Increased Levels Of Glutamine Research Articles

Plasma Metabolic and Lipidomic Fingerprinting of Individuals with Increased Intestinal Permeability.

The dual-sugar intestinal permeability test is a commonly used test to assess changes in gut barrier function. However, it does not identify functional changes and the exact mechanism of damage caused by the increased intestinal permeability. This study aims to explore the application of untargeted metabolomics and lipidomics to identify markers of increased intestinal permeability. Fifty fasting male participants (18–50 years) attended a single visit to conduct the following procedures: assessment of anthropometric measures, assessment of gastrointestinal symptoms, intestinal permeability test, and assessment of blood samples 90 min post-administration of the intestinal permeability test. Rhamnose and lactulose were analysed using gas chromatography-mass spectrometry (GC-MS). Untargeted polar metabolites and lipidomics were assessed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF MS). There was an elevated lactulose/rhamnose ratio in 27 subjects, indicating increased permeability compared to the remaining 23 control subjects. There were no significant differences between groups in characteristics such as age, body mass index (BMI), weight, height, and waist conference. Fourteen metabolites from the targeted metabolomics data were identified as statistically significant in the plasma samples from intestinal permeability subjects. The untargeted metabolomics and lipidomics analyses yielded fifteen and fifty-one statistically significant features, respectively. Individuals with slightly elevated intestinal permeability had altered energy, nucleotide, and amino acid metabolism, in addition to increased glutamine levels. Whether these biomarkers may be used to predict the early onset of leaky gut warrants further investigation.

Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes.

Dysregulation of skeletal muscle metabolism influences whole-body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes–associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlates inversely with BMI and insulin resistance index (HOMA-IR) in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulate the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase in glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.

Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors.

Rationale: Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity.Methods: A syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion.Results: We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice.Conclusions: Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.

Beta-catenin mutations in hepatocellular cancer, tumor cell metabolism, and the response of these tumors to mTOR inhibition.

583 Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.

Glutamatergic function in a genetic high-risk group for psychosis: A proton magnetic resonance spectroscopy study in individuals with 22q11.2 deletion

Glutamatergic dysregulation is one of the leading theories regarding the pathoaetiolopy of schizophrenia. Meta-analysis of magnetic resonance spectroscopy studies in schizophrenia shows increased levels of glutamate and glutamine (Glx) in the medial frontal cortex and basal ganglia in clinical high-risk groups for psychosis and increased glutamine levels in the thalamus, but it is unclear if this is also the case in people at genetic high risk for psychosis. The aim of this study was to investigate glutamatergic function in the anterior cingulate cortex, striatum and thalamus in carriers of a genetic variant (22q11.2 deletion) associated with a high risk for psychosis. 53 volunteers (23 22q11.2 deletion carriers and 30 controls) underwent proton magnetic resonance spectroscopy imaging and neuropsychological assessments for prodromal psychotic symptoms, schizotypy, anxiety, depression and FSIQ. We did not find any difference between groups in Glx in the anterior cingulate cortex, striatum or thalamus (Glx: t(50)=-1.26, p = 0.21; U = 251, z = −0.7, p = 0.49; U = 316, z= -0.26, p = 0.79, respectively). No correlation was detected between Glx levels in any region and symptomatology or FSIQ. Our findings indicate that glutamatergic function is not altered in people at genetic high risk of psychosis due to the 22q11.2 deletion, which could suggest that this is not the mechanism underlying psychosis risk in 22q11.2 deletion carriers.

Metabolite biomarkers of chlorothalonil exposure in earthworms, coelomic fluid, and coelomocytes

Earthworm (Eisenia fetida) metabolomics is a useful indicator of toxicant exposure. Extracts of whole earthworms are most commonly used to measure metabolic perturbations, in addition to coelomic fluid which has been used on a more limited basis. Coelomocytes are free moving cells found within earthworm coelomic fluid, and the potential of this compartment has not been evaluated for its utility in earthworm metabolomics. In this study, earthworms were exposed to 18.5 and 37.0 mg/kg chlorothalonil, a commonly used fungicide that targets glutathione. The metabolic impacts of a 14-day chlorothalonil exposure were assessed using 1H NMR and targeted LC-MS measurements of earthworm, coelomic fluid, and coelomocyte extracts. Coelomic fluid was identified as the most sensitive matrix for measuring the effects of chlorothalonil exposure, where an increase in glutamine levels was the only biomarker observed at both doses. At the high dose, multiblocked-orthogonal partial least squares-discriminant analysis (MB-OPLS-DA) supported increased N-acetylserine and ophthalmic acid levels as additional biomarkers of exposure in coelomic fluid. These perturbations may indicate increased oxidative stress, although no changes in glutathione were observed in any matrix.

Approach to Hyponatremia in Cirrhosis.

The patient in the case presented with hypervolemic hyponatremia associated with ascites and edema. The sNa concentration of 120 mmol/L is bordering severe hyponatremia and is associated with renal insufficiency. The management of this patient includes free water restriction, holding diuretics, and consideration of albumin infusion (Fig. ​(Fig.1).1). Tolvaptan is not recommended in patients with liver disease. Furthermore, hyponatremia and renal dysfunction are associated with poor prognosis. If the hyponatremia is persistent, liver transplant evaluation should be considered. Open in a separate window Figure 1 Algorithm depicting suggested management of hyponatremia in the patient with cirrhosis.

Immune and Metabolic Regulation Mechanism of Dangguiliuhuang Decoction against Insulin Resistance and Hepatic Steatosis.

Dangguiliuhuang decoction (DGLHD) is a traditional Chinese medicine (TCM) formula, which mainly consists of angelica, radix rehmanniae, radix rehmanniae praeparata, scutellaria baicalensis, coptis chinensis, astragalus membranaceus, and golden cypress, and used for the treatment of diabetes and some autoimmune diseases. In this study, we explored the potential mechanism of DGLHD against insulin resistance and fatty liver in vivo and in vitro. Our data revealed that DGLHD normalized glucose and insulin level, increased the expression of adiponectin, diminished fat accumulation and lipogenesis, and promoted glucose uptake. Metabolomic analysis also demonstrated that DGLHD decreased isoleucine, adenosine, and cholesterol, increased glutamine levels in liver and visceral adipose tissue (VAT) of ob/ob mice. Importantly, DGLHD promoted the shift of pro-inflammatory to anti-inflammatory cytokines, suppressed T lymphocytes proliferation, and enhanced regulatory T cells (Tregs) differentiation. DGLHD also inhibited dendritic cells (DCs) maturation, attenuated DCs-stimulated T cells proliferation and secretion of IL-12p70 cytokine from DCs, and promoted the interaction of DCs with Tregs. Further studies indicated that the changed PI3K/Akt signaling pathway and elevated PPAR-γ expression were not only observed with the ameliorated glucose and lipid metabolism in adipocytes and hepatocytes, but also exhibited in DCs and T cells by DGLHD. Collectively, our results suggest that DGLHD exerts anti-insulin resistant and antisteatotic effects by improving abnormal immune and metabolic homeostasis. And DGLHD may be a novel approach to the treatment of obesity-related insulin resistance and hepatic steatosis.

Metabonomic profiles delineate potential role of glutamate-glutamine cycle in db/db mice with diabetes-associated cognitive decline.

BackgroundDiabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear. In this study, 1H nuclear magnetic resonance-based metabonomics and immunohistochemistry was used to explore key metabolic alterations in hippocampus of type 2 diabetic db/db mice with cognition decline in order to advance understanding of mechanisms underlying the pathogenesis of the disease.ResultsMetabonomics reveals that lactate level was significantly increased in hippocampus of db/db mice with cognition decline compared with age-matched wild-type mice. Several tricarboxylic acid cycle intermediates including succinate and citrate were reduced in hippocampus of db/db mice with cognition decline. Moreover, an increase in glutamine level and a decrease in glutamate and γ-aminobutyric acid levels were observed in db/db mice. Results from immunohistochemistry analysis show that glutamine synthetase was increased and glutaminase and glutamate decarboxylase were decreased in db/db mice.ConclusionsOur results suggest that the development of diabetes-associated cognition decline in db/db mice is most likely implicated in a reduction in energy metabolism and a disturbance of glutamate-glutamine shuttling between neurons and astrocytes in hippocampus.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0223-5) contains supplementary material, which is available to authorized users.

Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder.

While the neurobiological basis and developmental course of attention-deficit/hyperactivity disorder (ADHD) have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD. This study examined the changes in cerebral levels of GABA+, glutamate and glutamine in children and adults with ADHD using edited magnetic resonance spectroscopy. We studied 89 participants (16 children with ADHD, 19 control children, 16 adults with ADHD and 38 control adults) in a subcortical voxel (children and adults) and a frontal voxel (adults only). ADHD adults showed increased GABA+ levels relative to controls (P=0.048), while ADHD children showed no difference in GABA+ in the subcortical voxel (P>0.1), resulting in a significant age by disorder interaction (P=0.026). Co-varying for age in an analysis of covariance model resulted in a nonsignificant age by disorder interaction (P=0.06). Glutamine levels were increased in children with ADHD (P=0.041), but there was no significant difference in adults (P>0.1). Glutamate showed no difference between controls and ADHD patients but demonstrated a strong effect of age across both groups (P<0.001). In conclusion, patients with ADHD show altered levels of GABA+ in a subcortical voxel which change with development. Further, we found increased glutamine levels in children with ADHD, but this difference normalized in adults. These observed imbalances in neurotransmitter levels are associated with ADHD symptomatology and lend new insight in the developmental trajectory and pathophysiology of ADHD.

Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness

Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.

P11 Induction of hyperammonaemia from the small and large intestine in patients with cirrhosis with magnetic resonance quantification of brain water and metabolites

IntroductionInduction of hyperammonaemia from glutaminase action in the small intestine1 or systemic catabolism of oral amino acids2 3 is well recognised but, although suggested in 1959 by Walser and Bodenlos,4...

Effect of Manganese Chloride on the Neurochemical Profile of the Rat Hypothalamus

Manganese (Mn(2+))-enhanced magnetic resonance imaging studies of the neuronal pathways of the hypothalamus showed that information about the regulation of food intake and energy balance circulate through specific hypothalamic nuclei. The dehydration-induced anorexia (DIA) model demonstrated to be appropriate for studying the hypothalamus with Mn(2+)-enhanced magnetic resonance imaging. Manganese is involved in the normal functioning of a variety of physiological processes and is associated with enzymes contributing to neurotransmitter synthesis and metabolism. It also induces psychiatric and motor disturbances. The molecular mechanisms by which Mn(2+) produces alterations of the hypothalamic physiological processes are not well understood. (1)H-magnetic resonance spectroscopy measurements of the rodent hypothalamus are challenging due to the distant location of the hypothalamus resulting in limited measurement sensitivity. The present study proposed to investigate the effects of Mn(2+) on the neurochemical profile of the hypothalamus in normal, DIA, and overnight fasted female rats at 14.1 T. Results provide evidence that γ-aminobutyric acid has an essential role in the maintenance of energy homeostasis in the hypothalamus but is not condition specific. On the contrary, glutamine, glutamate, and taurine appear to respond more accurately to Mn(2+) exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA.

Magnetic resonance quantification of water and metabolites in the brain of cirrhotics following induced hyperammonaemia

Hepatic encephalopathy (HE) is now thought to be caused by cerebral oedema although the precise pathogenesis is uncertain. We hypothesised that if ammonia is a key factor, induced hyperammonaemia would lead to transient changes in brain water distribution and metabolite concentration, detectable by diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). Thirteen cirrhotic patients being evaluated for liver transplantation were challenged with 54 g of equal parts of threonine, serine, and glycine. Conventional magnetic resonance imaging was performed to exclude structural lesions and localise regions of interest. DTI was used to generate white matter apparent diffusion coefficient (ADC) maps and proton MRS to measure brain metabolite concentrations before and after the challenge. The challenge caused a mean (±SD) rise in blood ammonia of 58 (±41) μmol/L, which was accompanied by a significant 9% increase in ADC (p=0.004). Increased ADC significantly correlated with blood ammonia (r=0.58, p=0.04). The change in ammonia levels also correlated with the increase in glutamine levels (r=0.78, p=0.002). Myo-inositol concentration decreased significantly by 0.7 (±0.7)mMol/L between scans and this correlated with the mean difference in ADC (r=0.59, p<0.04). These results show that ammonia can directly drive changes in brain water distribution as a mechanism for cerebral oedema development. Since cerebral astrocytes contain glutamine synthetase, our MRS data suggest intracerebral formation of glutamine from ammonia. The rapid decrease in myo-inositol indicates that this organic osmolyte plays a protective role in HE by release from astrocytes in order to maintain cell volume.

P57 Administration of branched chain amino acids to hyperammonemic cirrhotic animals is associated with worsening of hyperammonemia and increase in brain oedema

IntroductionDespite branched chain amino acids (BCAA) being used for over 30 years, its efficacy in treating hyperammonemia remains controversial. Recent studies suggest that the use of BCAA in cirrhosis is...

Interorgan ammonia, glutamate, and glutamine trafficking in pigs with acute liver failure

Ammonia reduction is the target for therapy of hepatic encephalopathy, but lack of quantitative data about how the individual organs handle ammonia limits our ability to develop novel therapeutic strategies. The study aims were to evaluate interorgan ammonia metabolism quantitatively in a devascularized pig model of acute liver failure (ALF). Ammonia and amino acid fluxes were measured across the portal drained viscera (PDV), kidneys, hind leg, and lungs in ALF pigs. ALF pigs developed hyperammonemia and increased glutamine levels, whereas glutamate levels were decreased. PDV contributed to the hyperammonemic state mainly through increased shunting and not as a result of increased glutamine breakdown. The kidneys were quantitatively as important as PDV in systemic ammonia release, whereas muscle took up ammonia. Data suggest that the lungs are able to remove ammonia from the circulation during the initial stage of ALF. Our study provides new data supporting the concept of glutamate deficiency in a pig model of ALF. Furthermore, the kidneys are quantitatively as important as PDV in ammonia production, and the muscles play an important role in ammonia removal.

Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole-induced seizures.

We examined the effect of melatonin on brain levels of amino acids and nitric oxide (NO) after pentylenetetrazole (PTZ)-induced seizures in rats. Animals were treated with melatonin (10-160 mg/kg, i.p.) 30 min before PTZ administration (100 mg/kg, s.c.), and were killed 3 hr later. At the dose of 80 mg/kg, melatonin significantly increased the latency (5.7-12.7 min) and decreased the duration (31.2-18.4 s) of the first seizure, reducing PTZ induced mortality from 87.5 to 25%. After kill, brains were removed and neurotransmitters and nitrite levels measured in prefrontal cortex (PF), parieto-temporal cortex (PF), striatum (ST), hippocampus (HP) and brain stem (BS) by high performance liquid chromatography. PTZ treatment increased glutamine levels in all brain areas studied, without changes in glutamate, gamma-amino butyric acid (GABA) and glycine. Aspartate and taurine increased in PF and PT and in HS and PT, respectively. Melatonin administration displayed a dose-dependent effect. At doses of 10-40 mg/kg, melatonin counteracted the PTZ-induced glutamine increase and reduced both glutamate and aspartate levels in the studied areas, with minor changes in GABA and glycine content. At doses of 80 and 160 mg/kg, the levels of glutamine, and glutamate, and to a lesser extent aspartate increased, whereas serine levels did not change. These two doses of melatonin also increased taurine, GABA and glycine in most brain areas studied. Treatment with melatonin (40-160 mg/kg) significantly decreased nitrite content in PT cortex, ST and BS areas of epileptic rats, without changes in the other brain regions. The results suggest that the anticonvulsant property of melatonin involves a modulation of both brain amino acids and NO production.

A new dimension of 1H-NMR spectroscopy in assessment of liver graft dysfunction.

High-resolution 1H-NMR spectroscopy of serum and urine samples of an 11-year-old male living related orthotopic liver transplant recipient is reported. Serum glutamine increased to abnormal levels along with simultaneous abnormal excretion of urinary glutamine post-transplantation. High levels of glutamine in both blood and urine and concomitant reduced urea levels in urine were found to be evidence of impairment in urea cycle and compatible with persistently abnormal graft function. Thus glutamine levels in serum and urine, and urea in the urine as observed by 1H-NMR spectroscopy highlight their important roles in monitoring liver graft function; increased glutamine levels lead to brain damage, if untreated.

The effect of sub-lethal ammonia exposure on fed and unfed rainbow trout: the role of glutamine in regulation of ammonia

Many species of fishes have evolved mechanisms for coping with ammonia caused by either high ammonia environments or an inability to excrete nitrogenous wastes. Rainbow trout ( Oncorhynchus mykiss), have not been known to have such a mechanism. The present study investigated whether rainbow trout can use amino acid synthesis and storage to cope with ammonia. Experiments were performed on fed and unfed rainbow trout under both control and elevated ammonia conditions (0 and 10 mg N/l (total ammonia nitrogen), pH 7.2). The results indicate that both feeding and ammonia exposure increased plasma ammonia significantly 6 h postprandial and post ammonia exposure. After 48 h the fed/ammonia exposed fish had plasma ammonia levels that were not significantly different than the fed/control fish. Plasma ammonia was reduced by more than 50%, attributable to ammonia being converted to glutamine in brain, liver and muscle tissue. Feeding alone also increased glutamine levels in brain tissue. Activity of glutamine synthetase in brain and liver was increased corresponding to an increase in glutamine concentrations when fish were exposed to ammonia. This is the first report showing that rainbow trout can detoxify endogenous and exogenous ammonia.

Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve.

Proton magnetic resonance spectroscopy (1H-MRS) has been used to assess the metabolic changes in the brain in patients with liver cirrhosis. Decreased myo-inositol and increased glutamine levels were noted to be the most sensitive spectroscopic markers for cirrhotic patients with hepatic encephalopathy (HE). The purpose of this study was to assess how the abnormalities seen on the 1H-MRS of the brain in patients with liver cirrhosis are related to clinical and laboratory parameters. In a prospective study, localized 1H-MRS was performed in the basal ganglia and parietal white matter regions in liver cirrhosis patients with (n = 48) and without (n = 52) HE and chronic hepatitis (CH) (n = 15), and in normal controls (n = 20). Among cirrhotic patients, the myo-inositol levels were significantly lower (p < 0.01) and the glutamine levels were higher (p < 0.05) for patients with HE than for those without HE. The myo-inositol and glutamine levels, respectively, were inversely (r = -0.50; p < 0.001) and linearly (r = 0.50; p < 0.001) related to the Child-Pugh score. However, by subgroup analysis of Child-Pugh class C patients, there were no significant differences in the myo-inositol and glutamine levels between cirrhotic patients with (n = 40) and without HE (n = 24). A follow-up study of eight cirrhotic patients with HE showed no significant differences in the myo-inositol and glutamine levels after clinical improvement of HE. The abnormalities seen on the 1H-MRS of the brain of patients with liver cirrhosis are not likely to reflect the severity of HE or acute alteration in the level of consciousness. Rather, we believe they represent the chronic metabolic derangement of the brain associated with hepatic functional reserve.