage, we used a co-culture model of hepatocytes and L. chagasi promastigote-infected peritoneal macrophages obtained from C57BL/6 or BALB/c mice. C57BL/6 macrophages killed intracellular parasites more efficiently than BALB/c macrophages, leading to higher number of intracellular amastigotes in the BALB/c culture during the entire course of infection. Early TNF-α production led to macrophages activation resulting in parasite growth control. Hepatic transaminases and lactate dehydrogenase were present at high levels in the supernatants of both co-cultures; concurrently, parasites were eliminated from infected macrophages. Nitric oxide production was higher in C57BL/6 co-cultures than in BALB/c co-cultures. Inhibitors of the oxidative burst and secreted proteinases protected hepatocytes against toxicity, and treatment with an inducible nitric oxide synthase inhibitor fully impeded the enzyme release. Our data suggest that the intracellular cytotoxic effects elicited by macrophages for parasite destruction are directly associated with hepatocyte damage, and that nitric oxide plays a pivotal role in this phenomenon.

Quantitative analysis of liver metabolites in three stages of the circannual hibernation cycle in 13-lined ground squirrels by NMR

Thirteen-lined ground squirrels and other circannual hibernators undergo profound physiological changes on an annual basis, transitioning from summer homeothermy [body temperature (T(b)) approximately 37 degrees C] to winter heterothermy (T(b) cycling between 0 degrees C and 37 degrees C). We hypothesize that these physiological changes are reflected in biochemical changes that provide mechanistic insights into, and biomarkers for, hibernation states. Here we report the results of an NMR-based metabolomics analysis of liver extracts from ground squirrels in three distinct physiological states of circannual hibernation: summer active (SA), late torpor (LT), and reentering torpor (Ent) after one of the euthermic arousals. Of the 43 identified and quantified metabolites, 36 differed among these three states and fell into two patterns of variation: 1) SA differed from both of the two winter states; or 2) the two winter states differed from each other, but one of the two was not different from SA. Concentrations of hepatic glucose, lactate, alanine, succinate, beta-hydroxybutyrate, glutamine, and betaine were identified as robust hepatic biomarkers that together distinguish among animals in these three states of the circannual hibernation rhythm. These data are consistent with a proposed two-switch model of hibernation, in which setting the summer-winter switch to winter enables expression of a distinct torpor-arousal switch. The summer-winter switch is characterized by the metabolites associated with the well-known switch from carbohydrate to lipid fuel utilization during hibernation. The torpor-arousal switch is characterized by the accumulation of metabolites of nitrogen (glutamine) and phospholipid (betaine) catabolism in LT with the capacity to act as protective osmolytes.

Severe myalgia associated with propofol sedation

EDITOR: Propofol is used when deep sedation, immobilization and quick emergence are required and is often used in children during magnetic resonance imaging (MRI) scans. Because the MRI scan is prolonged, a propofol infusion or repetitive small boluses are usually administered. A 13-yr-old patient (weight 44 kg), underwent MRI scan of the head for evaluation of recurrent headaches. The patient was otherwise healthy and a neurological examination performed by a paediatric neurologist was unremarkable. The patient received during the MRI scan a total dose of 120 mg propofol and was fully awakened at the end of the scan. An hour later, the patient complained of progressive pain in both of her calves. A physical examination revealed severe disabling muscle pain in both legs. No other abnormalities were found. Full blood count, biochemical analysis, and creatine–phosphate kinase levels were within normal range. Urinalysis was normal. No fever or haemodynamic abnormalities were found. After 3 days the muscle pain began to decrease and the patient was discharged 2 days later with minor myalgia. The MRI scan of the head was normal. The patient’s guardians refused muscle biopsy. Postoperative myalgia is a common complication which is usually associated with muscle relaxants and surgical stress. In the described case the patient was sedated solely with propofol for head MRI scan and developed severe myalgia. There are two possible causes for this presentation: propofol infusion syndrome and toxic myopathy. Several reports described the ‘propofol infusion syndrome’, occurring in patients receiving prolonged high-dose infusions of propofol (>75 μg kg−1 min−1 for >24 h) [1-3]. Most of these cases occurred in critically ill patients. The syndrome is characterized by severe metabolic acidosis, myocardial dysfunction, rhabdomyolysis, myoglobinuria, renal failure, hypoxia and death. The mechanism of muscle toxicity is unknown. Muscle pathology reveals necrosis of skeletal and cardiac muscle. Discontinuation of propofol with supportive therapy for myoglobinuria, metabolic acidosis, hyperkalaemia and renal failure is the mainstay of treatment [4]. The pathogenesis of propofol infusion syndrome is not fully explained and potential mechanisms include lactic acidosis, metabolic acidosis and mitochondrial toxicity. Lactic acid production is caused by low cardiac output or a regional steal syndrome due to propofol influence as a cardiodepressant, cardiac failure or septic shock. Metabolic acidosis may be caused by impaired hepatic lactate metabolism. Supportive evidence includes the development of a fatty or enlarged liver [5]. Intermediate dihydroxylated products of propofol are thought to have mitochondrial toxicity which could cause metabolic acidosis. Furthermore, there might be an occult mitochondrial dysfunction in the subjects who developed the syndrome [5,6]. Muscle tissue is highly sensitive to drugs and toxins because of its high metabolic activity and multiple potential sites for foreign substances to disrupt the energy-producing pathways. Children have reduced ability to metabolize or excrete drugs and thus have increased risk for toxic myopathy [7]. The exact incidence of toxic myopathy is unknown, but probably is often unrecognized. Early recognition of toxic myopathy is important since the likelihood of complete resolution is higher with early removal of the offending toxin. The diagnosis is based on lack of other known aetiology for the myopathy, lack of previous muscular symptoms and resolution of the symptoms after withdrawal of the suspected toxic agent. Drugs or toxins can produce mild symptoms of muscle pain and cramps, as in the patient we described, or cause a severe weakness, rhabdomyolysis, hyperkalaemia and renal failure [7]. In conclusion, this case of severe myalgia following propofol infusion might be caused by either a mild form of propofol infusion syndrome or toxic myopathy. Anaesthesia care providers should be aware of this complication and its causes.

Correlation of transcutaneous hepatic near‐infrared spectroscopy readings with liver surface readings and perfusion parameters in a piglet endotoxemic shock model

To determine whether transcutaneous liver near-infrared spectrophotometry (NIRS) measurements correlate with NIRS measurements taken directly from the liver surface, and invasive blood flow measurements. Laparotomy was performed in 12 Yorkshire piglets, and ultrasound blood flow probes were placed on the hepatic artery and portal vein. Intravascular catheters were inserted into the hepatic and portal veins for intermittent blood sampling, and a pulmonary artery catheter was inserted via the jugular vein for cardiac output measurements. NIRS optodes were placed on skin overlying the liver and directly across the right hepatic lobe. Endotoxemic shock was induced by continuous infusion of Escherichia coli lipopolysaccharide O55:B5. Pearson's correlations were calculated between the NIRS readings and the perfusion parameters. After endotoxemic shock induction, liver blood flow, and oxygen delivery decreased significantly. There were statistically significant correlations between the transcutaneous and liver-surface NIRS readings for oxyhemoglobin, deoxyhemoglobin, and cytochrome c oxidase concentrations. There were similar significant correlations of the transcutaneous oxyhemoglobin with both the mixed venous and hepatic vein saturation, and mixed venous and hepatic vein lactate. Transcutaneous NIRS readings of the liver, in an endotoxemic shock model, correlate with NIRS readings taking directly from the liver surface, as well as with global and specific organ-perfusion parameters.