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PubMed1986

Renal handling of carnitine in children with carnitine deficiency and hyperammonemia associated with valproate therapy.

Free and acylcarnitine in serum and urine samples were measured in five patients with hyperammonemia associated with anticonvulsant therapy including sodium valproate, of whom three had a Reye-like syndrome. All had considerable reduction in serum free carnitine and slight increase of acylcarnitine concentrations, suggesting increased conversion of free to acylcarnitine by valproate administration. Urinary excretion of both free and acylcarnitine was increased, accompanied by depressed reabsorption of free carnitine and decreased acylcarnitine/free carnitine clearance ratio. These results indicate a decreased threshold for free carnitine. The combination of these several factors may be responsible for carnitine deficiency in patients with hyperammonemia taking valproate.

Ammonia↗

PubMed1984

Hyperammonemia after transurethral resection of the prostate: a report of 2 cases.

We report on 2 patients who became deeply comatose after transurethral resection of the prostate. Both patients were severely hyponatremic and hyperammonemic but the course of the comas followed serum ammonia concentrations more closely than serum sodium concentrations. The genitourinary irrigant used in both procedures was a 1.5 per cent glycine solution. Serum amino acid analyses in 1 patient suggested that the postoperative hyperammonemia was due to catabolism of glycine absorbed during surgery. The inadequate activation of normal pathways of ammonia metabolism in this patient may have been caused by a partial deficiency of the urea cycle enzyme argininosuccinate synthetase. We believe that hyperammonemia should be considered as a cause of encephalopathy after transurethral resection of the prostate. The 1.5 per cent glycine genitourinary irrigating solution may not be as nontoxic as generally believed.

Aged↗

PubMed1984

Hyperammonemia in a boy with obstructive ureterocele and proteus infection.

We report on a boy with ureteroceles that obstructed the bladder outlet and ureters, who presented with sepsis and hyperammonemia despite normal liver function. The hyperammonemia was most likely caused by excessive absorption of ammonia produced by Proteus mirabilis in the obstructed urinary tract.

Ammonia↗

PubMed1996

Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma.

BACKGROUND/AIMS: Exogenous hyperammonemia is known to decrease the plasma levels of branched-chain amino acids (BCAA). To investigate whether changes in intracellular amino acid concentrations of muscle are associated with and may, at least in part, mediate this effect, experiments were carried out on a total of 60 male Wistar rats. METHODS: Five groups were formed in a randomized manner. Group A: no treatment; groups B1 and B2: 2-hour and 6-hour continuous central-venous infusions, respectively, of sodium salts; groups C1 and C2: 2-hour and 6-hour infusions of ammonium salts. We obtained venous blood samples and muscle biopsies. Plasma ammonia, whole blood glucose, serum insulin, blood pH, and amino acids in plasma as well as in the intracellular water of muscle were measured. RESULTS: As compared with control group A, groups C1 and C2 displayed a 3.3- and a 4-fold increase, respectively, in the plasma ammonium concentration. Regarding insulin, the ammonium-infused rats were similar to group A but not to the sodium-infused B groups, which had significantly lower insulin concentrations. Administering ammonium brought about a decline in BCAA concentrations in plasma after 2 hours and in muscle after 6 hours. The ammonium-induced fall in intracellular BCAA values was preceded by an increase of glutamine as well as by a decrease of glutamate and alanine in both plasma and muscle. CONCLUSIONS: It is pointed out that the inter-group differences in serum insulin, although possibly accounting for some of the findings, can by no means explain the entire pattern of amino acid concentrations seen after the ammonium infusions. Instead, our results agree with the hypothesis that hyperammonemia indirectly lowers the plasma levels of BCAA by stimulating glutamine synthesis, thus reducing the intracellular glutamate pool, which is likely to be restored, at least in part, by an intensified BCAA transamination. Clarification is needed as to whether carbon skeletons derived from valine and isoleucine additionally contribute to replenishing the glutamate pool.

Alanine↗

PubMed1997

L-ornithine vs. L-ornithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats.

BACKGROUND/AIMS: The effect of L-ornithine (ORN) and L-ornithine-L-aspartate (OA) therapy on "extracerebral" nitrogen metabolism, brain metabolism and neurotransmission has been investigated in portacaval shunted rats with hyperammonemia-induced encephalopathy. METHODS: One day before ammonium-acetate infusion, a portacaval shunt was performed in three experimental groups: 1-control rats, 2-ORN-treated rats and 3-OA-treated rats. Ammonium-acetate was given as an intravenous bolus injection (0.4 mmol.kg bw-1) followed by a constant infusion (1.9 mmol.kg bw-1.h-1) so that steady-state blood ammonia concentrations (500-800 microM) were obtained in the course of 5 h. After 1 h, ammonium-acetate infusion, either L-ornithine or L-ornithine-L-aspartate, was infused for the next 4 h (3.0 mmol.kg bw-1.h-1) in the treated groups. The following parameters were measured: clinical grade of encephalopathy, EEG activity (n = 10 - 20/group), amino acids in plasma (n = 10 - 20/group) and brain dialysate (n = 5 - 9/group), and brain metabolites obtained by in vivo cerebral 1H-MRS (n = 4 - 6/group). RESULTS: ORN and OA treatment resulted in significantly lower blood (34% and 39%) and brain (42% and 22%) ammonia concentrations, significantly higher urea production (39% and 86%) and significantly smaller increases in brain glutamine and lactate concentrations than in controls. These changes were associated with a significantly smaller increase in clinical grade of encephalopathy in ORN- and OA-treated rats, and a significant improvement in EEG activity in ORN-treated rats. OA-treated rats showed a significant increase in aspartate and glutamate concentrations in brain dialysate. CONCLUSIONS: The beneficial effects of both treatments on the manifestations of hyperammonemia-induced encephalopathy can be explained by a reduction in blood and brain ammonia concentrations. It is suggested that when OA is administered, the effect of ornithine is partly counteracted by aspartate, inducing high brain extracellular concentrations of the two excitatory amino acids glutamate and aspartate, and perhaps causing overstimulation of NMDA receptors.

Ammonia↗

PubMed1993

Hyperammonemia secondary to valproic acid as a cause of lethargy in a postictal patient.

Hyperammonemia has been described as a complication of valproic acid therapy but may often be overlooked as a cause of lethargy in the postictal patient who presents to the emergency department. We present the case of a postictal patient with lethargy, hyperammonemia, otherwise normal liver function tests, and a therapeutic valproic acid level. Based on our experience and on previously published data, serum ammonia levels appear to be indicated in all ED patients on valproic acid therapy who present with altered mental status. To the best of our knowledge, this has not been reported previously in the emergency medicine literature.

Adult↗

PubMed1998

Differential inhibition by hyperammonemia of the electron transport chain enzymes in synaptosomes and non-synaptic mitochondria in ornithine transcarbamylase-deficient spf-mice: restoration by acetyl-L-carnitine.

Sparse-fur (spf) mouse is the ideal animal model to study the neuropathology of congenital ornithine transcarbamylase (OTC) deficiency. Our current hypothesis implies that an ammonia-induced depletion of energy metabolism in the spf mouse, could be due to a reduction in the activities of the enzymes of the electron transport chain and a treatment with acetyl-L-carnitine could normalize this abnormality. We also hypothesized that there might be a differential degree of inhibition in synaptosomal and non-synaptic mitochondria, for the enzymes of the electron transport chain, caused by congenital hyperammonemia. We have therefore measured the activities of NADH-cytochrome C oxidoreductase, succinate cytochrome C oxidoreductase and cytochrome C oxidase in synaptosomes and non-synaptic mitochondria, isolated from spf mice and CD-1 controls with and without acetyl-L-carnitine treatment. Our results indicate a significant reduction (19-34%) in the activities of these complexes in synaptosomes in untreated spf mice, whereas in non-synaptic mitochondria, there was a tendency for the activities to decrease. Acetyl-L-carnitine treatment enhanced these activities (15-64%) for all the three enzyme complexes and its effect was more prominent on succinate cytochrome C oxidoreductase activity (64%). These studies point out that: (a) ammonia-induced disturbances in the energy metabolism could be more pronounced in neuronal mitochondria, and (b) the effect of acetyl-L-carnitine on the restoration of cerebral ATP in hyperammonemia could be through an enhancement of the activities of various electron transport chain enzymes.

Acetylcarnitine↗

PubMed1997

Portacaval shunting and hyperammonemia stimulate the uptake of L-[3H] arginine but not of L-[3H]nitroarginine into rat brain synaptosomes.

Elevated activities of nitric oxide synthase (NOS) have been reported previously in the brains of portacaval-shunted (PCS) rats, a model of chronic hepatic encephalopathy (HE). As L-arginine availability for nitric oxide synthesis depends on a specific uptake mechanism in neurons, we studied the kinetics of L-[3H]-arginine uptake into synaptosomes prepared from the brains of PCS rats. Results demonstrate that L-arginine uptake is significantly increased in cerebellum (60%; p < 0.01), cerebral cortex (42%; p < 0.01), hippocampus (56%; p < 0.01), and striatum (51%; p < 0.01) of PCS rats compared with sham-operated controls. Hyperammonemia in the absence of portacaval shunting also stimulated the transport of L-[3H]arginine; kinetic analysis revealed that the elevated uptake was due to increased uptake capacity (Vmax) without any change in affinity (Km). Incubation of cerebellar synaptosomes with ammonium acetate for 10 min caused a dose-dependent stimulation of L-[3H]arginine uptake. Neither portacaval shunting nor hyperammonemia had any significant effect on the synaptosomal uptake of NG-nitro-L-[3H]arginine. These studies demonstrate that increased NOS activity observed in experimental HE may result from increased availability of L-arginine resulting from a direct stimulatory effect of ammonia on L-arginine transport.

Acetates↗

PubMed1991

A nationwide survey on transient hyperammonemia in newborn infants in Japan: prognosis of life and neurological outcome.

A nationwide survey of transient hyperammonemia in newborns was carried out in Japan. A total of 18 patients, consisting of 12 male and 6 female infants, were reported from 11 facilities. These neonates exhibited hyperammonemia with plasma ammonia levels in the range from 124 to 6256 micrograms/dl. Four newborn infants of the 18 died in the neonatal period, and an additional one died in the early infancy. Among the 13 infants who were alive at the time of this survey, 6 had neurological sequelae, including mental retardation, spastic quadriplegia and epilepsy. The multivariate analysis revealed that the Apgar score at 1 minute, peak plasma ammonia concentration, birth weight and sex were significant factors affecting the prognosis of life.

Ammonia↗

PubMed1976

Urea-cycle enzyme deficiencies and an increased nitrogen load producing hyperammonemia in Reye's syndrome.

Assay of urea-cycle enzymes in liver tissue showed ornithine transcarbamylase activities of 18 to 72 per cent of the normal mean in eight patients with Reye's syndrome, below the range of normal in seven of eight, and, in six cases, as low as those in females with X-linked deficiency of this enzyme. Carbamyl phosphate synthetase activities were less than 32 per cent of controls in two patients. Argininosuccinate synthetase and lyase activities were normal in seven patients. Arginase was normal in two biopsy specimens, but below normal in four of five autopsy specimens. The Km's for ornithine and carbamyl phosphate, pH optimum, and heat lability of ornithine transcarbamylase were normal. Two patients excreted 0.64 and 0.58 g per kilogram per day of urinary nitrogen at the peak of hyperammonemia, in spite of peritoneal dialysis. The hyperammonemia of Reye's syndrome apparently results from excess waste nitrogen that overwhelms the ability of reduced ornithine transcarbamylase (and occasionally carbamyl phosphate synthetase) to detoxify the ammonia load.

Adolescent↗

PubMed1978

Transient hyperammonemia of the preterm infant.

We report on five preterm infants (34 to 36 weeks' gestation) in whom an overwhelming illness developed within the first 48 hours of life. Each had mild respiratory distress that progressed within 48 hours to deep coma requiring ventilatory assistance. Ammonia concentrations in the plasma ranged from 844 to 7640 microgram per deciliter. Four received exchange transfusion and peritoneal dialysis; ammonia values returned to the normal range (less than 150 mug per deciliter) within 72 hours and remained there even after protein challenge. These four subsequently fed and developed normally. The fifth infant died without an attempt to lower plasma ammonia. In this infant (and two of the others) urea-cycle enzymes measured in liver tissue were in the normal range. Transient hyperammonemia of unknown cause may be a relatively common variety of neonatal hyperammonemia; it responds well to prompt diagnosis and aggressive therapy.

Ammonia↗

PubMed1984

Hyperammonemia and orotic aciduria in portacaval-shunted rats.

The effect of a portacaval shunt-induced alteration in liver function on nitrogen metabolism was studied in rats. Within a few days after surgery, portacaval-shunted rats grew with an average daily gain in body weight equal to sham-operated control rats. Within 1 week after surgery, portacaval-shunted rats excreted 20% more orotic acid in their urine compared to control rats. The difference increased to 37% after 3 weeks. Plasma ammonia levels were elevated by 78% in portacaval-shunted rats compared to control rats after 2 weeks. Portacaval-shunted rats injected with a challenging load of ammonium chloride (5 mmol/kg) excreted half as much orotic acid in their urine over a 24-hour period as similarly injected controls. The simultaneous injection of 1.5 mmol/kg of arginine prevented the ammonia-induced increase in orotic acid excretion in both shunted and control rats. However, feeding rats diets supplemented with 1% arginine did not prevent the chronic hyperammonemia and orotic aciduria produced by the construction of portacaval shunts. Similar experiments with diets supplemented with 1% sodium benzoate to induce alternative pathways for nitrogen excretion were also without effect. These results are in contrast to recent clinical studies reporting the effectiveness of sodium benzoate in treating hyperammonemia in patients with urea cycle enzyme defects.

Ammonia↗

PubMed1984

Partial ornithine transcarbamylase deficiency associated with recurrent hyperammonemia, lethargy and depressed sensorium.

A 6-year-old boy presented with recurrent coma associated with hyperammonemia and infection is reported. A liver biopsy revealed decreased ornithine transcarbamylase (OTC) activity (16% of normal). The enzymatic abnormality in the child is supported by the finding of elevated orotic acid excretion in his mother following a protein load, compatible with an X-linked pattern of inheritance. Since initiation of a dietary arginine supplement, the child has not had recurrent episodes of hyperammonemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed1993

Cerebral cortex ammonia and glutamine metabolism in two rat models of chronic liver insufficiency-induced hyperammonemia: influence of pair-feeding.

Enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis, and glutamine release into the bloodstream have been hypothesized to deplete cerebral cortex glutamate pools. We investigated this hypothesis in rats with chronic liver insufficiency-induced hyperammonemia and in pair-fed controls to rule out effects of differences in food intake. Cerebral cortex plasma flow and venous-arterial concentration differences of ammonia and amino acids, as well as cerebral cortex tissue concentrations, were studied 7 and 14 days after surgery in portacaval-shunted/bile duct-ligated, portacaval-shunted, and sham-operated rats, while the latter two were pair-fed to the first group, and in normal unoperated ad libitum-fed control rats. At both time points, arterial ammonia was elevated in the chronic liver insufficiency groups and arterial glutamine was elevated in portacaval shunt/biliary obstruction rats compared to the other groups. In the chronic liver insufficiency groups net cerebral cortex ammonia uptake was observed at both time points and was accompanied by net glutamine release. Also in these groups, cerebral cortex tissue glutamine, many other amino acid, and ammonia levels were elevated. Tissue glutamate levels were decreased to a similar level in all operated groups compared with normal unoperated rats, irrespective of plasma and tissue ammonia and glutamine levels. These results demonstrate that during chronic liver insufficiency-induced hyperammonemia, the rat cerebral cortex enhances net ammonia uptake and glutamine release. However, the decrease in tissue glutamate concentrations in these chronic liver insufficiency models seems to be related primarily to nutritional status and/or surgical trauma.

Amino Acids↗

PubMed1984

Hyperammonemia in asterixis induced by carbamazepine: two case reports.

Two patients developed asterixis while they were taking carbamazepine at "therapeutic" levels. The only laboratory abnormality was slight hyperammonemia. It occurred with normal hepatic function as a dose-related effect. In fact, the blood ammonia level decreased and asterixis ceased when carbamazepine was stopped or reduced in dosage. The relationship between asterixis and hyperammonemia during carbamazepine therapy is discussed.

Aged↗

PubMedDate not supplied

Persistent hyperammonemia in two related Morgan weanlings.

Persistent hyperammonemia was diagnosed in 2 Morgan fillies with clinical signs that developed early in the postweaning period. Diagnostic evaluation, including routine serum chemistries, CBC, liver biopsy, hepatic ultrasonography, liver function test, and necropsy findings did not support a toxic, developmental, or infectious cause. Abnormal serum amino acid and urine orotic acid concentrations suggest that the foals may have had an inherited disorders described in humans as hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome. The disorder is thought to be caused by a defective mitochondrial transporter protein, such that ornithine, required for complete urea synthesis, is deficient, thus causing increases in blood ammonia and ornithine concentrations.

Amino Acids↗

PubMed1996

Hyperammonemia in a patient with short bowel syndrome and chronic renal failure.

A patient with short bowel syndrome (SBS) and renal failure developed a disturbance of consciousness with hyperammonemia. Abnormally low concentrations of ornithine, citrulline, and arginine were observed on the plasma aminogram. These results suggested that the activities of amino acid synthetase localized in the small intestinal flora were lost. The small intestine is required for arginine synthesis; thus, infusion limited to the essential amino acids to SBS patients will cause a deficiency of the urea cycle intermediates, ornithine, citrulline, and arginine and may lead to hyperammonemia. In addition, the renal insufficiency may have caused decreased excretion of ammonia. In this patient, supplemental arginine improved the symptoms.

Aged↗

PubMed1990

Hyperammonemia in multiple myeloma.

Two patients with multiple myeloma who appeared to be producing ammonia are reported. Both patients showed hyperammonemia and amino acid disturbances, such as a low Fischer ratio. One patient had Bence Jones protein (lambda) type myeloma and became comatose, but the hyperammonemia and disturbance of consciousness were improved by chemotherapy for the myeloma. The other patient had IgA kappa type myeloma and somnolence and died of malignant pleurisy despite intensive chemotherapy. Autopsy showed widespread multiple myeloma and an almost normal liver. Ammonia levels in the supernatant of cultured myeloma cells from the patient's pleural effusion increased almost linearly from the time of cell seeding. These observations showed that ammonia was produced at a high level by these human myeloma cells. We also found that one of the common myeloma cell lines, RPMI 8226, could produce ammonia as well.

Amino Acids↗