Elevated Blood Ammonia Levels Research Articles

Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

BackgroundThis study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD.MethodsA retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children’s Hospital of Fujian Province in China.ResultsFive boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation.ConclusionsThe clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients.

Implications of Genetic Factors Underlying Mouse Hydronephrosis: Cautionary Considerations on Phenotypic Interpretation in Genetically Engineered Mice.

Hydronephrosis, the dilation of kidneys due to abnormal urine retention, occurs spontaneously in certain inbred mouse strains. In humans, its occurrence is often attributed to acquired urinary tract obstructions in adults, whereas in children, it can be congenital. However, the genetic factors underlying hydronephrosis pathogenesis remain unclear. We investigated the cause of hydronephrosis by analyzing tetraspanin 7 (Tspan7) gene-modified mice, which had shown a high incidence of hydronephrosis-like symptoms. We found that these mice were characterized by low liver weights relative to kidney weights and elevated blood ammonia levels, suggesting liver involvement in hydronephrosis. Gene expression analysis of the liver suggested that dysfunction of ornithine transcarbamylase (OTC), encoded by the X chromosome gene Otc and involved in the urea cycle, may contribute as a congenital factor in hydronephrosis. This OTC dysfunction may be caused by genomic mutations in X chromosome genes contiguous to Otc, such as Tspan7, or via the genomic manipulations used to generate transgenic mice, including the introduction of Cre recombinase DNA cassettes and cleavage of loxP by Cre recombinase. Therefore, caution should be exercised in interpreting the hydronephrosis phenotype observed in transgenic mice as solely a physiological function of the target gene.

Assessment of the Risk of Malnutrition or Frailty Among Patients Undergoing Liver Transplantation: A Hospital-Based Prospective Study.

We aimed to explore the status of nutritional and frailty in patients undergoing liver transplantation and the associated influencing factors. We conducted a follow-up analysis of 44 patients who underwent liver transplantation between 2021 and 2022. We followed up and recorded the nutritional status and risk of weakness at different time-points (days 1, 2, 3, 6, 9, and 12) postoperatively. Patient information regarding demographics, physical examination, medical history, and perioperative blood tests were collected. Binary logistic regression was applied to identify risk factors for weakness after liver transplantation. The cohort comprised 44 liver transplant recipients, with a mean age of 47.66 years (standard deviation=9.49 years). Initial analysis revealed that, compared to the group without nutritional risks, the group with nutritional risks displayed elevated age and preoperative blood ammonia levels one week post-surgery. Moreover, this group had reduced levels of albumin and total bile acid preoperatively. Patients with preoperative nutritional risks were also prone to similar risks 2 weeks postoperatively. Further, a correlation was observed between preoperative pulmonary infections and increased frailty risk 6 days postoperatively. At both 9 and 12 days postoperatively, patients with frailty risk exhibited higher preoperative white blood cell counts and ammonia levels than those without. Multivariable analysis, controlling for confounding factors, indicated a significant association between preoperative nutritional status and nutritional risk 2 weeks postoperatively, as well as a link between preoperative white blood cell count and frailty risk at 12 days postoperatively. There was a significant correlation between preoperative nutritional status and nutritional risk 2 weeks after liver transplantation, and preoperative white blood cell count was an independent risk factor for weakness 12 days postoperatively. Preoperative nutritional management for patients could potentially mitigate the likelihood of adverse clinical outcomes.

An orally deliverable ornithine-based self-assembling polymer nanomedicine ameliorates hyperammonemia in acetaminophen-induced acute liver injury.

l-Ornithine (Orn) is a core amino acid responsible for ammonia detoxification in the body via the hepatic urea cycle. Clinical studies in Orn therapy have focused on interventions for hyperammonemia-associated diseases, such as hepatic encephalopathy (HE), a life-threatening neurological symptom affecting more than 80% of patients with liver cirrhosis. However, its low molecular weight (LMW) causes Orn to diffuse nonspecifically and be rapidly eliminated from the body after oral administration, resulting in unfavorable therapeutic efficacy. Hence, Orn is constantly supplied by intravenous infusion in many clinical settings; however, this treatment inevitably decreases patient compliance and limits its application in long-term management. To improve the performance of Orn, we designed self-assembling polyOrn-based nanoparticles for oral administration through ring-opening polymerization of Orn-N-carboxy anhydride initiated with amino-ended poly(ethylene glycol), followed by acylation of free amino groups in the main chain of the polyOrn segment. The obtained amphiphilic block copolymers, poly(ethylene glycol)-block-polyOrn(acyl) (PEG-block-POrn(acyl)), enabled the formation of stable nanoparticles (NanoOrn(acyl)) in aqueous media. We employed the isobutyryl (iBu) group for acyl derivatization in this study (NanoOrn(iBu)). In the healthy mice, daily oral administration of NanoOrn(iBu) for one week did not induce any abnormalities. In the mice exhibiting acetaminophen (APAP)-induced acute liver injury, oral pretreatment with NanoOrn(iBu) effectively reduced systemic ammonia and transaminases levels compared to the LMW Orn and untreated groups. The results suggest that the application of NanoOrn(iBu) is of significant clinical value with the feasibility of oral delivery and improvement in APAP-induced hepatic pathogenesis. STATEMENT OF SIGNIFICANCE: Liver injury is often accompanied by hyperammonemia, a life-threatening condition characterized by elevated blood ammonia levels. Current clinical treatments for reducing ammonia typically entail the invasive approach of intravenous infusion, involving the administration of l-ornithine (Orn) or a combination of Orn and L-aspartate. This method is employed due to the poor pharmacokinetics associated with these compounds. In our pursuit of enhancing therapy, we have developed an orally administrable nanomedicine based on Orn-based self-assembling nanoparticle (NanoOrn(iBu)), which provides sustained Orn supply to the injured liver. Oral administration of NanoOrn(iBu) to healthy mice did not cause any toxic effects. In a mouse model of acetaminophen-induced acute liver injury, oral administration of NanoOrn(iBu) surpassed Orn in reducing systemic ammonia levels and liver damage, thereby establishing NanoOrn(iBu) as a safe and effective therapeutic option.

Hyperammonemia Secondary to 5-Fluorouracil.

5-fluorouracil (5-FU) is one of the most common adjuvant antineoplastic agents used in the treatment of localized and metastatic colon cancer. Frequent side effects of 5-FU include myelosuppression, mucositis, nausea, vomiting, and diarrhea. However, hyperammonemic encephalopathy is a rare neurologic toxicity that can occur after 5-FU chemotherapy administration. Patients with 5-FU-induced hyperammonemic encephalopathy often exhibit symptoms of altered mental status with no radiologic abnormalities or laboratory abnormalities except for significantly elevated ammonia levels with occasional lactic acidosis and respiratory alkalosis. We report a case of a patient with stage IV colon adenocarcinoma who experienced altered state of consciousness due to hyperammonemia during the administration of palliative chemotherapy with 5-FU, bevacizumab, and leucovorin. On cycle 1 day 2 of chemotherapy, the patient became drowsy and confused at home, prompting a visit to the emergency department and ultimately hospital admission. Laboratory tests revealed an elevated blood ammonia level (838 μg/dL). After an extensive negative workup, his altered state of consciousness was thought to be secondary to 5-FU-induced hyperammonemia. Upon admission, 5-FU was immediately discontinued and the patient was treated with lactulose enemas, intravenous fluids, rifaximin, and continuous renal replacement therapy with gradual recovery to baseline mental status. It is crucial for advanced practitioners to be aware of this rare side effect to ensure prompt diagnosis and maximize treatment effectiveness.

Results of a multicenter prospective observational study “Clinical significance of hyperammonemia in patients with post-Covid syndrome (LIRA - COVID)”: efficacy of L-ornithine L-aspartate

Epidemiological data suggests that approximately 10-65% of patients with mild to moderate COVID-19 have persistent symptoms already after an acute infection, which may last for six months or more. Previous clinical studies have shown that similar symptoms may also occur in the liver. Russian scientists have studied the phenomenon of hyperammonemia in the acute phase of COVID-19, but the problem of elevated blood ammonia levels in post - COVID syndrome has not been studied before. One possible option for the correction of hyperammonemia is the L-ornithine - L-aspartate (LOLA) preparation. The aim of the study was to investigate the manifestation of hyperammonemia in post - COVID syndrome and the possibility of its correction by using LOLA. Eighty-three patients (mean age 51.71 ± 12.82) with post-COVID syndrome, attention and memory impairment, chronic fatigue, hyperammonemia, 2-fold increase of alanine transaminase (ALT) and aspartate transaminase (AST) levels were included into multicenter, prospective observational study. L-ornithine-L-aspartate (LOLA) was given (3 g 3 times per day orally) for 4 weeks to correct hyperammonemia. Patients were accessed by the number connection test (NCT), fatigue evaluation test, measurement of ammonia and ALT, AST levels at baseline, and after 4 weeks. At week 4 the ammonia level was significantly decreased in 81 patients (97.6%). Time (sec) to complete the NCT was 49,43 ± 15,85 vs 64.67 ± 24.95 at baseline (p<0.001). Before treatment, the majority of patients had stage 1 hepatic encephalopathy (HE) - 50.6% and stage 1-2 (intermediate) HE - 30.1%, stage 2 HE - 10.9%, stage 3 HE - 2.4%. After LOLA treatment, the distribution changed: 41% of patients had no HE, 36.1% had stage 1 of HE, 22.9% had stage 1-2 (intermediate) of HE, and stage 2 and 3 of HE was no longer defined. The mean score in fatigue evaluation test was 46,27 ± 10.0 vs 64,71 ± 19,18 at baseline (p<0.001). ALT and AST levels were 47,83 ± 38,21 units/l vs 95,75 ± 68.99 units/l at baseline and 40,10 ± 35,97 units/l vs 78,51 ± 90,90 units/l at baseline respectively (p<0.001). This study showed that the inclusion of LOLA in a dose of 3 g 3 times a day for 4 weeks was associated with significant improvement in the objective and subjective outcomes in patients with post-COVID syndrome.

Hyperammonemia in a septic patient with Ureaplasma parvum arthritis: a case report

BackgroundSeptic arthritis requires prompt diagnosis and treatments. Rare pathogens should be considered when patients respond poorly to the initial antibiotic treatments. Ureaplasma parvum is an opportunistic pathogen that commonly resides in the human urogenital tract. Its infection commonly causes hyperammonemia. Hyperammonemia from Ureaplasma parvum septic arthritis has never been reported previously.Case presentationA 65-year-old male presented with fever and left lower leg pain and swelling for more than ten days. Septic arthritis and sepsis were considered after laboratory tests and arthrocentesis. However, he responded poorly to the antibiotic treatments, including cefoperazone-sulbactam, imipenem-cilastatin, and linezolid. His mental status deteriorated rapidly with elevated blood ammonia levels with unremarkable liver function test and sonogram examination results. Despite the treatments with lactulose, L-ornithine L-aspartate, mannitol, and hemodialysis therapy to lower his ammonia level, his blood ammonia level remained persistently high. Finally, metagenomic sequencing of the left knee synovial fluid reported Ureaplasma parvum, which was considered to contribute to his hyperammonemia.ConclusionUreaplasma parvum could cause septic arthritis with hyperammonemia. Genetic tests, such as polymerase chain reaction and next-generation sequencing techniques, could provide a sensitive and fast diagnosis of Ureaplasma parvum.

Imaging findings in a minipig with congenital portosystemic shunt.

A 15-month-old, male minipig was presented with a clinical history of seizure activity for one year. The minipig was the smallest among the littermates and was referred due to an elevated blood ammonia level with suspected portosystemic shunt (PSS). Ultrasound and CT angiography were consistent with a congenital extrahepatic PSS. To the author's knowledge, this is the first description of a congenital extrahepatic PSS diagnosed by ultrasound and contrast-enhanced computed tomography in a minipig (pig). Partial shunt closure was performed by interventional stent application.

Risk factors of elevated blood ammonia level in epilepsy patients treated with lamotrigine.

The aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level.This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for 3 years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Total of 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils affected blood ammonia level. Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG.

A rare thyroid disorder mimicking mitochondrial disease

&amp;lt;p&amp;gt;Introduction. Patients affected with Allan-Herndon-Dudley syndrome (AHDS) have a deficiency of monocarboxylate transporter 8 (MCT8), a protein primarily responsible for the transport of triiodothyronine (T3) into the brain. This X-linked disorder affects almost exclusively males with clinical presentation encompassing developmental delay, axial hypotonia, dystonia, poor head control, quadriplegia and absence of speech. Case reports. Patient 1 is a male child referred to a hospital investigation at 11 months due to severe developmental delay and elevated blood ammonia level (163 mcmol/L). Hypotonia and dystonic movements were noted at admission, with facial dysmorphic features. Laboratory findings revealed increased blood lactate (17.2 mmol/L), alanine (533 mcmol/L) and ammonia (391 mcmol/L) concentrations. Serum creatine-kinase levels showed substantial increase over the course of hospitalization up to 6,855 IU/L. Clinical exome sequencing detected a novel hemizygous frameshift insertion c.1456insC in gene SLC16A2, predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Segregation genetic testing of the family members revealed that mother, maternal uncle and maternal grandmother carry the same mutation in SLC16A2. The boy`s mother experienced learning difficulties through childhood while maternal uncle is severely affected by AHDS. Patient 2 is a boy referred to clinical geneticist due to severe psychomotor delay of unknown etiology. Moderate serum lactate elevation was the only laboratory abnormality during initial investigations. Diagnosis of AHDS was established by clinical exome sequencing, and subsequent hormonal evaluation revealed increased triiodothyronine (T3) level which corresponds well to genetic diagnosis. Conclusion. Presence of lactic acidosis and/or hyperammonemia in children with severe developmental delay is not specific for inborn disorders of energy production, such as mitochondrial disease. Clinicians should consider thyroid hormones profiling in cases of unexplained severe developmental delay in male children, especially if associated with axial hypotonia and dystonic movements.&amp;lt;/p&amp;gt;

CPS1 T1405N polymorphism, HDL cholesterol, homocysteine and renal function are risk factors of VPA induced hyperammonemia among epilepsy patients

PurposeValproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl-Phosphate Synthase 1 (CPS1) is an enzyme catalyzing the initial step of removing ammonia from blood. Studies have demonstrated that the CPS1 polymorphism rs1047891-A allele carriers were susceptible to VPA-induced HA. However, the evidences remained controversial. In this study, we sought to validate the association between rs1047891 and VPA-induced HA by combining the association results from previous studies together. MethodsWe first conducted a systematic meta-analysis to determine whether rs1047891 was statistically significant. Then, we further evaluated the pleiotropic effects of rs1047891 using published genome-wide association studies (GWAS) and UKBB results. A conditional analysis was conducted to investigate whether the association between rs1047891 and VPA-induced HA was mediated by cardiovascular or renal disease risk factors or vice versa. ResultsThe allelic, dominant and recessive ORs of rs1047891-A were all significant in our fixed-effect meta-analysis. In GWAS catalog and UKBB data, rs1047891 was associated with basal metabolic rate, adiposity and hematology traits, cardiovascular and renal disease risk factors. We further proved that plasma HDL cholesterol and homocysteine level, in addition to eGFR by serum creatinine, were associated with VPA-induced HA risk independently from rs1047891 polymorphism. ConclusionIn conclusion, the SNP rs1047891 was associated with VPA-induce HA among epilepsy patients. Meanwhile, plasma HDL cholesterol and homocysteine level had independent effects from it.

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia.

OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

The Effect of Cisplatin on Blood Ammonia Elevation by Alanyl-Glutamine Supplementation

Background: Although there are many clinical studies in which the beneficial effect of glutamine formulation on mucositis induced by chemo/radiotherapy was evaluated, the results are sometimes conflicting with the report of clinical deterioration. Then, we hypothesized that chemotherapy may increase the incidence of hyperammonemia without comparable change of major parameters of hepatic/renal disorder. Methods: To verify our hypothesis, we examined the increase in blood ammonia level with 1-h intravenous infusion of alanyl-glutamine on day 1–4 after cisplatin (CDDP) administration in rats and assessed the correlation with hepatic/renal parameters. Results: Hepatic parameters (glutamate-oxaloacetic transaminase [GOT] and glutamic-pyruvic transaminase [GPT]) with CDDP did not change until day 3 and only GOT increased on day 4. Renal parameters (plasma creatinine, blood urea nitrogen) with CDDP continuously increased up to day 4. Alanyl-glutamine infusion significantly elevated blood ammonia level of CDDP rats with the peak on day 3, although the same dose did not change that of control rats. Conclusion: These results indicates that CDDP enhances the increase in blood ammonia level by glutamine supplementation without correlating with primary parameters for hepatic/renal dysfunction.

Acute Ammonia Intoxication-Induced Seizures but not Ammonia Per Se Contribute to the Electrophysiological Changes in Rat Brain

Background and Aim: Hepatic encephalopathy (HE) is a major complication in patients with mild to severe liver disease. HE is characterized by confusion, inverted sleep-wake cycles, disorientation, behavioral changes, impaired cognition, and motor disturbances, as well as increased brain edema and intracranial pressure. The molecular basis for these changes in HE remains unclear. Elevated blood and brain ammonia levels have been strongly implicated in its pathogenesis. Whether ammonia play any role in electrophysiological changes in HE that may be involved in neurobehavioral, biochemical and molecular changes observed in HE was examined. Methods: Male Wister albino rats were injected (i.p) with ammonium acetate (500 and 800 mg/kg) and liver toxin acetaminophen (AMPN, 500 mg/kg). Results: The AACE-treated group developed seizures within 10 min and survived post-treatment without any additional seizure incident. However, more than 70% of AMPN treated animals died after 56 hours. Hippocampal slices were prepared from these animals (1 hr after AACE and 40 h after AMPN, pre-coma stage) and electrophysiological changes were measured. A paired-pulse facilitation (PPF) sequence in which stimulation pulse pairs were delivered at intervals of 20-480 ms and the filed excitatory postsynaptic potential (EPSP) slope were calculated. A depressed PPF was observed in slices from both AACE and AMPN treated animals. Further, inhibition of seizures in AACE group showed reversal of these electrophysiological changes, while these inhibitors failed to prevent electrophysiological changes induced by AMPN. Additionally, seizure inducing agent's picrotoxin (PCT) and pentylenetetrazol (PTZ) showed electrophysiological changes similar to AACE, and that inhibition of PCT and PTZ induced seizures reversed electrophysiological changes. Conclusion: These findings suggest that the effect of acute ammonia intoxication on electrophysiological changes may be due to the effect of ammonia-induced seizures, but not due to ammonia per se. The author have none to declare.

170. PhaseRx mRNA Technology Platform Uses SMARTT Polymer Technology® to Target and Deliver mRNA to the Liver and Treat a Urea Cycle Disorder in a Mouse Disease Model

Messenger RNA (mRNA) is a promising alternative in both the viral and non-viral DNA-based gene delivery fields. Current viral vectors for gene therapy are associated with serious safety concerns and nonviral vectors are limited by low gene transfer efficiency. mRNA gene expression in the liver can be used for treatment of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes expressed solely or predominantly in the liver. SMARTT Polymer Technology® has been developed into a robust platform for RNA therapeutics. Optimization of the mRNA technology platform has led to stepwise improvements in mRNA delivery to the liver using GalNAc targeted polymers. We demonstrated a 5,000-fold improvement in activity over our first generation delivery system.Urea cycle disorders result from single gene mutations that lead to deficiency in one of the six enzymes in the urea cycle pathway. This deficiency can trigger elevated blood ammonia levels, also known as hyperammonemia, a life-threatening illness that leads to brain damage, coma or even death in humans. The deficient protein is intracellular and IV protein therapeutics are ineffective. Liver transplantation is the only cure for urea cycle disorders but is limited by the shortage of donors and complications associated with rejection and infection of the transplant. There is a dire need for new treatment options.Using the mRNA technology platform, we have demonstrated preclinical proof of concept in a urea cycle disorder mouse disease model. Treatment with therapeutic mRNA shows normalization of blood ammonia levels in hyperammonemic mice. Therapeutic mRNA expression is detected in the liver after a single mRNA dose with good duration of expression. The treatment was well tolerated, with no toxicities associated with both single and multiple dosing regimens.This mRNA technology platform provides a significant opportunity for the treatment of urea cycle disorders and other orphan liver diseases.

Seven patients of argininemia with spastic tetraplegia as the first and major symptom and prenatal diagnosis of two fetuses with high risk

Argininemia is a rare disorder of urea cycle defect. The clinical manifestations of this disorder are similar to those of cerebral palsy so that the diagnosis is usually much delayed. This study aimed to investigate the phenotypes and genotypes of seven Chinese patients suffering from argininemia. Three boys and four girls with spastic tetraplegia were diagnosed as argininemia by blood aminoacids analysis and ARG1 gene study. Patients were given a protein-restricted diet, citrulline, sodium benzoate, and other treatment intervention. The mother of Patient 5 and 6 accepted genetic counseling and underwent prenatal diagnosis by amniocentesis. Seven patients presented with progressive spastic tetraplegia and poor physical growth from the age of 1 month to 4 years. Argininemia was found at the age of 1 year and 10 months to 12 years. Five patients had mental retardations. Three had seizures. Their blood arginine elevated (86.66 to 349.83 µmol/L, normal controls 5 to 25 µmol/L). Liver dysfunction was found in six patients. Five patients had elevated blood ammonia levels. In four patients, cerebral atrophy was observed by cranial magnetic resonance imaging. Nine mutations in the ARG1 gene were identified from 7 patients. Only two mutations, c.703G > A in exon 7 and c.32T > C in exon 1 had been reported. c.34G > T, c.53G > A, c.67delG, c.232dupG, c.374C > T, c.539G > C and c.646-649delCTCA, were novel mutations of ARG1. A homozygous mutation c.703G > A was found in the amniocytes of Patient 5's mother, indicating that the fetus was affected by argininemia. Induced abortion was performed. c.53G > A from Patient 6 was not found in the amniocytes of her mother, indicating that the fetus was not affected by hepatocyte arginase deficiency. The result was confirmed by postnatal mutation analysis of cord blood and the normal blood arginine of the newborn. Argininemia is one of the few treatable causes of pediatric spastic paralysis. In this study, seven Chinese patients with spastic tetraplegia were detected by blood aminoacids analysis and confirmed by molecular analysis. Seven novel mutations on ARG1 gene were identified. Prenatal diagnosis of the fetus of a family was performed by amniocytes ARG1 gene analysis.

Elevated Blood Ammonia Level Is a Potential Biological Risk Factor of Behavioral Disorders in Prisoners.

Hydrothion (H2S) and ammonia (NH3) can be toxic for the human central nervous system and cause psychological disturbances and behavioral disorders. In order to evaluate the association between the two potential toxicants and mental health, in this study, we compare a male prisoner and control population. Forty-nine male prisoners and 52 control volunteers took part in the study. An aggressive behavior assessment, the Self-Rating Depression Scale (SDS), and the State-Trait Anxiety Inventory (STAI) were used to characterize the participants' mental health status. Venous blood was collected for detection of H2S and NH3. The results indicated that blood NH3 was significantly higher in male prisoners than in controls. However, blood H2S was significantly lower. Blood NH3 was also significantly and positively correlated with prisoners. In the multivariate adjusted models, after controlling for age, education, marital status, and BMI, we found a positive association between NH3 and prisoners, but not blood H2S. While the functions of the two toxicants were quite different, blood NH3 may be a potential biological risk factor for behavioral disorders and blood H2S showed neuroprotection. Additionally, the impact of other factors such as diet and gut bacteria should be considered when evaluating risk for behavioral disorders.

Characterization of uncommon portosystemic collateral circulations in patients with hepatic cirrhosis.

The purpose of the present study was to characterize uncommon portosystemic collateral circulation in hepatic cirrhosis. Portosystemic uncommon collateral circulation (UCC) was detected, characterized and evaluated by a combination of spiral computed tomography angiography, three-dimensional imaging angiography and electronic gastroscopy in patients diagnosed with hepatic cirrhosis. In total, 118 cases with UCC were detected from a pool of 700 hepatic cirrhosis patients with portal hypertension. The incidence was 16.86% and included cases with splenic-renal, gastro-renal, paravertebral, retroperitoneal, gastric-splenic and cardio-phrenic angle vein shunts. The occurrence rate of UCC formation increased with the Child-Pugh grade. Compared with common collateral circulations, the incidence of severe esophageal or gastric fundus varicose veins, severe portal hypertensive gastropathy and the incidence of a large quantity of ascites was much lower in the patients with UCC (P<0.01), whereas the incidence of hepatic encephalopathy and chronic elevated blood ammonia levels was significantly higher (P<0.01). The incidence of uncommon portosystemic collateral circulation is extremely common in patients with liver cirrhosis and is associated with the Child-Pugh grades of hepatic function. UCC can aid in the relief of the complications derived from portal hypertension, but it may increase the incidence of hepatic encephalopathy and chronic elevated blood ammonia levels.

Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies.

Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH₄Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95, and synaptotagmin levels. Conditioned media from TSP-1 over-expressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types, also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE. Defective release of astrocytic factors may impair synaptic integrity in chronic hepatic encephalopathy. We found a reduction in the release of the astrocytic matricellular proteins thrombospondin-1 (TSP-1) in ammonia-treated astrocytes; such reduction was associated with a decrease in synaptic proteins caused by conditioned media from ammonia-treated astrocytes. Exposure of neurons to CM from ammonia-treated astrocytes, in which TSP-1 is over-expressed, reversed (by approx 75%) the reduction in synaptic proteins. NF-kB = nuclear factor kappa B; PSD95 = post-synaptic density protein 95; ONS = oxidative/nitrative stress.

Brain edema in acute liver failure: mechanisms and concepts

Brain edema and associated increase in intracranial pressure continue to be lethal complications of acute liver failure (ALF). Abundant evidence suggests that the edema in ALF is largely cytotoxic brought about by swelling of astrocytes. Elevated blood and brain ammonia levels have been strongly implicated in the development of the brain edema. Additionally, inflammation and sepsis have been shown to contribute to the astrocyte swelling/brain edema in the setting of ALF. We posit that ammonia initiates a number of signaling events, including oxidative/nitrative stress (ONS), the mitochondrial permeability transition (mPT), activation of the transcription factor (NF-κB) and signaling kinases, all of which have been shown to contribute to the mechanism of astrocyte swelling. All of these factors also impact ion-transporters, including Na(+), K(+), Cl(-) cotransporter and the sulfonylurea receptor 1, as well as the water channel protein aquaporin-4 resulting in a perturbation of cellular ion and water homeostasis, ultimately resulting in astrocyte swelling/brain edema. All of these events are also potentiated by inflammation. This article reviews contemporary knowledge regarding mechanisms of astrocyte swelling/brain edema formation which hopefully will facilitate the identification of therapeutic targets capable of mitigating the brain edema associated with ALF.