SEARCH · PubMed Health

Results for “hyperammonemia”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 721 records · Page 40Linked to original sources

PubMed1975

Lysinuric protein intolerance.

Lysinuric protein intolerance (LPI), an autosomal recessive defect of diamino acid transport, is characterized chemically by renal hyperdiaminoaciduria, especially lysinuria, and by impaired formation of urea with hyperammonemia after protein ingestion. Our 20 patients thrived during breast-feeding, but ingestion of cow's milk caused diarrhea and vomiting. When able to select their diet, they rejected all protein-rich foods. They were short staturated and had weak atrophic muscles, osteoporosis, hepatomegaly and often splenomegaly. Four patients were mentally retarded. Fifteen patients had leukocyte counts below 4,000/mm3, and 17 patients had platelet counts below 150,000/mm3. Serum lactate dehydrogenase activity was constantly increased, and transaminase and aldolase activities were often increased. In the infants' livers, changes were only revealed by electron microscopy: increased and vesicular smooth endoplasmic reticulum, and abundance of glycogen particles in the hepatocytes. In the older patients, light microscopy demonstrated clearly limited areas where hepatocytes had large pale cytoplasm and small pyknotic nuclei. The diamino acids lysine, arginine and ornithine had plasma concentrations only one-third to one-half the normal mean; the renal clearances were clearly increased. Oral diamino acid loading tests suggested impaired intestinal absorption. Urea is built in the liver through transformation of ornithine to arginine, and cleavage of arginine to ornithine and urea. The addition of ornithine to an intravenous I-alanine loading prevented the hyperammonemia and normalized the urea production. Therefore, the diet has been supplemented with arginine, and more protein has been added. This therapy has lead to a remarkable catch-up growth in some patients. The pathophysiology of LPI is explained. Because of defective intestinal absorption and incrased renal loss, the diamino acids have a low plasma concentration. Their transport from plasma to hepatocytes is also impaired, and the liver becomes deficient in ornithine. This retards the urea cycle, and leads to postprandial hyperammonemia and protein aversion. The presence of the transport defect in the hepatocytes distinguishes LPI from other hyperdibasicaminoacidurias.

Adolescent↗

PubMed1983

Free fatty acids in an animal model of Reye's syndrome.

Recent studies have indicated that viral infections, aspirin treatment and hyperammonemia are associated with Reye's syndrome. It has also been reported that free fatty acids in serum and total lipids in the liver of Reye's syndrome patients are elevated during illness. The role of the lipid changes in the development of the disorder cannot be optimally studied in human patients, because infection and aspirin ingestion occur prior to the earliest symptoms of Reye's syndrome. Effects of influenza B infection, aspirin treatment and hyperammonemia on the level of free fatty acids, total lipids and triacylglycerols in serum and liver of an animal model of Reye's syndrome are reported here. Hyperammonemia was produced in young, male ferrets either by feeding them small amounts of an arginine-deficient diet after overnight fasting or by an intraperitoneal injection of jackbean urease. The ferret model resembled Reye's syndrome in developing increased levels of individual and total serum free fatty acids, liver triacylglycerol and total lipids. The results also indicate that influenza infection or aspirin treatment, or both, while increasing the severity of encephalopathy in the deficient ferrets, did not cause a significant change in the level of serum free fatty acids. Other results suggest that elevation of serum ammonia, serum free fatty acid or liver lipids, either singly or in various combinations, does not provide conditions that can explain the rapidly developing encephalopathy in the arginine-deficient ferrets.

Ammonia↗

PubMed1991

EEG changes during recovery from acute severe neonatal citrullinemia.

We report our observations of serial clinical and EEG examinations in 3 neonates during recovery from acute severe encephalopathy due to citrullinemia. Their electroclinical picture closely resembles the clinical stages of experimental models of hyperammonemia in monkeys. The length of the EEG interburst interval, a quantitative measure of EEG background abnormality, correlated with elevated serum levels of ammonia and suggests that hyperammonemia itself is a key figure in the genesis of encephalopathy in this condition. Finally, the manner in which the EEG normalizes during recovery from hyperammonemia in this setting suggests that burst-suppression resembles an exaggerated regression to the discontinuity of the very premature infant.

Ammonia↗

PubMed1992

Normal N-acetylglutamate concentration measured in liver from a new patient with N-acetylglutamate synthetase deficiency: physiologic and biochemical implications.

N-Acetyl-L-glutamate synthetase (NAG synthetase) is a mitochondrial matrix enzyme which catalyzes the synthesis of N-acetyl-Lglutamate (NAG), a physiologic activator of the urea cycle enzyme carbamylphosphate synthetase I. Deficiency of NAG synthetase in humans has been reported only three times previously. Two cases presented with uncontrolable neonatal hyperammonemia leading to death, while a third child presented with hyperammonemia and a neurodegenerative picture at 15 months of age after previously being healthy. We report here a new case of NAG synthetase deficiency who presented at 4 years, 10 months of age with an episode of hyperammonemia. Diagnosis was made at age 5 years, 6 months when a liver biopsy showed 9.7% of normal activity. Urine orotic acid was low, and total NAG content in liver was normal. Liver pathology revealed micro- and macrovesicular fat and mitochondria of irregular size and shape with intracristae crystallizations. NAG content in liver in patients with NAG synthetase deficiency has not previously been reported. Its normal value in the face of NAG synthetase deficiency suggests an abnormal localization of NAG to the cytoplasm and the likelihood of aberrant cytoplasmic synthesis of this compound. Additional physiologic implications of this speculative abnormal compartmentalization are discussed.

Acetyltransferases↗

PubMedDate not supplied

Unusual biochemical and clinical features in a girl with ornithine transcarbamylase deficiency.

A girl, ultimately diagnosed as having profound ornithine transcarbamylase (OTC) deficiency, presented as a neonate with feeding intolerance, irritability, and seizures without concurrent hyperammonemia. Developing normally until ten months of age, the girl subsequently experienced two episodes of hyperammonemia, which were associated with focal seizures and residual hemiparesis. She continued to have profound neurologic impairment and seizures and died at 26 months of age, despite appropriate dietary protein restriction, sodium benzoate, and arginine supplementation. Symptomatic OTC deficiency has not been previously reported unassociated with hyperammonemia. The recurrent cerebrovascular episodes are distinctly uncommon in patients with urea cycle enzymopathies.

Amino Acid Metabolism, Inborn Errors↗

PubMed2006

Chronic exposure to ammonia alters basal and NMDA-induced phosphorylation of NMDA receptor-subunit NR1.

Hyperammonemia is responsible for many of the neurological alterations in patients with hepatic encephalopathy by mechanisms that remain unclear. Hyperammonemia alters phosphorylation of brain protein kinase C substrates and impairs N-methyl-d-aspartate (NMDA) receptor-associated signal transduction. The aim of this work was to analyze, in rat cerebellar neurons in culture, the effects of ammonia exposure on NMDA receptor phosphorylation, MK801 binding and surface expression. Ammonia reduces MK801 binding to NMDA receptors and the surface expression of the NR1 and NR2A subunits. As phosphorylation of serines in the NR1 C1 cassette has been implied in receptor trafficking, we assessed whether hyperammonemia alters phosphorylation of these serines. Basal phosphorylation of serines 890, 896 and 897 was increased in neurons exposed to ammonia, while NMDA-induced phosphorylation of S896 and S897 was reduced. Exposure to ammonia also increased basal phosphorylation of Akt but reduced NMDA and BDNF stimulation of Akt phosphorylation. These results suggest that alterations in receptor surface expression and possibly the phosphorylation state of the NR1 subunit of NMDA receptors may contribute to the impairment by ammonia of signal transduction pathways modulated by NMDA receptors.

Ammonia↗

PubMed1986

Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder associated with hyperammonemia. Heterozygous females have variable clinical expression, ranging from asymptomatic illness to recurrent episodes of hyperammonemic coma. We studied 17 OTC-deficient kindreds containing 114 women at risk for heterozygosity. Sixty-one of these women were designated heterozygotes by pedigree analysis, history of protein intolerance, protein tolerance tests, or DNA probe studies. Eleven (18%) of the 61 heterozygotes had experienced encephalopathic episodes; nine (82%) girls died during these episodes. Our findings indicate that there is a significant risk of symptomatic hyperammonemia in females heterozygous for OTC deficiency. We suggest that, within OTC-deficient kindreds, females at risk should be identified early, by means of protein tolerance tests and DNA probe studies. Those who develop significant hyperammonemia after a protein load should be considered for long-term alternate pathway therapy and should receive aggressive therapy during hyperammonemic episodes.

Amino Acid Metabolism, Inborn Errors↗

PubMed1989

Periodic hyperammonemic encephalopathy associated with a ureterosigmoidostomy.

Ureterosigmoidostomy, a urinary diversion procedure performed for treatment congenital urologic defects or bladder cancer, may be associated with hyperammonemia. A delayed periodic encephalopathy, characterized by dysarthria, ataxia, and coma, developed in a 44-year-old woman who had undergone this procedure. Hyperammonemia-associated neurotoxicity resolved after surgical revision of the ureterosigmoidostomy to a uretero-ileostomy. Therefore, a treatable episodic encephalopathy may occur in association with hyperammonemia in patients who have undergone ureterosigmoidostomy.

Adult↗

PubMed1998

Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis.

BACKGROUND/AIM: Abnormalities in brain organic osmolytes are associated with hepatic encephalopathy and with chronic hyponatremia. In spite of the high frequency of hyponatremia in acute and chronic hepatic failure, its role in the development of neurological complications in liver disease is poorly understood. We aimed to study the effect of prior hyponatremia on the development of ammonia-induced brain edema in rats after portacaval anastomosis. In this model, brain swelling is mediated in part through an increase in brain glutamine, an organic osmolyte. METHODS: Hyponatremia was induced in rats with 1-desamino-8-D-arginine vasopressin (DDAVP) administered through an osmotic minipump for 1 week. This was followed by performance of a portacaval anastomosis and ammonia infusion. At the end of the infusion, brain water (density gradient) and key brain organic osmolytes (HPLC) were measured. RESULTS: Rats with hyponatremia showed a decrease in all three brain organic osmolytes measured: glutamine, myo-inositol and taurine. Hyperammonemia resulted in the expected rise in glutamine, with a reduction of myo-inositol and taurine. In the combined group (hyponatremia plus hyperammonemia), the rise in brain glutamine induced by ammonia infusion was attenuated (10.6+/-0.9 mM/kg vs. 15.5+/-0.8 mM/kg hyperammonemia alone; p<0.05). In spite of this limited rise in brain glutamine, ammonia infusion to hyponatremic rats exacerbated brain swelling (82.3+/-0.3% vs. 80.6+/-0.1%; p<0.05). CONCLUSIONS: Hyponatremia worsens brain swelling in a model of ammonia-induced brain edema. The decrease in the concentration of brain organic osmolytes induced by hyponatremia does not protect the brain from the development of ammonia-induced brain edema.

Ammonia↗

PubMedDate not supplied

Effects of ammonia and hepatic failure on the net efflux of endogenous glutamate, aspartate and taurine from rat cerebrocortical slices: modulation by elevated K+ concentrations.

Cerebrocortical minislices derived from control rats ("control slices") and from rats with thioacetamide (TAA)-induced hepatic failure showing moderate hyperammonemia and symptoms of hepatic encephalopathy (HE) ("HE slices"), were incubated with physiological saline in the absence or presence of 5 mM ammonium acetate ("ammonia"), at potassium ion (K+) concentrations ranging from 5 to 15 mM. The efflux of endogenous aspartate (Asp), glutamate (Glu) and taurine (Tau) to the incubation medium was assayed by HPLC. At 5 mM K+, perfusion of control slices with ammonia did not affect Glu and slightly depressed Asp efflux. Raising K+ concentrations in the incubation medium to 7.5 led to inhibition of Glu and Asp efflux by ammonia and the inhibitory effect was further potentiated at 10 mM K+. The inhibition was also significant at 15 mM K+. This suggests that, depression of excitatory neurotransmission associated with acute hyperammonemia is more pronounced under conditions of intense neuronal activity than in the resting state. HE moderately increased the efflux of Glu and Asp, and the stimulatory effect of HE on Glu and Asp efflux showed virtually no variation upon changing K+ concentration up to 15 mM. Ammonia strongly, and HE moderately, increased Tau efflux at 5 mM K+. However, both the ammonia- and HE-dependent Tau efflux decreased with increasing K+ concentration in the medium and was no longer significant at 10 mM concentration, indicating that intense neuronal activity obliterates the neuroprotective functions of this amino acid triggered by hyperammonemia.

Ammonia↗

PubMed1998

In vitro excess ammonia production in human myeloma cell lines.

It is well known that cases with multiple myeloma reveal various clinical manifestations such as pancytopenia, hyperproteinemia, renal dysfunction, bone lesions, hypercalcemia and immunodeficiency. Recently, a few more clinical features associated with myeloma, such as salivary type hyperamylasemia and elevated serum C-reactive protein (CRP) concentration, have been reported. The elevation of CRP is thought to be related to interleukin-6 (IL-6) production by myeloma cells, because of identification of IL-6 as an autocrine and/or paracrine growth factor for myeloma cells. More recently, there have been several reports of cases with myeloma associated with hyperammonemia. This hyperammonemia is not considered to be due to liver dysfunction, because in most of these cases tests revealed normal hepatic function, and some cases showed different patterns of serum amino acid distribution than that associated with hepatic failure. However, there have been no apparent observations of ammonia production by myeloma cells. In this study, we used six human myeloma cell lines including KMS-18, which was recently established from a myeloma case associated with hyperammonemia. These lines were treated with MRA (mycoplasma removal agent) to observe ammonia production in vitro. They produced and released significantly higher levels of ammonia into culture medium than non-myeloma hematological cell lines or the HepG2 human hepatic carcinoma cell line. Although attempts to analyze the relative expression levels of the enzymes related to ammonia biosynthesis using the reverse transcriptase-polymerase chain reaction assay failed to detect any differences between these myeloma lines and other cell lines, in vitro excess ammonia production by the myeloma cells was confirmed and the relevance to clinical manifestations is discussed.

Ammonia↗

PubMed1999

Chronic exposure to ammonia alters pathways modulating phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture.

Hyperammonemia is considered the main cause for the neurological alterations found in hepatic failure. However, the mechanisms by which high ammonia levels impair cerebral function are not well understood. It has been shown that chronic hyperammonemia impairs signal transduction pathways associated with NMDA receptors and also alters phosphorylation of some neuronal proteins. The aim of the present work was to analyze the effects of chronic exposure to ammonia on phosphorylation of microtubule-associated protein 2 (MAP-2) in intact neurons in culture and to assess whether modulation of MAP-2 phosphorylation by glutamate receptor-associated transduction pathways is altered in neurons chronically exposed to ammonia. It is shown that chronic exposure to ammonia increases basal phosphorylation of MAP-2 by approximately 70%. This effect seems to be due to a decreased tonic activation of NMDA receptors and of calcineurin. Chronic exposure to ammonia also alters the modulation of MAP-2 phosphorylation by NMDA receptors and metabotropic glutamate receptors. In neurons exposed to ammonia, treatment with NMDA for 30 min induced a significant decrease in phosphorylation of MAP-2. Activation of metabotropic glutamate receptors with (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid significantly increased phosphorylation of MAP-2 in control neurons, whereas in neurons exposed to ammonia the response was the opposite, with 1-aminocyclopentane-1,3-dicarboxylic acid inducing a dephosphorylation of MAP-2. These results indicate that ammonia alters significantly signal transduction pathways associated with different types of glutamate receptors. This would lead therefore to significant alterations in glutamatergic neurotransmission, which would contribute to the neurological alterations found in hyperammonemia and in hepatic encephalopathy.

Ammonia↗

PubMed1986

Effect of arginine-free diet on ammonia metabolism in young and adult ferrets.

Two-month-old, male ferrets were fasted for 16 h and fed a synthetic, arginine-free diet. Within 2-3 h after ingesting the diet, they developed hyperammonemia and encephalopathy. Ammonia levels in the serum, brain and cerebrospinal fluid were greatly elevated compared to those of ferrets fed the synthetic diet supplemented with arginine. Orotic acid and glucose levels in serum were also significantly elevated. Urinary orotic acid was significantly increased but citrate and creatinine level were unaltered. Adult (18-mo-old) ferrets did not develop hyperammonemia and encephalopathy after eating the arginine-free diet. Serum and urinary orotic acid levels were significantly elevated in the adult ferrets fed arginine-free diet. Hyperammonemia and encephalopathy were prevented in young ferrets by supplying dietary arginine and abbreviated by ornithine injections given during encephalopathy. These results suggest that young ferrets are unable to meet their ornithine needs from precursors other than arginine, whereas adult ferrets appear to be able to synthesize ornithine from sources other than dietary arginine. Intraperitoneal injection of sodium benzoate to young ferrets fed arginine-free diet failed to decrease serum ammonia levels.

Aging↗

PubMed1984

Siblings with carbamyl phosphate synthetase I deficiency.

This paper concerns with two autopsied cases of siblings who died from cerebral disturbances. In these patients hyperammonemia developed in the neonatal phase due to carbamyl phosphate synthetase I (CPS I) deficiency. The patient in Case 1 was admitted 2 days after birth because of oliguria and vomiting. Hyperammonemia developed and she died on the 43rd day. In Case 2 hyperammonemia developed from the 2nd day after birth and she expired on the 42nd day. In both cases the diagnosis of CPS I deficiency was established from autopsy findings of the liver.

Amino Acid Metabolism, Inborn Errors↗

PubMedDate not supplied

Effects of valproate and citrulline on ammonium-induced encephalopathy.

Hyperammonemia is a recognized side effect of treatment with the antiepileptic drug (AED) valproate (VPA). Encephalopathic complications have also been observed in some patients receiving VPA therapy. The relation between VPA-induced hyperammonemia and encephalopathy is not clear, however. A model of ammonium (NH4+)-induced coma was used to investigate the contribution of VPA and to assess the efficacy of citrulline (a urea cycle intermediate) on hyperammonemia and encephalopathy. In groups of 6-12 rats, administration of VPA (2.5 mmol/kg) was associated with (a) a decrease in the dose of NH4+ that produces coma in 50% of the animals (CD5) from 6.1 to 3.6 mmol/kg, and (b) significant increases in blood ammonia concentrations in NH(4+)-treated animals. In addition, clear evidence also showed that in the presence of VPA, a lesser concentration of ammonia produced coma. Citrulline treatment (5.0 mmol/kg) was associated with (a) an increase in the CD50 value of NH(4+)-treated animals from 6.1 to 8.6 mmol/kg, (b) a statistically significant decrease in ammonia concentration at all doses examined, (c) complete protection from encephalopathic effects of NH4+ at citrulline concentrations three- to tenfold greater than basal levels; and (d) a 24% increase in the CD50 value and a statistically significant decrease in ammonia concentration of VPA/NH(4+)-treated animals. These findings indicate that VPA has a dual effect on encephalopathy and that citrulline should benefit those patients treated with VPA who experience adverse encephalopathic effects.

Ammonia↗

PubMed1983

Treatment of epileptic patients with valproic acid does not modify plasma and urine short-chain-fatty acids.

The purpose of this study was to evaluate the possible modifications of the plasma and urine short-chain-fatty acid (SCFA) patterns indiced by treatment with valproic acid (VPA). Increased amounts of SCFAs in patients under VPA treatment may explain the presence of VPA-induced hyperammonemia, toxic encephalopathies and rarer Rey-like syndromes recently observed. For this reason we assayed SCFA levels in the plasma and looked for propionic acid in the urine of 10 epileptic patients to whom it was decided to add VPA to their previously unsatisfactory anti-epileptic treatment. This was carried out prior to and during therapy with VPA. 5 of these patients developed toxic encephalopathy with hyperammonemia induced by VPA. Our data show that plasma and urine SCFAs are not modified by VPA treatment. This is so even in patients who have toxic encephalopathy with hyperammonemia indiced by this drug.

Adolescent↗

PubMed2000

Interaction of glutamine and arginine on cerebrovascular reactivity to hypercapnia.

Glutamine is purported to inhibit recycling of citrulline to arginine and to limit nitric oxide release in vitro. However, vasoactive effects of glutamine have not been clearly demonstrated in vivo. During hyperammonemia, impaired cerebrovascular reactivity to CO(2) is related to glutamine accumulation. We tested the hypotheses that 1) glutamine infusion in the absence of hyperammonemia impairs cerebrovascular CO(2) reactivity and 2) arginine infusion preserves CO(2) reactivity during glutamine infusion and during hyperammonemia. Pentobarbital sodium-anesthetized rats were equipped with a closed cranial window for measuring pial arteriolar diameter. Intravenous infusion of 3 mmol. kg(-1). h(-1) of L-glutamine for 6 h produced threefold increases in plasma and cerebrospinal fluid concentrations. Dilation to hypercapnia was reduced by 45% compared with that of a time control group at 6 h but not at 3 h of glutamine infusion. Coinfusion of 2 mmol. kg(-1). h(-1) of L-arginine with glutamine maintained the hypercapnic vasodilation at the control value. Infusion of ammonium acetate at a rate known to produce threefold increases in cortical tissue glutamine concentration resulted in no significant hypercapnic vasodilation. Coinfusion of arginine with ammonium acetate maintained hypercapnic vasodilation at 60% of the control value. Arginine infusion did not augment hypercapnic vasodilation in a control group. We conclude that glutamine modulates cerebrovascular CO(2) reactivity in vivo. Glutamine probably acts by limiting arginine availability because the vascular inhibitory effect required >3 h to develop and because arginine infusion counteracted the vascular effect of both endogenously and exogenously produced increases in glutamine.

Acetates↗

PubMed1975

Citric, orotic, and other organic acids in rats injected with active or inactive urease.

Male rats were fed laboratory chow or a purified L-amino acid diet containing 11.2 or 5.6 g arginine/kg. Hyperammonemia was produced by injection of crystalline jackbean urease. Control animals were injected with saline or inactivated urease. Rats injected with 55 U urease activity/kg body wt (an LD50 dose) exhibited acute signs of hyperammonemia and elevated orotate and citrate in their urine. Plasma glucose, lactate, citrate, and alpha-ketoglutarate concentrations were also markedly elevated. Three injections of active urease (10 U/kg body wt) given at intervals of about 10 h produced hyperammonemia, which persisted for 25 h after the first injection. Blood glucose and ammonia concentrations were increased 2.6- and 22-fold, respectively, when compared with controls. Total urinary citrate excretion for 25 h was 371 mueq for active urease-injected rats compared with 62 mueq for rats injected with inactivated urease. Rats fed a purified amino acid diet containing 5.6 g arginine/kg excreted greater quantities of urea, citrate, and orotic acid than rats fed 11.2 g arginine/kg of diet. Injection of active urease increased citrate excretion by rats fed either concentration of dietary arginine. Changes produced with active urease were not observed if inactivated urease was injected.

Acetates↗