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PubMed2004

Urinary alpha-ketoglutarate is elevated in patients with hyperinsulinism-hyperammonemia syndrome.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most frequent cause of recurrent episodes of hypoglycemia in infancy and results from different underlying genetic defects. The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from dominant germ line mutations within the glutamate dehydrogenase gene (GLUD1, OMIM *138130). Diagnosis of this entity is of clinical importance since invasive diagnostic procedures which are performed to identify focal pancreatic lesions are not necessary in HHS. Therefore, we investigated whether urinary concentration of alpha-ketoglutarate (alpha-KG) is elevated in patients with hyperinsulinism. METHODS: Excretion of alpha-KG was measured by gas-chromatography/mass spectrometry (GC/MS) in eight patients with an activating GLUD1 mutation and 90 controls. RESULTS: Urinary alpha-KG was significantly elevated in seven of eight patients when compared to controls. Hyperammonemia was found in six of the eight patients with HHS. No relation was found between the underlying GLUD1 mutation and the level of urinary alpha-KG as well as the presence or absence of hyperammonemia. CONCLUSION: Urinary alpha-KG is elevated in most patients with HHS and should be included in the work-up of patients with hyperinsulinism.

Adolescent↗
PubMedDate not supplied

[A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder].

Several cases of Parkinsonian syndrome, cognitive impairment or hyperammonemia induced by sodium valproate have been described in the literature. We report the first case presenting an association of the three adverse effects occurring with divalproate sodium prescribed for bipolar disorder: a 58-year-old man with a history of bipolar type I disorder presented with Parkinsonian syndrome and cognitive impairment of insidious onset. This patient had been treated for several years with lithium carbonate, with a successful effect on mood swings, but with distressing adverse effects such as hand tremor and diarrhoea. Lithium therapy was progressively withdrawn while sodium divalproate was initiated. Associated medications, unchanged for several years, were amisulpride (daily dose: 100 mg), liothyronine, ciprofibrate and benfluorex. The patient was treated with sodium divalproate for seven months (daily dose: 1,000 mg), and with trihexyphenidyle for one month for extrapyramidal symptoms. At hospital admission, he presented with temporal disorientation, slowed thinking, severe anterograde memory deficits, and Parkinsonian syndrome. The minimal mental state (MMS) score was 16 (maximum: 30). The patient was anxious but did no present with mood symptoms. He also developed hyperammonemia (124 micromol/liter, normal range: 15 to 60 micromol/liter) without signs or biochemical evidence of hepatic failure. Valproate concentrations were within the therapeutic ranges (79 mg/l, normal range: 50 to 100 mg/l). The CT-scan showed cerebral and cerebellar atrophy with enlarged ventricles. The electroencephalogram showed generalized slowing waves. All the symptoms resolved within one month after the withdrawal of divalproate: the extrapyramidal hypertonia resolved, the MMS score was 29. The CT-scan and the electroencephalogram returned to normal. The divalproate was replaced by lithium. After a one-year follow-up, the cognitive and neurological symptomatology did not reappear at the exception of the pre-existing hand tremor. The pathophysiology of valproate induced hyperammonemic encephalopathy remains unclear. A possible mechanism is neuronal toxicity induced by increased intracellular concentrations of glutamate and ammonium in astrocytes. Indeed, these abnormal intracellular concentrations increase the intracellular osmolarity and thus induce rise in intracranial pressure and cerebral oedema. Reversible dementia could be due to a direct toxic effect of valproate on the central nervous system or to an indirect effect mediated through valproate-induced hyperammonemia. It has been suggested that the occurrence of extrapyramidal syndrome could be explained by a disturbance in the GABAergic pathways inducing reversible dopamine inhibition. A drug adverse reaction should always be considered when a patient treated with valproate presents with extrapyramidal symptoms and cognitive disorders even when valproate concentrations are within standard therapeutic ranges.

Antipsychotic Agents↗
PubMed2003

Inhibition of acute hyperammonemia-induced convulsions by systemically administered gamma aminobutyric acid in rats.

The present study has investigated the effects of intraperitoneally administered gamma aminobutyric acid (GABA) on ammonium chloride-induced hyperammonemia and convulsions in rats. Systemically administered GABA did not alter the concentration of GABA in the brain of control as well as hyperammonemic animals. However, hyperammonemia-induced convulsions were inhibited by GABA in a dose-dependent manner. This was accompanied by a dose-dependent decrease in the concentrations of ammonia in both blood and brain and an elevation of glutamine in the blood. These results suggest that GABA has the potential to prevent acute hyperammonemia by increasing detoxification of ammonia to glutamine. As a result, the diffusion of ammonia from blood into the brain has been decreased. This accounts for an inhibition of convulsions by systemically administered GABA in hyperammonemic animals.

Ammonia↗
PubMed2002

Effects of hyperammonemia and liver failure on glutamatergic neurotransmission.

Glutamate is the main excitatory neurotransmitter in mammals. Glutamatergic neurotransmission involves several steps, beginning with release of glutamate from the presynaptic neuron. Glutamate in the extracellular space activates glutamate receptors present in the synaptic membranes, leading to activation of signal transduction pathways associated with these receptors. To avoid continuous activation of glutamate receptors, glutamate is removed from the synaptic cleft by specific glutamate transporters located mainly on astrocytes. All these steps are tightly modulated under physiological conditions, and alterations of any of the above steps may result in impairment of glutamatergic neurotransmission, leading to neurological alterations. There are studies in the literature reporting alterations in all these steps in hyperammonemia and/or hepatic failure. Glutamatergic neurotransmission modulates important cerebral processes. Some of these processes are altered in patients with liver disease and hepatic encephalopathy, who show altered sleep-wake patterns, neuromuscular coordination, and decreased intellectual capacity. The alterations in glutamatergic neurotransmission may be responsible for some of these neurological alterations found in hepatic encephalopathy. The effects of hyperammonemia and liver failure on different steps of glutamatergic neurotransmission including alterations of glutamate concentration in the extracellular fluid in brain, transport and transporters of glutamate, the content and function of different types of glutamate receptors and signal transduction pathways. Alterations induced by hyperammonemia and liver failure on the glutamate-nitric oxide-cGMP pathway in brain may result in changes in long-term potetiation and learning ability.

Amino Acid Transport System X-AG↗
PubMed2001

Reversible parkinsonism and hyperammonemia associated with portal vein thrombosis.

Portal-systemic encephalopathy may be seen with hyperammonemia that complicates chronic liver disease. We report an unusual case of reversible parkinsonism associated with hyperammonemia and portal vein thrombosis. An active 90-year-old male developed motor slowing and resting hand tremor over 6 months. Examination showed asterixis, bradykinesia, cogwheel rigidity, rest tremor, and a parkinsonian gait. Serum venous ammonia was elevated at 145 microM. The next day, the patient became comatose and serum ammonia was 178 microM. With lactulose therapy, serum ammonia level normalized and examination showed only minimal parkinsonism after 1 week. An abdominal CT scan identified portal vein thrombosis with porto-systemic shunting that reversed after 7 months of treatment. Examination 2 years later showed no signs of parkinsonism. Parkinsonism can dominate the clinical picture of patients with hyperammonemia before the onset of encephalopathy.

Aged↗
PubMed2006

Diarrhea and hyperammonemia in a horse with progressive neurologic signs.

A 2-year-old, Quarter Horse filly was referred to Michigan State University, Veterinary Teaching Hospital with a 2-3 day history of depression and partial anorexia progressing to severe, watery diarrhea with severe neurologic abnormalities, including repetitive muscle fasciculations, muscle stiffening, and collapse. Laboratory findings included severe polycythemia, neutropenia, metabolic acidosis, and electrolyte and fluid loss, consistent with watery diarrhea and endotoxic shock. Increased creatine kinase and aspartate transaminase activities were consistent with recent transport and the muscle abnormalities. Severe hyperammonemia (1369.0 micromol/L; control value, 15.3 micromol/L) was found, without other substantial laboratory evidence of hepatic dysfunction. The horse was euthanized because of poor prognosis and rapid clinical deterioration. Necropsy findings were unremarkable with the exception of severe diffuse colitis. Culture of colonic contents recovered >1000 colony-forming units of Clostridium perfringens. Based on these findings, marked hyperammonemia in this filly was attributed to changes in colonic flora leading to increased bacterial production of ammonia that was readily absorbed through the inflamed bowel wall, exceeding the hepatic capacity for deamination. Intestinal bacteria as a source of hyperammonemia in the absence of hepatic disease has been linked rarely to positive culture results for clostridial organisms.

Animals↗
PubMed2004

Hyperammonemia, bane of the brain.

Ammonia, normally produced from catabolism of amino acids, is a deadly neurotoxin. As such, the concentration of free ammonia in the blood is very tightly regulated and is exceeded by two orders of magnitude by its physiologic derivative, urea. The normal capacity for urea production far exceeds the rate of free ammonia production by protein catabolism under normal circumstances, such that any increase in free blood ammonia concentration is a reflection of either biochemical or pharmacologic impairment of urea cycle function or fairly extensive hepatic damage. Clinical signs of hyperammonemia occur at concentrations > 60 micromol/L and include anorexia, irritability, lethargy, vomiting, somnolence, disorientation, asterixis, cerebral edema, coma, and death; appearance of these findings is generally proportional to free ammonia concentration, is progressive, and is independent of the primary etiology. Causes of hyperammonemia include genetic defects in the urea cycle ("primary") or organic acidemias ("secondary"), as well as genetic or acquired disorders resulting in significant hepatic dysfunction. Thus, because of the neurotoxic implications of hyperammonemia and the typical absence of other specific laboratory abnormalities, appearance of the clinical signs should trigger an emergent search for elevated blood ammonia concentration.

Brain Diseases, Metabolic↗
PubMedDate not supplied

Arginine deficiency-induced hyperammonemia in a home total parenteral nutrition-dependent patient: a case report.

BACKGROUND: Patients with short bowel syndrome and renal dysfunction with TPN dependence are at high risk for developing hyperammonemia if the TPN does not contain sufficient quantities of arginine. Providing proper nutrition support is essential in the management of these patients. METHODS: We report on a patient with short bowel syndrome, TPN dependence, and normal renal function who developed hyperammonemic encephalopathy due to inadvertent lack of arginine in his TPN. RESULTS: The patient was successfully treated with hemodialysis and an IV arginine infusion to resolve the hyperammonemia. His home TPN was also adjusted such that arginine was added to his subsequent solutions. CONCLUSIONS: Our patient underscores the importance of adequate and sustained arginine supplementation to avoid hyperammonemia in TPN dependent patients with short bowel syndrome.

Adult↗
PubMed2001

Heliox use in the treatment of acute hyperammonemia.

The objective of this study was to evaluate a new method for the treatment of acute hyperammonemia with a helium-oxygen mixture (heliox). We conducted a prospective, randomized, controlled study of male Sprague-Dawley rats. Experimental hyperammonemia was induced by 7 days of a high-ammonia diet. Subsequently, the animals were randomly divided into two groups: the study group treated with heliox breathing for 24 hours and a control group breathing room air for 24 hours. A prospective, randomized, controlled laboratory animal study was conducted at an animal research facility. The baseline plasma ammonia level was 9.49 +/- 10.96 micromol/L. After 7 days of a high-ammonia diet, the plasma ammonia level rose to 31.53 +/- 8.86 micromol/L. There was a significant statistical difference between the plasma ammonia level following 24 hours of heliox therapy (23.14 +/- 13.97 micromol/L) and the ammonia level in the control group (42.31 +/- 24.25 micromol/L) (P < .05). Heliox breathing was found to be an efficient treatment modality for decreasing plasma ammonia levels in an animal model. Further studies are required to evaluate its potential application in the treatment of patients with hyperammonemia.

Administration, Inhalation↗
PubMed2001

Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients.

Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene, resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 micromol/L, normal <50 micromol/L) was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC(50), or concentrations required for 50% inhibition of GDH activity, ranging from 140 to 580 nM, compared with control IC(50) value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were performed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene.

Adolescent↗
PubMed2004

Valproic acid-induced hyperammonemia and thrombocytopenia in an elderly woman.

OBJECTIVE: To describe a case of oral valproic acid-induced hyperammonemia and thrombocytopenia in an elderly patient. CASE SUMMARY: A 76-year-old white woman presented to the emergency department with generalized weakness, confusion, nausea, and vomiting. She was taking sodium divalproex 750 mg 3 times daily, with valproic acid concentration 144 mg/L. She was admitted to the medical ward. The dose of sodium divalproex was decreased and discontinued. During her hospital stay, the woman's ammonia level rose to 211 microg/dL despite a normal valproic acid concentration. She was confused, somnolent, and had decreased mobility. Her platelet count decreased from 133 to 86 x 10(3)/mm(3). Gabapentin was prescribed for seizure control. The patient's mental status, ammonia level, and platelet count returned to baseline following discontinuation of valproic acid. DISCUSSION: It has been reported that valproic acid can interfere with the enzyme carbamoylphosphate synthetase, which is responsible for incorporating ammonia into the urea cycle. It has also been reported that valproic acid can increase the transport of glutamine across the mitochondrial membrane in the kidney, thereby increasing the production of ammonia. The etiology of valproic acid-induced thrombocytopenia has not been elucidated. Using the Naranjo probability scale, a probable relationship between hyperammonemia and valproic acid and a possible relationship between thrombocytopenia and valproic acid were determined. CONCLUSIONS: Valproic acid can be associated with hyperammonemia and thrombocytopenia. Clinicians should be aware of changes in patients' cognitive and functional capacity, especially elderly patients on sodium divalproex.

Aged↗
PubMed2004

Ultrasonographic findings in dogs with hyperammonemia: 90 cases (2000-2002).

OBJECTIVE: To determine ultrasonographic abnormalities in dogs with hyperammonemia. DESIGN: Retrospective study. ANIMALS: 90 client-owned dogs with hyperammonemia. PROCEDURE: Ultrasonography of the abdominal vessels and organs was performed in a systematic way. Dogs in which the ultrasonographic diagnosis was a congenital portosystemic shunt were included only if they underwent laparotomy or necropsy. Dogs in which the abdominal vasculature appeared normal and dogs in which the ultrasonographic diagnosis was acquired portosystemic shunts and portal hypertension were included only if liver biopsy specimens were submitted for histologic examination. RESULTS: Ultrasonography excluded portosystemic shunting in 11 dogs. Acquired portosystemic shunts were found in 17 dogs, of which 3 had arterioportal fistulae and 14 had other hepatic abnormalities. Congenital portosystemic shunts were found in 61 dogs, of which 19 had intrahepatic shunts and 42 had extrahepatic shunts. Intrahepatic shunts originated from the left portal branch in 14 dogs and the right portal branch in 5. Extrahepatic shunts originated from the splenic vein, the right gastric vein, or both and entered the caudal vena cava or the thorax. Ultrasonography revealed splenic-caval shunts in 24 dogs, right gastric-caval shunts in 9 dogs, splenic-azygos shunts in 8 dogs, and a right gastric-azygos shunt in 1 dog. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that ultrasonography is a reliable diagnostic method to noninvasively characterize the underlying disease in dogs with hyperammonemia. A dilated left testicular or ovarian vein was a reliable indicator of acquired portosystemic shunts.

Animals↗
PubMedDate not supplied

Transient hyperammonemia in a neonate.

Neonatal hyperammonemia is a medical emergency requiring a multidisciplinary teamwork for early recognition and early treatment. The causes of neonatal hyperammonemia vary. The transient hyperammonemia of the neonate (THAN) occurs mostly in premature babies, and the prognosis is usually better than for urea cycle disorders. Here we present a near-term premature male infant with THAN. He exhibited the symptoms during the first 36 hours of life and survived after continuous arteriovenous hemodiafiltration (CAVHD). Nutritional support and sodium benzoate were also given. The diagnosis was based on laboratory tests. Long-term follow-up of neurodevelopment was suggested.

Anti-Infective Agents↗
PubMed1993

Quinolinic acid in children with congenital hyperammonemia.

Levels of the excitotoxin quinolinic acid (QUIN) were measured in the cerebrospinal fluid of infants and children with congenital hyperammonemia. Twofold to tenfold elevations of QUIN were found in 4 neonates in hyperammonemic coma (QUIN range, 250-990 nM; control mean, 110 +/- 90 nM; p < 0.005). Similar elevations of neopterin were found (range, 24-75 nM; control mean, 9.0 +/- 4.9 nM; p < 0.005). In addition, significant elevations of QUIN were found in 14 older children with congenital hyperammonemia (mean, 50 +/- 20 vs 17 +/- 6 nM; p < 0.05). Neopterin levels were not elevated in these children. The QUIN may originate from an increase in tryptophan transport across the blood-brain barrier or from induction of indolamine-2,3-dioxygenase activity. These findings support a role for QUIN in the neuropathology of congenital hyperammonemia. They also suggest the potential utility of N-methyl-D-aspartate receptor-blocking agents or inhibitors of QUIN synthesis in the treatment of hyperammonemic coma.

Ammonia↗
PubMedDate not supplied

The association of hepatic glycogen depletion with hyperammonemia in cirrhosis.

Hyperammonemia is a well-recognized metabolic abnormality which occurs in cirrhotic patients with advanced liver dysfunction. We recently documented that hyperglucagonemia that occurs as a result of hepatic glycogen depletion may be responsible for this hyperammonemia by promoting gluconeogenesis to provide glucose as a fuel for functioning of several organ systems. Thus, hepatic glycogen depletion may be the initial process responsible for hyperammonemia. Since the glucose rise following intravenous glucagon administration is a reflection of hepatic glycogen breakdown, we studied the effect of glucagon (1 mg) injection on plasma glucose, insulin and ammonia levels after an overnight fast in cirrhotic patients and normal subjects. Glucose rise was significantly stunted, and ammonia rise was significantly greater in patients with advanced liver dysfunction as compared to normal subjects. Furthermore, the smaller the glucose increment, the earlier the ammonia rise. The smallest glucose responses were seen in the patients with the highest basal plasma ammonia levels. Finally, significant negative relationships were noted between the glucose response to glucagon administration (delta glucose) and the degree of liver dysfunction as reflected by Composite Clinical Laboratory Index, as well as basal ammonia and ammonia responses (delta ammonia) on the other. Therefore, this study suggests that hepatic glycogen depletion may be the initial event leading to elevated plasma ammonia concentrations in hepatic cirrhosis.

Adult↗
PubMed1995

Hyperammonemia increases serotonin 1A receptor expression in both rat hippocampus and a transfected hippocampal cell line, HN2-5.

Hyperammonemia is an important cause of cerebral dysfunction in liver failure. We used two well-established models to induce hyperammonemia in rats, injection of urease and injection of methionine sulfoximine (MSO). Urease gave a 10-fold increase in blood ammonia while MSO, a glutamine synthetase inhibitor, gave a 4-fold increase in blood ammonia with no increase in brain glutamine levels. We observed a 2-fold increase in 5-HT1A receptor (5-HT1A-R) expression ([3H] 8-OH-DPAT binding) in hippocampus, and little change elsewhere, including thalamus in both models, thus eliminating a role for increased glutamine in the receptor induction. In contrast, a 4 to 8-fold increase in 5-HT1A-R mRNA was observed both in hippocampus and thalamus, suggesting some post-transcriptional regulation. In the absence of glutamine, ammonium acetate treatment of a hippocampal cell line which had been engineered to stably express the 5-HT1A-R (HN2-5) gave a 1.5-fold increase in [3H] 8-OH-DPAT binding and a 4-fold increase in the mRNA levels for the 5-HT1A-R. We conclude that the cell line HN2-5 is a good model for studying some of the biochemical sequelae of hyperammonemia and that changes in brain function are not only at the metabolic level, as thought earlier, but can also occur at the transcriptional level.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Chronic hyperammonemia in rats impairs activation of soluble guanylate cyclase in neurons and in lymphocytes: a putative peripheral marker for neurological alterations.

Chronic hyperammonemia impairs the glutamate-nitric oxide-cGMP pathway in rat brain in vivo. The aims of this work were to assess whether hyperammonemia impairs modulation of soluble guanylate cyclase, and to look for a peripheral marker for impairment of this pathway in brain. We activated the pathway at different steps using glutamate, SNAP, or YC-1. In control neurons these compounds increased cGMP by 7.4-, 9.7- and 7.2-fold, respectively. In ammonia-treated neurons formation of cGMP induced by glutamate, SNAP, and YC-1 was reduced by 50%, 56%, and 52%, respectively, indicating that hyperammonemia impairs activation of guanylate cyclase. This enzyme is also present in lymphocytes. Activation of guanylate cyclase by SNAP or YC-1 was impaired in lymphocytes from hyperammonemic rats. These results suggest that determination of the activation of soluble guanylate cyclase in lymphocytes could serve as a peripheral marker for impairment of the neuronal glutamate-nitric oxide-cGMP pathway in brain.

Ammonia↗
PubMed1993

Effect of urease-induced hyperammonemia on metabolism of guanidino compounds.

We previously reported that guanidino compounds produced by the catabolism of arginine play an important role in the pathophysiology of acute hyperammonemia. In order to understand the metabolism of guanidino compounds during sustained hyperammonemia, we investigated the effect of intraperitoneal urease injection (800 IU/kg) on the levels of guanidino compounds in blood, liver, kidney, and brain of rats. Control rats received an equal volume of saline. Eight hours following injection, rats were sacrificed and blood and tissues were removed. Ammonia and urea were determined by enzymatic and colorimetric assays, respectively. Guanidino compounds were analyzed by high-performance liquid chromatography. Blood and tissue ammonia were significantly increased and urea decreased in urease-treated animals. Blood and kidney arginine levels were significantly decreased although hepatic arginine was increased following urease injection. Elevated hepatic arginine may be due to the rapid conversion of urea to ammonia by urease and the development of a futile urea cycle. Catabolites produced by the transamidination of arginine were significantly decreased in the blood, liver, kidney, and brain of urease-treated rats, whereas acetylation of hepatic arginine to alpha-N-acetylarginine was increased. Blood and tissue guanidinosuccinic acid levels were not elevated during urease induced hyperammonemia, supporting the hypothesis that urea is a precursor for the synthesis of guanidinosuccinic acid.

Ammonia↗