Hyperammonemia In Patients Research Articles

Urinary 2-hydroxy-5-oxoproline, the lactam form of α-ketoglutaramate, is markedly increased in urea cycle disorders

α-Ketoglutaramate (KGM) is the α-keto acid analogue of glutamine, which exists mostly in equilibrium with a lactam form (2-hydroxy-5-oxoproline) under physiological conditions. KGM was identified in human urine and its concentration quantified by gas chromatography/mass spectrometry (GC/MS). The keto acid was shown to be markedly elevated in urine obtained from patients with primary hyperammonemia due to an inherited metabolic defect in any one of the five enzymes of the urea cycle. Increased urinary KGM was also noted in other patients with primary hyperammonemia, including three patients with a defect resulting in lysinuric protein intolerance and one of two patients with a defect in the ornithine transporter I. These findings indicate disturbances in nitrogen metabolism, most probably at the level of glutamine metabolism in primary hyperammonemia diseases. Urinary KGM levels, however, were not well correlated with secondary hyperammonemia in patients with propionic acidemia or methylmalonic acidemia, possibly as a result, in part, of decreased glutamine levels. In conclusion, the GC/MS procedure has the required lower limit of quantification for analysis of urinary KGM, which is markedly increased in urea cycle disorders and other primary hyperammonemic diseases.

Role of Helicobacter pylori infection in the pathogenesis of minimal hepatic encephalopathy and effect of its eradication

Helicobacter pylori (H. pylori) bacteria convert urea to ammonia, which has been implicated in causation of hepatic encephalopathy in patients with liver cirrhosis. The role of H. pylori infection in causation of minimal hepatic encephalopathy (MHE) has not been well studied. We looked at the relationship of H. pylori infection with MHE and hyperammonemia in patients with liver cirrhosis and the effects of anti-H. pylori treatment in patients with MHE and H. pylori infection. Patients with liver cirrhosis underwent psychometric tests for detection of MHE, rapid urease test to look for evidence of H. pylori infection and measurement of fasting blood ammonia levels. Patients with MHE were treated with triple-drug anti-H. pylori treatment for one week. Rapid urease test, blood ammonia levels, and psychometric tests were repeated four weeks after treatment. H. pylori infection was found more often in patients with MHE (63%) than in those without MHE (37%). Blood ammonia levels were significantly higher in patients with MHE than those without. After H. pylori treatment in patients with MHE, blood ammonia levels showed a significant decline and psychometric test results returned towards normal. In patients with liver cirrhosis, there is a significant association between H. pylori infection and MHE. Anti-H. pylori therapy results in reduction in blood ammonia levels and improvement in MHE.

New trends in surgical treatment for portal hypertension

A number of surgical procedures have been developed to manage esophageal varices. Broadly, these can be classified as shunting and non-shunting procedures. While total shunt effectively reduces the incidence of variceal bleeding, it is associated with a high risk of hepatic encephalopathy. The distal splenorenal shunt (DSRS), a selective shunt, was developed by Warren in 1967 to preserve portal blood flow through the liver while lowering variceal pressure. The hope was that both bleeding and hyperammonemia would be prevented. The DSRS effectively prevents rebleeding, but still carries a risk of hyperammonemia. We improved the DSRS procedure by additionally performing splenopancreatic disconnection (SPD, i.e. skeletonization of the splenic vein from the pancreas to its bifurcation at the splenic hilum) and gastric transection (GT, i.e. transection and anastomosis of the upper stomach with an autosuture instrument). An alternative to shunting was developed by Sugiura and Futagawa in 1973. Esophageal transection (ET) divides and reanastomoses the distal esophagus and devascularizes the distal esophagus and proximal stomach; splenectomy, selective vagotomy, and pyloroplasty are performed concomitantly. DSRS was more effective than ET in preventing recurrence of esophageal varices, but was associated with a higher incidence of hyperammonemia. The incidence of hyperammonemia in patients who underwent DSRS with SPD plus GT was significantly lower than that in patients who underwent DSRS alone or those who underwent DSRS with SPD. In conclusion, there are various surgical treatments for esophagogastric varices. Distal splenorenal shunt with SPD plus GT is considered an adequate treatment for patients with esophagogastric varices.

A critical analysis of studies assessing L-ornithine-L-aspartate (LOLA) in hepatic encephalopathy treatment

Experimental and clinical studies suggest that LOLA may have a favorable influence on hepatic encephalopathy due to the effect on the reduction of ammonia, and improvement of the symptoms and laboratory findings. To evaluate and to critically analyze the efficacy and/or effectiveness results of the use of LOLA when compared to placebo in the treatment of hepatic encephalopathy. LILACS, SciELO, MEDLINE, PubMed database and Cochrane Collaboration Register of Controlled Trials were searched from 1966 to September of 2006. The review has included all the randomized controlled double-blind clinical trials performed in humans in English language. Four studies published between 1993 and 2000 were selected and reviewed. LOLA was showed as being able to reduce hyperammonemia in patients with hepatic encephalopathy, when compared to patients in the placebo group. Although the trials have shown efficacy of LOLA in reducing hyperammonemia of hepatic encephalopathy, sufficient evidence of a significant beneficial effect of LOLA on patients with hepatic encephalopathy was not found. The studies performed in this area were small, with short follow-up periods and half of them showed low methodological quality.

Osmotic Demyelination Syndrome as a Consequence of Treating Hyperammonemia in a Patient with Ornithine Transcarbamylase Deficiency

A 7-year-old female patient with a new diagnosis of ornithine transcarbamylase deficiency was treated for hyperammonemia with a standard protocol. Several days later, she developed ataxia, dysmetria, and dysarthria. Magnetic resonance imaging of the brain demonstrated pontine and extrapontine white matter changes consistent with osmotic demyelination. Classically described as a consequence of hyponatremia treatment, osmotic demyelination syndrome has rarely been associated with other entities. This case suggests a potentially serious complication of the standard therapy for hyperammonemia in patients with ornithine transcarbamylase deficiency.

バルプロ酸服用中のてんかん患者における高アンモニア血症発生リスクに関する症例対照研究

Hyperammonemia is an adverse effect of valproic acid,though it is rarely associated with fatal encephalopathy or disturbance of consciousness.The purpose of this study was to investigate the clinical risk factors for hyperammonemia in patients with epilepsy undergoing valproic acid therapy.To do this,we conducted a survey retrospectively from January 2006 to June 2008.We also performed a case-control study in which blood ammonia levels and other data were measured in inpatients and outpatients,defining hyperammonemia as a blood ammonia level exceeding 200μg/dL.There were 90 cases and 450 controls.Multiple logistic regression analysis was also performed to investigate the risk factors for hyperammonemia,using the cases as a criterion variable.The explanatory variables were factors that showed significance (P<0.05)in univariate analysis.According to multiple regression analysis,risk factors for hyperammonemia were phenytoin coadministration (odds ratio (OR),5.89;95% confidence interval (CI),3.41 to 10.2;p<0.001),phenobarbital coadministration (OR,2.30;95% CI,1.28 to 4.11;p=0.005),and dose of valproic acid (per mg/kg/day,OR,1.05;95% CI,1.02 to 1.07;p<0.001).However,slow-release valproic acid formulations reduced the risk of hyperammonemia (OR,0.51;95% CI,0.30 to 0.85;p= 0.010).In conclusion,identification of risk factors for hyperammonemia due to valproic acid in epileptic patients can help minimize adverse effects.

Postchemotherapy Hyperammonemic Encephalopathy Emulating Ornithine Transcarbamoylase (OTC) Deficiency

A young patient with hepatocellular carcinoma receiving chemotherapy presented with encephalopathy. Evaluation of the patient revealed a metabolic profile consistent with ornithine transcarbamoylase (OTC) deficiency, an inherited disorder of the urea cycle. The evaluation yielded a plasma amino acid analysis consistent with OTC deficiency. However, genetic analysis did not reveal a somatic mutation of the OTC gene in this patient. The hyperammonemic encephalopathy was reversed by the infusion of arginine, a common treatment for hereditary OTC deficiency. This case may represent a distinct syndrome of reversible hyperammonemia in patients with hepatocellular carcinoma.

Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia?

BackgroundHyperammonemia in patients with methylmalonic aciduria (MMA) and propionic aciduria (PA) is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises.Case presentationWe described two patients (one with MMA and one with PA) with hyperammonemia at diagnosis. Carglumic acid, when associated with standard treatment of organic acidurias, may be helpful in normalizing the ammonia level.ConclusionEven though the usual treatment which decreases toxic metabolites remains the standard, carglumic acid could be helpful in lowering plasma ammonia levels over 400 micromol/L more rapidly.

Hyperammonemia Due to Valproic Acid in the Psychiatric Setting

Hyperammonemia Due to Valproic Acid in the Psychiatric Setting

Hyperammonemia Due to Valproic Acid in the Psychiatric Setting

In 1980 Coulter and Allen (1) reported the first case of hyperammonemia, to our knowledge, with otherwise normal hepatic function tests in a child with epilepsy treated with valproic acid. Since that time, there have been several additional case reports and studies within the neurology literature that have established hyperammonemia with otherwise normal hepatic function as a potential side effect of valproic acid, especially in children and adolescents (2). Settle (3) published the first case of hyperammonemia, to our knowledge, in a psychiatric setting in 1995. Several additional cases have followed it. Unfortunately, to date, to our knowledge, there has only been one prospective study published within the psychiatric literature (4). We present here a patient’s history that illustrates how the symptoms of a psychiatric disorder might make the diagnosis of hyperammonemic encephalopathy difficult.

Hypothesis: proposals for the management of a neonate at risk of hyperammonaemia due to a urea cycle disorder

It is difficult to prevent hyperammonaemia in patients with urea cycle disorders that present in the newborn period. This is true, even if treatment is started prospectively because of an affected relative. We propose several additional measures that could be used in conjunction with conventional therapy to improve the metabolic control. Catabolism could be reduced by delivering the babies by elective caesarean section, by starting intravenous glucose immediately after delivery and, possibly, by using beta-blockers or octreotide and insulin. The effectiveness of sodium benzoate and sodium phenylbutyrate might be increased by giving phenobarbital to the mother before delivery and subsequently to the baby to induce the enzymes for conjugation. We would expect the proposed measures to reduce the risk of hyperammonaemia and to improve the outcome for these patients. They have not, however, previously been used in this context, so families would need to be counselled carefully and controlled studies should be undertaken.

Utilização de probiótico e de lactulose no controle de hiperamonemia causada por desvio vascular portossistêmico congênito em um cão

O desvio vascular portossistêmico pode ser congênito ou adquirido nos cães. A enfermidade pode levar a alterações neurológicas decorrentes de encefalopatia hepática e a hiperamonenia é um dos mecanismos implicados na fisiopatologia deste quadro. O tratamento clínico visa a reduzir os níveis séricos de amônia com o uso de antibióticos e lactulose. Em humanos com hepatopatias, os probióticos podem ser utilizados para reduzir a hiperamonemia. A resposta clínica e laboratorial de um cão com desvio vascular portossistêmico foi demonstrada com a utilização de lactulose e de probiótico, isoladamente e associados, sendo que a melhor evolução foi obtida na terapia conjunta.

Metabolic changes associated with hyperammonemia in patients with propionic acidemia

Propionic acidemia is an autosomal recessive disorder caused by deficiency of propionyl CoA carboxylase. Affected patients can develop severe hyperammonemia, whose causative mechanism is unknown. In this study, we monitored changes in metabolic parameters associated with hyperammonemia in patients with propionic acidemia. Levels of ammonia were correlated with plasma levels of individual amino acids and carnitine and with urinary organic acids. Significance of correlations was determined with analysis of variance. Hyperammonemia positively correlated with an increase in branched-chain amino acids (leucine and isoleucine) and a decrease in glutamine/glutamate and esterified carnitine. The urinary excretion of methylcitric acid, formed by the combination of propionic acid with oxaloacetate from the Krebs cycle, increased while that of citric acid decreased with hyperammonemia. These results suggest that in propionic acidemia, hyperammonemia is triggered by catabolism with the accumulation of propionic acid derivatives. The decrease of the plasma levels of glutamine/glutamate with hyperammonemia in patients with propionic acidemia indicates that the mechanism producing hyperammonemia differs from that in urea cycle defects. The increase in methylcitric acid and decline in citric acid urinary excretion suggest that hyperammonemia in propionic acidemia might be related to inability to maintain adequate levels of glutamine precursors through a dysfunctional Krebs cycle.

Lipopolysaccharide‐induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat† ‡

Glutamine synthetase (GS) in the liver is restricted to a small perivenous hepatocyte population and plays an important role in the scavenging of ammonia that has escaped the periportal urea-synthesizing compartment. We examined the effect of a single intraperitoneal injection of lipopolysaccharide (LPS) in vivo on glutamine synthesis in rat liver. LPS injection induced expression of inducible nitric oxide synthase, which was maximal after 6 to 12 hours but returned toward control levels within 24 hours. Twenty-four hours after LPS injection, an approximately fivefold increase in tyrosine-nitrated proteins in liver was found, and GS protein expression was decreased by approximately 20%, whereas GS activity was lowered by 40% to 50%. GS was found to be tyrosine-nitrated in response to LPS, and immunodepletion of tyrosine-nitrated proteins decreased GS protein by approximately 50% but had no effect on GS activity. Together with the finding via mass spectrometry that peroxynitrite-induced inactivation of purified GS is associated with nitration of the active site tyrosine residue, our data suggest that tyrosine nitration critically contributes to inactivation of the enzyme. In line with GS inactivation, glutamine synthesis from ammonia (0.3 mmol/L) in perfused livers from 24-hour LPS-treated rats was decreased by approximately 50%, whereas urea synthesis was not significantly affected. In conclusion, LPS impairs hepatic ammonia detoxification by both downregulation of GS and its inactivation because of tyrosine nitration. The resulting defect of perivenous scavenger cell function with regard to ammonia elimination may contribute to sepsis-induced development of hyperammonemia in patients who have cirrhosis.

A Case of Serum Amino Acid Disturbance with Hyperammonemia in Patient with Primary Amyloidosis

There have been reports that hyperammonemia and amino acid disturbance can cause loss of consciousness in patients with multiple myelomas and normal liver function. We experienced a case of a 71-years-old female patient with amyloidosis, who had shown disturbance of consciousness. At that time, the serum ammonia level was elevated; serum amino acids disturbance was also noted. In particular, the decrease in branched-chain amino acids and increase in aromatic amino acids results in a low Fisher ratio. The Fisher ratio, the ratio of branched-chain to aromatic amino acids, has been suggested as an important indicator of consciousness disturbance. We report, for the first time in Korea, a case of amyloidosis, with mental disturbance due to serum amino acid disturbance. (Korean J Hematol 2005;40:54-57.)

The relationship of plasma glutamine to ammonium and of glycine to acid-base balance in propionic acidaemia.

Hyperammonaemia is a common and serious complication of propionic acidaemia. Treatment of hyperammonaemia with sodium phenylacetate or phenylbutyrate has not been well studied in this disorder. We reviewed the medical records of 5 patients with propionic acidaemia over a 16-year period. We collected information on events where plasma amino acids and ammonium, plasma acids and acid-base balance, or all 3 parameters were obtained simultaneously. All patients were on protein-restricted diet and carnitine throughout the period. In contrast to hyperammonaemia in patients with a urea cycle disorder, plasma glutamine levels were below the normal mean and there was no correlation between plasma ammonium and glutamine levels. The absence of positive correlation between plasma glutamine and ammonium suggests that the routine use of sodium phenylacetate or phenylbutyrate to treat hyperammonaemia in propionic acidaemia should be questioned until further studies are done. Throughout follow-up of our propionic acidaemia patients, we have observed that plasma glycine levels correlated positively with serum bicarbonate. The association of high plasma glycine with good acid-base balance might have a potential role in management and warrants further investigation.

Helicobacter pylori infection induces hyperammonaemia in Mongolian gerbils with liver cirrhosis

BACKGROUND AND AIMSWe previously reported the effect of Helicobacter pylori eradication on hyperammonaemia in patients with liver cirrhosis. However, the role of H pylori as a cause of hyperammonaemia is...

Post-feeding hyperammonaemia in patients with transjugular intrahepatic portosystemic shunt and liver cirrhosis: role of small intestinal ammonia release and route of nutrient administration

BACKGROUNDHyperammonaemia is a pathogenetic factor for hepatic encephalopathy that may be augmented after a transjugular intrahepatic portosystemic shunt (TIPS). Experimental data suggest that hyperammonaemia may be caused to a large...

Effects of Helicobacter pylori eradication therapy on hyperammonaemia in patients with liver cirrhosis.

Helicobacter pylori has strong urease activity. Ammonia produced by H pylori in the stomach can be a source of systemic ammonia in patients with hepatic dysfunction. The effect of the eradication of H pylori on hyperammonaemia was examined in patients with liver cirrhosis. Ammonia concentrations in blood and gastric juice were analysed in 50 patients with liver cirrhosis and hyperammonaemia. All patients were first treated with a low protein diet, kanamycin, lactulose, and branched chain enriched amino acid solution. Hyperammonaemia remained in 18 patients. These 18 patients were divided into three groups according to the status of H pylori infection; those with a diffuse distribution of H pylori in the stomach (group I), those with a regional distribution (group II), and those without H pylori (group III). These patients were given 30 mg iansoprazole, 1000 mg amoxicillin, and 400 mg clarithromycin or 500 mg metronidazole for two weeks to eradicate H pylori. In group I ammonia concentrations in blood and gastric juice were significantly reduced after H pylori eradication. The blood ammonia concentration at 12 weeks after the eradication was still significantly lower than that before eradication. In groups II and III the ammonia concentrations in blood and gastric juice were not significantly reduced after eradication therapy. The diffuse distribution of H-pylori in the stomach contributes partly to hyperammonaemia in patients with liver cirrhosis, and the eradication of H pylori is effective in patients with hyperammonaemia with diffuse H pylori infection in the stomach.

'Late onset' ornithine transcarbamylase deficiency: function of three purified recombinant mutant enzymes.

Although many mutations in the ornithine transcarbamylase gene have been correlated with 'late onset' of hyperammonemia in patients, the effects of these mutations on enzyme function are largely unknown. Three recurrent mutations (R40H, R277W and R277Q) found in patients with 'late onset' disease were incorporated into 'mature' human ornithine transcarbamylase cDNA and overexpressed in Escherichia coli. The three recombinant mutant enzymes were purified to homogeneity on an affinity column and their biochemical characteristics were compared to the wild type enzyme. The R277W and R277Q mutants display markedly reduced affinity for L-ornithine, loss of substrate inhibition, alkaline shift of pH optimum, and reduced thermal stability compared to the wild type enzyme. These differences, particularly the reduced affinity for L-ornithine, are sufficient to account for their biochemical effects. In contrast, the 'mature' R40H mutant was biochemically indistinguishable from the wild type enzyme in vitro.