Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

 By using homozygosity mapping and positional cloning, we have shown that adult-onset type II citrullinemia (CTLN2) is caused by mutations of the SLC25A13 gene, which is localized on chromosome 7q21.3 and encodes a mitochondrial solute carrier protein named citrin. So far, we have reported nine mutations, most of which cause loss of citrin, and we have established several methods for DNA diagnosis. These methods have shown that more than 90% of the patients diagnosed as suffering from CTLN2 by enzymatic analysis carry SLC25A13 mutations in both alleles, indicating that CTLN2 is caused by citrin deficiency. Furthermore, by using the same DNA diagnosis methods, we discovered that 70 neonates or infants suffering from a particular type of neonatal hepatitis carry the same SLC25A13 mutations. Since the symptoms of the neonates are different from those of the more severe CTLN2 and usually ameliorate without special treatment, we designated the neonatal disease neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). We conclude that citrin deficiency causes NICCD in neonates and CTLN2 in adults through the additional effects of genetic or environmental modifiers. Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle. It is, however, still difficult to understand the cause of the hepatic deficiency of argininosuccinate synthetase protein in CTLN2. Received: March 20, 2002 / Accepted: March 28, 2002     

The development of excitatory transmitter amino acid-containing neurons in the rat visual cortex

The excitatory amino acids l-glutamate and l-aspartate are believed to be utilized as neurotransmitters by the pyramidal neurons in the mammalian cerebral cortex. These cells can be recognized early in development, while glutamate might play an important part in the maturation and plasticity of the cortex. Here, we used light and electron microscopic immunocytochemistry to study the time of appearance and maturation of glutamate and aspartate in neurons of the rat visual cortex. Glutamate- and aspartate-immunoreactive cells were first detected in deep cortical layers at postnatal day 3. During the next 3 weeks, labelled neurons were observed progressively in more superficial layers, but did not demonstrate their adult pattern of distribution until postnatal week 4. Electron microscopic analysis showed that glutamate- and aspartate-labelled neurons gradually develop their cytological and synaptic features during the first 4 postnatal weeks, with this process of differentiation originating in the deep cortical layers and progressively extending to the superficial layers. These findings suggest that cortical pyramidal neurons begin to express detectable levels of transmitter glutamate and/or aspartate after they have completed their migration. Their neurochemical differentiation follows an inside-out pattern similar to the pattern described for the genesis and morphological differentiation of this population of cortical neurons.     

Changes in glutamate-related enzyme activities in the striatum of the rat following lesion of corticostriatal fibres

Summary The behaviour of enzymes putatively involved in glutamate/aspartate transmitter metabolism (glutamate dehydrogenase, aspartate aminotransferase, alanine aminotransferase,-glutamyltranspeptidase) was studied in the striatum 3, 7, 14 days and 7 weeks after mechanical destruction of corticostriatal fibres. For a period of up to seven days after unilateral lesion, enzyme activities were significantly diminished (by up to 13% based on protein) in the ipsilateral striatum as compared to the striatum of the intact side. Later, the enzyme activities in the ipsilateral striatum recovered. After seven weeks, an increase was observed for glutamate dehydrogenase activity, whereas the activity of alanine aminotransferase showed a transient rise at the end of the second week. The decrease in enzyme levels is interpreted as being attributable to the destruction of nerve endings which are considered to be glutamatergic, interfering with various compensating processes (e.g. glial cell proliferation) which occur with advancing times after lesion.     

Comparison of glutamate metabolism in low K (LK), high K and high glutathione (HK/HG) and high K and low glutathione (HK/LG) dog red blood cells

The reasons for the high accumulation of glutamate (Glu), aspartate (Asp) and glutamine (Gin) in high K and high glutathione (HK/HG) dog red blood cells (DRBCs) have been explained as due to enhanced Glu/Asp influxes. However, in our study, Glu/Asp influxes in high K and low glutathione (HK/LG) DRBCs were low, whereas their cellular Asp and Gin contents were high. In low K (LK) DRBCs, there were also other variant cells with high Asp accumulation, but extremely low Glu/Asp influxes. So, the high amino acid accumulation in DRBCs of these new variants might not be due to Glu/Asp influxes. To examine the high accumulation of these amino acids in these variant DRBCs, first, LK and HK/LG DRBCs were classified into two subgroups with their Na-dependent Glu/Asp influxes; one had clear Na-dependent Glu/Asp transport (GAT⁺), and the other failed to have any transport (GAT⁻). The influxes of both Glu and Asp in HK/HG DRBCs were the highest, and the order was HK/HG>LK/GAT⁺>HK/LG/GAT⁺>>LK/GAT⁻=HK/LG/GAT⁻. LK/GAT⁺ cells represented normal DRBCs. Glu/Asp influxes were only trace in both LK/GAT⁻ and HK/LG/GAT⁻ cells, but Glu and Asp concentration was high in HK/LG/GAT⁻ cells whereas Asp concentration was high in LK/GAT⁻ cells. In HK/HG cells, the conversion of Glu into Gin in whole cells was several fold higher than in the other cell groups due to the differing amount of the substrate of glutamine synthetase, Glu, but glutamine synthetase activity itself was not different among these cell groups. Furthermore, glutamine synthetase and glutaminase activities were not different among the cell groups. Therefore, these enzymes were not involved in the high amino acid accumulation.     

Hypothermia decreases excitatory neurotransmitter release in bacterial meningitis in rabbits

The excitatory neurotransmitters glutamate (GLU) and aspartate (ASP) are involved in the pathogenesis of neuronal injury in meningitis. Based on past findings that the induction of moderate hypothermia (32-34 degrees C) attenuates the release of GLU in ischemic brain injury, this study was designed to detect if the application of moderate hypothermia decreases the release of excitatory amino acids (EAA) from brain tissue of animals with bacterial meningitis. Also examined was whether meningitis induces the expression of 72-kDa heat shock protein (HSP 70) in the cerebellum and how hypothermia affects it, for induction of HSP 70 has been used as a sensitive marker of neuronal stress in other forms of brain injury. Meningitis was induced by injecting Group B Streptococcus (GBS) into the cisterna magnae of rabbits. Antibiotic treatment began 16 h later. At this time the animals were anesthetized, instrumented, and randomized to normothermic (Nor) or hypothermic (Hy) conditions. Temperatures were strictly regimented for the following 10 h while maintaining stable cardiorespiratory parameters. Cerebrospinal fluid (CSF) samples were then withdrawn to measure concentrations of bacteria, protein, and amino acids. Meningitis causes CSF contents of GLU and ASP to increase significantly. Hypothermia treated animals demonstrated a 40-50% reduction in CSF GLU and ASP. Meningitis induced the expression of HSP 70 in the cerebellum while hypothermic animals experienced a significant decrease HSP 70 induction. These data demonstrate that hypothermia produces an attenuation of the release of excitatory neurotransmitters in meningitis and suggest that this treatment may attenuate neuronal stress.     

Motor effects following application of putative excitatory amino acid antagonists to the region of the mesencephalic dopamine cell bodies in the rat

Summary The excitatory amino acid antagonists 2-amino-5-phosphonovalerate and -D-glutamylglycine have been applied focally to the ventral tegmental area and both the pars compacta and pars reticulata of the substantia nigra of the rat. The injections were performed under halothane anaesthesia so that behavioural effects could be observed 5 min afterwards. Bilateral application of either antagonist to the ventral tegmental area and the pars compacta of the substantia nigra induced enhanced locomotor activity in an open field. This effect was blocked by pretreatment of the animals with a low dose of the dopamine receptor antagonist fluphenazine. Bilateral application of either antagonist to the pars reticulata of the substantia nigra produced sedation and a reduction in locomotor activity. Unilateral injection of either of the excitatory amino acid antagonists into the pars reticulata or pars compacta of the substantia nigra both resulted in contraversive circling behaviour The effect of intranigral (both pars compacta and reticulata) 2-APV and -DGG was accompanied by a significant increase in concentrations of both 3,4-dihydroxyphenylacetic acid (to 158–160% of control following injection into pars compacta, and 134–146% of control injected into pars reticulata) and homovanillic acid (to 161–166% of control following injection into pars compacta, and 186–210% of control injected into pars reticulata) in the ipsilateral, striatum. Pretreatment of these animals with fluphenazine (0.3 mg/kg) antagonized this circling behaviour.These results indicate that antagonism, of excitatory amino acid receptors in the region of the midbrain of the rat leads to specific behavioural effects, which may in part be mediated through the ascending dopaminergic projections.Abbreviations used 2-APV 2-amino-5-phosphonovaleric acid - -DGG -D-glutamylglycine - SN substantia nigra - VTA ventral tegmental area - HVA homovanillic acid - DOPAC 3,4-dihydroxyphenylacetic acid A preliminary communication of this work was presented to the British Pharmacological Society in Bradford, April 1981     

N-甲基-D-天门冬氨酸受体及其调控的钙内流在大鼠感染性脑损伤中的变化

为探讨Ｎ－甲基－Ｄ－天门冬氨酸（ＮＭＤＡ）受体及其调控的钙内流在感染性脑损伤发病机制中的作用，采用Ｆｕｒａ－２／Ａｍ荧光法检测大鼠大脑皮质突触体内游离钙浓度（［Ｃａ＋＋］ｉ）。结果表明，注射百日咳杆菌组的［Ｃａ＋＋］ｉ较对照组显著增加（Ｐ均＜０．０１），并与注菌时间呈正相关关系（４小时ｖｓ０．５小时和２４小时ｖｓ４小时，Ｐ＜０．０５和＜０．０１）。ＮＭＤＡ受体的非竞争性拮抗剂ＭＫ－８０１预处理组（ＭＢＰ）的［Ｃａ＋＋］ｉ、脑含水量和伊文思蓝含量均较注菌组显著减少（Ｆ值分别为７２．２５、１６．８９、１４．３６，Ｐ＜０．０１和＜０．０５），并以２４小时［Ｃａ＋＋］ｉ减少最为明显（Ｐ＜０．０１）。提示ＮＭＤＡ受体调控的神经元内钙超载在感染性脑损伤、尤其在迟发性脑损伤的发病机制中起着重要作用。