L-carnitine for valproic acid-induced toxicity.

AIMS: Review the effectiveness and dosing of L-carnitine for valproic-acid induced toxicity. METHODS: A literature review of the pharmacokinetics and clinical use of L-carnitine was performed. RESULTS: Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L-carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg, and the fraction excreted unchanged in urine is 0.73-0.95, suggesting that renal clearance of L-carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations. CONCLUSIONS: There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.

Regulation of autophagy by ST3GAL2-mediated α2-3 sialylated glycosphingolipids in hepatic encephalopathy.

In neurological diseases, the regulation of autophagy plays a crucial role in their pathology, particularly the relationship between autophagy and hepatic encephalopathy (HE) which merits detailed investigation. Glycosphingolipids are abundant and broadly functional in the nervous system and are closely associated with autophagy. However, the specific link and mechanisms between glycosphingolipids and autophagy in HE remain unclear. This study aims to explore the impact of glycosphingolipid changes on the autophagy in HE and its potential mechanisms. Utilizing lectin microarrays, we observed elevated expression levels of α2-3 sialylated glycosphingolipid in the brain tissue of HBV transgenic mice and ammonia-induced astrocyte models, suggesting that the increase in α2-3 sialylated glycosphingolipid is related to HE. Further research revealed that the increased expression of α2-3 sialylated glycosphingolipid, mediated by ST3GAL2, affects autophagy by regulating the autophagy initiation complex Vps34-Beclin-1. In summary, our research not only comprehensively reveals the changes in brain glycosphingolipid during HBV-related HE but also elucidates the interactions and regulatory mechanisms between α2-3 sialylated glycosphingolipid and autophagy. This study provides a new perspective on understanding the pathogenesis of HE and offers novel theories and targets for future research and treatment strategies.

Hyperammonaemia: review of the pathophysiology, aetiology and investigation.

Acute hyperammonaemia is a medical emergency as it can progress to cerebral oedema, seizures, coma and death. Hepatic encephalopathy secondary to cirrhotic disease or portosystemic shunting are relatively well-known causes, but non-cirrhotic aetiologies of acute hyperammonaemia are less well-known, especially in the emergency department. However, an elevated ammonia is not required to make the diagnosis of hepatic encephalopathy. Although measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status, as early identification allows early effective management which may prevent irreversible brain damage, there is currently reduced awareness among physicians of the non-cirrhotic aetiologies of acute hyperammonaemia. Furthermore, measurement of ammonia in patients with cirrhosis has been shown to have low sensitivity and specificity, and not to have altered management in the majority of cases; thus, measurement of ammonia is currently not recommended in guidelines for management of hepatic encephalopathy. We sought to describe the pathophysiology of hyperammonaemia and review the non-cirrhotic causes. This was achieved by review of MEDLINE, PubMed and Web of Science databases to include published English literature within the last 20 years. We also present a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases.

Ureaplasma urealyticum infection following organ transplantation: a case report and narrative review.

OBJECTIVE: One case of Ureaplasma urealyticum (UU) infection after kidney transplantation was reported, and relevant literature was collected to provide a scientific reference basis for clinical diagnosis and treatment. METHODS: A case of UU infection after renal transplantation in our hospital was analyzed retrospectively. PubMed, Embase and Cochrane databases were searched for case reports of UU infection after organ transplantation before 30 June 2024. The clinical and laboratory characteristics, treatment and prognosis of UU infection were summarized and analyzed. RESULTS: A 65-year-old man underwent renal transplantation on 26 January 2022 due to chronic renal disease (grade 2) caused by focal sclerosing glomerulonephritis. Hyperammonaemia and coma occurred after the operation, and the patient died. A total of 38 case reports or series of cases were included in this study, involving 44 patients. The case reports included 22 cases of kidney transplantation, 11 cases of lung transplantation, 4 cases of heart transplantation,1 case of liver transplantation and 6 cases of multiple organ transplantation. Ureaplasma urealyticum infection occurred in 74.47% of cases within 1 month after transplantation, and the main symptoms after the infection were mental. After the onset of the disease, the most abnormal examination index was the increase of blood ammonia, followed by the increase of white blood cells. Therapeutic drugs included tetracyclines (doxycycline or minocycline), quinolones and azithromycin. The clinical symptoms could be significantly improved after 24 h of taking the fastest-acting medication. The highest mortality rate was in patients infected with Ureaplasma after lung transplantation. CONCLUSION: Early identification of UU and timely and correct drug treatment are essential to saving the lives of patients.

Pyroglutamate acidosis 2023. A review of 100 cases.

This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.

Acceptability of plasma ammonia results when samples are not transported and processed under ideal conditions.

BACKGROUND: It is recommended that samples for plasma ammonia analysis are kept chilled and processed promptly as in vitro metabolism causes falsely elevated results. Rejection of unsuitable samples can cause delayed diagnosis and treatment of hyperammonaemia with potentially serious clinical consequences. The Metabolic Biochemistry Network (MetBioNet) hyperammonaemia guideline recommends analysis of samples not collected under ideal conditions and reporting with appropriate comments. An audit found that some laboratories did not follow this guidance. An investigation was performed into whether storage at controlled room temperature and delayed sample processing affected interpretation of plasma ammonia results. METHODS: Eleven healthy volunteers provided informed consent. Blood was taken from each into 14 paediatric EDTA blood sample tubes, one placed immediately on ice, the others in a rack at room temperature. The chilled and baseline room temperature samples were centrifuged and plasma analysed by the Roche Ammonia (NH3L2) method. Samples stored at room temperature were analysed at 10-min intervals up to 2 h. RESULTS: Baseline room temperature ammonia was higher than in the chilled sample (19 ± 6.6 µmol/L [mean ± standard deviation] and 18 ± 6.6 µmol/L, respectively). Ammonia increased further by 0.09 ± 0.02 µmol/L per minute to 30 ± 8.4 µmol/L at 2 h. No result was above the reference range (50 µmol/L). No healthy subject with normal baseline ammonia would have been erroneously identified as having hyperammonaemia. CONCLUSIONS: Results support MetBioNet guidance that laboratories accept blood samples for ammonia analysis which are not processed under ideal conditions.

Clinical experience with glycerol phenylbutyrate in 20 patients with urea cycle disorders at a UK paediatric centre.

In urea cycle disorders (UCDs) ammonia scavenger drugs, usually sodium-based, have been the mainstay of treatment. Increasingly, glycerol phenylbutyrate (GPB, Ravicti®) is being used but scant real-world data exist regarding clinical outcomes. A retrospective study of UCD patients initiated on or switched to GPB was performed at a UK centre. Data on population characteristics, treatment aspects, laboratory measurements, and clinical outcomes were collected before and after patients started GPB with a sub-group analysis undertaken for patients with ≥12 months of data before and after starting GPB. UCDs included arginosuccinate synthetase deficiency (n = 8), arginosuccinate lyase deficiency (n = 6), ornithine carbamoyltransferase deficiency (n = 3), and carbamoyl phosphate synthetase 1 deficiency (n = 3). In the sub-group analysis (n = 11), GPB resulted in lower plasma ammonia (31 vs. 41 µmol/L, p = 0.037), glutamine (670 vs. 838 µmol/L, p = 0.002), annualised hyperammonaemic episodes (0.2 vs. 1.9, p = 0.020), hospitalisations (0.5 vs. 2.2, p = 0.010), and hyperammonaemic episodes resulting in hospitalisation (0.2 vs. 1.6, p = 0.035) reflecting changes seen in the whole group. Overall, patients exposed to sodium and propylene glycol levels above UK daily limits reduced by 78% and 83% respectively. Mean levels of branched chain amino acids, haemoglobin, and white cell count were unchanged. Two adverse drug reactions (pancytopenia, fatigue/appetite loss) resolved without GPB discontinuation. Patients/families preferred GPB for its lower volume, greater palatability and easier administration. GPB appeared to improve biochemical measures and clinical outcomes. The causes are multi-factorial and are likely to include prolonged action of GPB and its good tolerability, even at higher doses, facilitating tighter control of ammonia.

Detection and Quantification of Ammonia as the Ammonium Cation in Human Saliva by 1H NMR: A Promising Probe for Health Status Monitoring, with Special Reference to Cancer.

Ammonia (NH3) has been shown to be a key biomarker for a wide variety of diseases, such as hepatic and chronic kidney diseases (CKD), and cancers. It also has relevance to the oral health research area, and, hence, its determination in appropriate biofluids and tissues is of much importance. However, since it contains exchangeable >N-H protons, its analysis via 1H NMR spectroscopy, which is a widely employed technique in untargeted metabolomic studies, is rendered complicated. In this study, we focused on the 1H NMR analysis of this biomarker in less invasively collected human saliva samples, and we successfully identified and quantified it as ammonium cation (NH4+) in post-collection acidulated forms of this biofluid using both the standard calibration curve and standard addition method (SAM) approaches. For this purpose, n = 27 whole mouth saliva (WMS) samples were provided by healthy human participants, and all donors were required to follow a fasting/oral environment abstention period of 8 h prior to collection. Following acidification (pH 2.00), diluted WMS supernatant samples treated with 10% (v/v) D2O underwent 1H NMR analysis (600 MHz). The acquired results demonstrated that NH4+ can be reliably determined in these supernatants via integration of the central line of its characteristic 1:1:1 intensity triplet resonance (complete spectral range δ = 6.97-7.21 ppm). Experiments performed also demonstrated that any urease-catalysed NH3 generation occurring post-sampling in WMS samples did not affect the results acquired during the usual timespan of laboratory processing required prior to analysis. Further experiments demonstrated that oral mouth-rinsing episodes conducted prior to sample collection, as reported in previous studies, gave rise to major decreases in salivary NH4+ levels thereafter, which renormalised to only 50-60% of their basal control concentrations at the 180-min post-rinsing time point. Therefore, the WMS sample collection method employed significantly affected the absolute levels of this analyte. The LLOD was 60 µmol/L with 128 scans. The mean ± SD salivary NH4+ concentration of WMS supernatants was 11.4 ± 4.5 mmol/L. The potential extension of these analytical strategies to the screening of other metabolites with exchangeable 1H nuclei is discussed, as is their relevance to the monitoring of human disorders involving the excessive generation and/or uptake of cellular/tissue material, or altered homeostasis, in NH3.

Hyperammonaemic encephalopathy: a remarkably rare complication after bariatric surgery.

Hyperammonaemia is a metabolic disorder with elevated blood ammonia levels. Here we describe a case of hyperammonaemia associated encephalopathy as an incredibly rare, potentially fatal and treatable complication associated with bariatric surgery. This case highlights the importance of longer-term follow-up after bariatric surgery.

Indole-3-carbinol ameliorated the thioacetamide-induced hepatic encephalopathy in rats.

Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)- 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management.

Valproate-induced hyperammonemic encephalopathy treated by L-ornithine-L-aspartate: a case report.

A 63-year-old man developed reduced consciousness and dysphagia progressively. Examination and parameters were normal, except for a Glasgow Coma Scale score of seven, and his grading on the swallow water test increased from grade 1 to grade 5. Brain imaging and blood tests were unexplainable except by high plasma ammonia. His past medical history included cerebral infarction, hypertension and epilepsy induced by cerebral hyperperfusion syndrome. He was rceiving antiepileptic treatment of continuously intravenously pumped sodium valproate of 64 mg/h for 4 days, which overlapped for 12 hours with taking 500 mg sustained release tablets. Sodium valproate was stopped; testing demonstrated normal plasma concentrations of sodium valproate and elevated concentrations of ammonia. Ornithine aspartate was administrated. The patient's level of responsiveness and ammonia levels gradually improved. The patient was also being treated with ceftriaxone sodium for a hypostatic pneumonia and with desmopressin for diabetes insipidus. There is an association between sodium valproate and hyperammonaemia and encephalopathy. Immediate recognition of the serious but uncommon adverse effects is essential. To our knowledge this is the first report of ornithine aspartate being used in this disorder.

Mitochondrial carbonic anhydrase VA and VB: properties and roles in health and disease.

Carbonic anhydrase V (CA V), a mitochondrial enzyme, was first isolated from guinea-pig liver and subsequently identified in mice and humans. Later, studies revealed that the mouse genome contains two mitochondrial CA sequences, named Car5A and Car5B. The CA VA enzyme is most highly expressed in the liver, whereas CA VB shows a broad tissue distribution. Car5A knockout mice demonstrated a predominant role for CA VA in ammonia detoxification, whereas the roles of CA VB in ureagenesis and gluconeogenesis were evident only in the absence of CA VA. Previous studies have suggested that CA VA is mainly involved in the provision of HCO3 - for biosynthetic processes. In children, mutations in the CA5A gene led to reduced CA activity, and the enzyme was sensitive to increased temperature. The metabolic profiles of these children showed a reduced supply of HCO3 - to the enzymes that take part in intermediary metabolism: carbamoylphosphate synthetase, pyruvate carboxylase, propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase. Although the role of CA VB is still poorly understood, a recent study reported that it plays an essential role in human Sertoli cells, which sustain spermatogenesis. Metabolic disease associated with CA VA appears to be more common than other inborn errors of metabolism and responds well to treatment with N-carbamyl-l-glutamate. Therefore, early identification of hyperammonaemia will allow specific treatment with N-carbamyl-l-glutamate and prevent neurological sequelae. Carbonic anhydrase VA deficiency should therefore be considered a treatable condition in the differential diagnosis of hyperammonaemia in neonates and young children.

Hyperammonaemia disrupts daily rhythms reversibly by elevating glutamate in the central circadian pacemaker.

Patients with cirrhosis exhibit features of circadian disruption. Hyperammonaemia has been suggested to impair both homeostatic and circadian sleep regulation. Here, we tested if hyperammonaemia directly disrupts circadian rhythm generation in the central pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. Wheel-running activity was recorded from mice fed with a hyperammonaemic or normal diet for ~35 days in a 12:12 light-dark (LD) cycle followed by ~15 days in constant darkness (DD). The expression of the clock protein PERIOD2 (PER2) was recorded from SCN explants before, during and after ammonia exposure, ±glutamate receptor antagonists. In LD, hyperammonaemic mice advanced their daily activity onset time by ~1 h (16.8 ± 0.3 vs. 18.1 ± 0.04 h, p = .009) and decreased their total activity, concentrating it during the first half of the night. In DD, hyperammonaemia reduced the amplitude of daily activity (551.5 ± 27.7 vs. 724.9 ± 59 counts, p = .007), with no changes in circadian period. Ammonia (≥0.01 mM) rapidly and significantly reduced PER2 amplitude, and slightly increased circadian period. The decrease in PER2 amplitude correlated with decreased synchrony among circadian cells in the SCN and increased extracellular glutamate, which was rescued by AMPA glutamate receptor antagonists. These data suggest that hyperammonaemia affects circadian regulation of rest-activity behaviour by increasing extracellular glutamate in the SCN.

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Recurrent hyperammonaemia in a patient with carbonic anhydrase VA deficiency.

Carbonic anhydrase VA deficiency is a recently described inherited cause of paediatric hyperammonaemia. Most published cases describe patients with only one episode of hyperammonaemia whilst others report patients who had up to three metabolic crises with the first invariably being the most severe. We describe a patient with carbonic anhydrase VA deficiency who experienced 7 hyperammonemic episodes over a 3-year period, up to age 5 years 9 months. These episodes did not clearly decrease in severity over time. This report expands the clinical phenotype and the age window for metabolic crises associated with this condition.

Infusion of an acidified ethanolic-dextrose solution enhances urinary ammonium excretion and increases acid resilience in non-mechanically ventilated acidotic rabbits.

Hitherto, the rabbit has long been known to have a very poor tolerance to non-volatile acid. In this study, we tested the hypothesis that acid resilience in the acidotic rabbit can be increased by enhancing the plasma availability of a naturally occurring volatile fatty acid, namely acetate. To ascertain the relative merits of the respiratory and renal systems in contributing to that resilience, we conducted our studies in non-ventilated and mechanically ventilated acidotic animals. Using ethanol as a feeder of acetate, and to counteract the antidiuretic effects of surgical interventions, we induced acidosis in anaesthetised rabbits, by intravenously infusing an acidified ethanolic dextrose solution. We observed very potent respiratory regulation of arterial blood pH coupled with a notable renal response by way of a 25-fold increase in urinary ammonium excretion in the non-ventilated group. In contrast, arterial blood pH plummeted much more rapidly in the mechanically-ventilated animals, but the compensated renal response was enormous, in the form of an 85 -fold increase in urinary ammonium output. Despite this significant adaptive renal response, the non -mechanically ventilated group of rabbits showed the greater acid resilience. This was attributed to an acetate stimulated flux through a series of metabolic pathways, generating supplementary buffer in the form of bicarbonate and ammonia, complemented by a robust respiratory response.

Abnormal brain oxygen homeostasis in an animal model of liver disease.

Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.

Risk factors and outcome of hyperammonaemia in people with epilepsy.

BACKGROUND: Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear. OBJECTIVE: To identify risk factors for hyperammonaemia and investigate the impact of its management on clinical outcomes. METHODS: We carried out a retrospective observational study of adults with epilepsy who had ammonia tested over a 3-year period. Hyperammonaemia was defined as ammonia level > 35 µmol/L. Patients were classified into two groups: hyperammonaemic and non-hyperammonaemic. Association analyses and linear regression analysis were used to identify risk factors for hyperammonaemia. RESULTS: We reviewed 1002 ammonia requests in total and identified 76 people with epilepsy who had ammonia concentration measured, including 26 with repeated measurements. 59/76 (78%) were found to have hyperammonaemia. There was borderline statistical significance of hyperammonaemia being less common in patients with an established monogenic/metabolic condition than in those with structural or cryptogenic epilepsy (P = 0.05). Drug resistance, exposure to stiripentol and oxcarbazepine were identified as risk factors for hyperammonaemia. We found a dose-dependent association between valproate and hyperammonaemia (P = 0.033). Clinical symptoms were reported in 22/59 (37%) of the hyperammonaemic group. Improved clinical outcomes with concurrent decrease in ammonia concentration were seen in 60% of patients following treatment adjustment. CONCLUSIONS: Drug resistance and exposure to stiripentol, oxcarbazepine or high-dose valproate are associated with an increased risk of hyperammonaemia. Clinicians should consider symptoms related to hyperammonaemia in patients on high-dose valproate or multiple antiseizure treatments. Prompt identification of hyperammonaemia and subsequent treatment adjustments can lead to improved clinical outcomes.

Hepatic Encephalopathy Is Not Always due to Liver Cirrhosis.

Hepatic encephalopathy (HE) is a frequent and debilitating complication of liver disease and is oftentimes associated with hyperammonaemia. However, hyperammonaemia may occur in underlying conditions other than acute or chronic liver failure and clinical awareness is needed in order to be recognized and treated properly. A 24-year-old woman presented herself to our emergency department with acute confusion and altered mental state due to severe hyperammonaemia. The patient was diagnosed in the age of 14 with ornithine transcarbamylase (OTC) deficiency and was incompliant regarding her diet and suggested medication to treat this disorder. She was treated with sodium benzoate 250 mg/kg i.v., sodium phenylbutyrate/sodium phenylacetate 250 mg/kg i.v., L-arginine 250 mg/kg i.v., and received continuous hemofiltration. Under simultaneous medical treatment and haemodialysis, ammonia levels dropped to normal within 24 h and symptomatic encephalopathy ceased completely. OTC deficiency is rare in adults, and the majority of patients are diagnosed in childhood. It can lead to death if not diagnosed and treated properly. Our case underlines the importance of considering causes of HE other than liver cirrhosis.

Recommendations for the Diagnosis and Therapeutic Management of Hyperammonaemia in Paediatric and Adult Patients.

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200−350 µmol/L in children up to 18 months of age and >150−200 µmol/L after that age.