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In the urea cycle: ammonia and bicarbonate form carbamoylphosphate via carbamoyl phosphate synthetase1 (CPS1). This reaction requires N-acetylglutamate (acquired via a reaction catalysed by N-acetylglutamate synthase (NAGS)), Mg2+ and MgATP. Carbamoylphosphate combines with ornithine in a reaction catalysed by ornithine carbamoyltransferase (OTC) to form citrulline. Citrulline is transported to the cytosol and combines with aspartate to form argininosuccinate (reaction catalysed by argininosuccinate synthetase (ASS1)). Argininosuccinate is then cleaved by argininosuccinate lyase (ASL) yielding fumarate and arginine. Arginase (ARG1) cleaves arginine, producing urea and ornithine. Urea is excreted as waste and ornithine is transported back to the mitochondria to be used in subsequent cycles of urea synthesis. In the pericentral hepatocytes, ammonia ‘escaping’ the urea cycle is metabolized to glutamine (reaction catalysed by glutamate–ammonia ligase (GLUL).
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The detoxification of ammonia occurs mainly through conversion of ammonia to urea in the liver via the urea cycle and glutamine synthesis. Congenital portosystemic shunts (CPSS) in dogs cause hyperammonemia eventually leading to hepatic encephalopathy. In this study, the gene expression of urea cycle enzymes (carbamoylphosphate synthetase (CPS1), o...
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Background
Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limite...
http://ijp.mums.ac.ir/article_16335.html
Background: The diagnosis of inborn errors of metabolism is generally challenging. We aimed to explore various types of urea cycle disorders (UCDs) and their clinical presentations among pediatric patients.
Materials and methods: This case-control study was conducted on 86 participants categorized into 43 p...
In 2012 we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35,000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have ela...
The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.
To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry.
We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OT...
Citations
... These included genes associated with liver regeneration (HGF, TGFβ), angiogenesis (HIF1a, VEGFR2), inflammation (IL1β, IL6, SERPINB1), urea cycle enzymes (CPS1, NAGS), natriuretic peptides (NPPA, NPPC, NPR1, NPR2), and metabolism (FGF21). Gene selection was based on those of interest from previous studies in dogs [14,[16][17][18][19][20]29]. Initial optimization of the multiplex assay also included primers targeting MAT2A, although it was not possible to successfully multiplex this with other genes of interest in the assay. ...
... Elevated CPS1 expression has been demonstrated in human patients with poor liver function and with hepatocellular injury [40,41]. However, dogs with CPSS expressed lower CPS1 than unaffected control dogs, and this did not resolve upon successful shunt attenuation surgery [29]. CPS1 is a critical part of the urea cycle, involved in generating carbomyl phosphate from ammonia, bicarbonate, and ATP [42]. ...
Congenital portosystemic shunts (CPSS) are vascular anomalies resulting in liver hypoplasia and hepatic insufficiency. Cats with CPSS typically show signs of hepatic encephalopathy associated with increased ammonia, inflammatory cytokines, and oxidative stress. Surgical attenuation of the CPSS results in improved liver function, resolution of clinical signs, and increased portal blood flow. Hepatic gene expression has not previously been investigated in cats with CPSS. Here, we compared the hepatic expression of genes involved in the urea cycle (CPS1, NAGS), angiogenesis (VEGFR2, NPPA, NPR1, NPPC, NPR2, HIF1a), liver regeneration (SERPINB1, HGF, TGFβ), and metabolism (FGF21) from a small series of cats (n = 18) with CPSS to that of control cats (n = 10). The expression of TGFβ, VEGFR2, HGF, FGF21, and CPS1 was significantly elevated in liver biopsies from cats with CPSS. Cats that could only tolerate partial closure of their CPSS had increased hepatic expression of SERPINB1, HIF1a, and NPR2 compared with those that could tolerate complete ligation. Furthermore, there were no significant correlations between gene expression and pre-operative plasma ammonia concentrations in cats with CPSS. The changes in hepatic gene expression in cats with CPSS are in direct contrast to those seen in dogs with CPSS, suggesting alternative mechanisms may be involved in mediating hepatic changes in cats with CPSS.
... Congenital portosystemic shunt is the most common cause of hyperammonemia in many canine breeds. 240 Xanthinuria can occur in patients on allopurinol treatment. 241 An inborn error of metabolism is usually a rare disease, but when inborn errors of metabolism are considered as a group they become relatively common. ...
Inborn errors of metabolism are genetic disorders caused by a block in a metabolic pathway, affecting both humans and animals. Individually, they are rare diseases, but as a group they are relatively common. As most of them have recessive inheritance, a new case may seem like just a sporadic case. The high degree of inbreeding in dog breeds increases the frequency of heterozygotes in populations, maintaining mutations (variants) in healthy individuals and, consequently, increasing the risk of disease recurrence (homozygotes). General practitioners' familiarization with this subject is a significant factor in identifying new cases, contributing to increased knowledge about inborn errors of metabolism and their control. To help general practitioners, we use a clinical genetics approach covering key genetic, metabolic, diagnostic, and therapeutic aspects, offering an overview that integrates knowledge about these diseases in dogs and humans.
... Hepatic encephalopathy (HE) is a spectrum of neurologic abnormalities seen in patients with moderate to severe liver dysfunction (1,2). Severity can range from subtle and episodic to severe clinical signs including altered mentation (obtunded, stuporous, comatose), ataxia, blindness, muscle tremors, and focal or generalized seizures (2,3). The exact mechanism of HE is not fully understood, with suggested mechanisms including an altered blood-brain-barrier (4-6), cerebral blood flow or cerebral energy metabolism, changes in central and neuromuscular neurotransmission, amino acid imbalance, or oxidative and neuroinflammatory damage (3,4,(6)(7)(8). ...
... Severity can range from subtle and episodic to severe clinical signs including altered mentation (obtunded, stuporous, comatose), ataxia, blindness, muscle tremors, and focal or generalized seizures (2,3). The exact mechanism of HE is not fully understood, with suggested mechanisms including an altered blood-brain-barrier (4-6), cerebral blood flow or cerebral energy metabolism, changes in central and neuromuscular neurotransmission, amino acid imbalance, or oxidative and neuroinflammatory damage (3,4,(6)(7)(8). It is widely accepted that hyperammonemia is a key component in the development of HE (3,5,6,8). Ammonia is highly lipophilic and easily crosses cell membranes, including the blood-brain barrier (5,7,8). ...
... The exact mechanism of HE is not fully understood, with suggested mechanisms including an altered blood-brain-barrier (4-6), cerebral blood flow or cerebral energy metabolism, changes in central and neuromuscular neurotransmission, amino acid imbalance, or oxidative and neuroinflammatory damage (3,4,(6)(7)(8). It is widely accepted that hyperammonemia is a key component in the development of HE (3,5,6,8). Ammonia is highly lipophilic and easily crosses cell membranes, including the blood-brain barrier (5,7,8). Ammonia is produced as the end product of protein metabolism in the intestinal tract (2,4,6). ...
A 5-month-old male intact Great Pyrenees was presented for an acute onset of severe neurologic signs (stupor, absent menace, intermittent head turn to the left). The patient's history included possible naproxen ingestion with a maximum ingested dose of 59 mg/kg, exceeding the reported dose of >50 mg/kg known to cause neurologic signs. Blood sampling for baseline bloodwork was performed, and intravenous lipid emulsion (ILE) was subsequently administered, for treatment of the suspected toxicosis. Due to severe and life-threatening neurologic signs, other methods of decontamination were contraindicated and unlikely to be effective; extracorporeal therapy was also unavailable. Complete resolution of neurologic signs occurred 30 min after completion of ILE therapy. At this time, the owners found the missing naproxen tablets after returning home and the bloodwork results returned revealing findings consistent with hepatic encephalopathy. The fasted blood ammonia concentration immediately prior to ILE administration was 702.1 μg/dL (reference interval, RI: 24–36 μg/dL) and decreased to 194.1 μg/dL 24 h later. In the first 24 h, the patient also received three doses of lactulose, N-acetylcysteine, and intravenous fluids. The patient was subsequently diagnosed with a single, large intrahepatic portosystemic shunt via computed tomography and underwent an endovascular coil embolization procedure. Given the rapid and dramatic improvement in severe neurologic signs after ILE therapy alone, it is strongly suspected that this treatment resulted in improvement of hepatic encephalopathy.
... Capillarisation of part of the liver sinusoids can have a major impact on liver metabolism, especially since different liver function zones are responsible for metabolism of different nutrients and drugs (Gumucio, 1983;Kietzmann, 2017). A study evaluating gene expression and distribution of enzymes of the urea cycle and other ammonia-metabolising pathways in the liver of dogs with congenital PSS, found that enzymes which are normally found in the periportal zone in healthy dogs lacked a clear zonal distribution (van Straten et al., 2014). ...
... While genes involved in the detoxification of ammonia and in glutamine synthesis are relatively stable, genes involved in glucose and drug metabolism are more influenced by blood flow and oxygen tension (Cast et al., 2015). (van Straten et al., 2014); however, it is also possible that capillarisation in the periportal zone in dogs with congenital PSS causes redistribution of gene-expression. As metabolic pathways involving amino acids, carbohydrates, fatty acids and detoxification of products/drugs other than ammonia all have significant portal-tocentral differences (Berndt et al., 2021), similar differences in all metabolic pathways can be expected. ...
... The plasma amino acid concentrations and serum vitamin concentrations in our study equally suggested the presence of liver dysfunction, which even seems to be present beyond three months postoperatively. Our findings corroborate with the fact that one to three months after surgical attenuation aberrant gene expression and distribution of enzymes linked to the ammonia metabolising pathways persist (van Straten et al., 2014). ...
... A zonated metabolic pattern is also known for ammonia metabolism [14]. While urea-cycle enzymes detoxify ammonia by high capacity and low affinity mechanism in the periportal and midzonal regions, low remaining ammonia concentrations are removed from the sinusoidal blood by a pericentral ring of glutamine synthetase positive hepatocytes that act by a low capacity, high affinity mechanism [15][16][17]. Further zonated functions include glycolysis, gluconeogenesis, glycogenesis, the TCA-cycle, glutamine metabolism and lipogenesis [2,7]. ...
Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2 −/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated 'periportalization' was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.
... This results in a decrease in ureagenesis and causes hyperammonemia. 11 Decreased expression of the urea cycle enzymes, which has been shown to occur in CPSS dogs, 12 also may play a role in the pathogenesis of hyperammonemia in affected dogs. ...
Background
Hyperammonemia can result in hepatic encephalopathy, which in severe cases eventually can lead to coma and death. In dogs, congenital portosystemic shunts (CPSS) are the most common cause for hyperammonemia. Conservative treatment consists of a protein modified diet, nonabsorbable disaccharides, antibiotics, or some combinations of these. Sodium benzoate (SB) and sodium phenylbutyrate (SPB) both are used in the acute and long‐term treatment of humans with hyperammonemia caused by urea cycle enzyme deficiencies. Both treatments are believed to lower blood ammonia concentrations by promoting excretion of excess nitrogen via alternative pathways.
Objectives
To evaluate the efficacy and safety of PO treatment with SB and SPB on hyperammonemia and clinical signs in CPSS dogs.
Methods
Randomized, double‐blind, placebo‐controlled crossover trial. Concentrations of blood ammonia and bile acids were measured in CPSS dogs before and after a 5‐day treatment with SB, SPB, and placebo. A wash‐out period of 3 days was used between treatments. A standard questionnaire was developed and distributed to owners to evaluate clinical signs before and after each treatment.
Results
Blood ammonia concentrations were not influenced by any of the treatments and were comparable to those observed during placebo treatment. In addition, SB and SPB treatment did not result in improvement of clinical signs. Adverse effects during treatment included anorexia, vomiting, and lethargy.
Conclusions and Clinical Importance
Based on our results, we conclude that SB or SPB are not useful in the conservative treatment of hyperammonemia in dogs with CPSS.
... Affected dogs generally show symptoms before the age of two, but some patients do not develop clinical symptoms until they are older [3]. The most common symptoms are anxiety, lethargy and apathy while intrahepatic portosystemic shunts and cirrhosis cause hepatic encephalopathy more commonly [4,5]. Ultrasonography, magnetic resonance imaging and/or computed tomography were used for definitive diagnosis [6]. ...
Portosystemic shunt is an abnormal vascular connection between the portal and systemic venous system. Due to this abnormal network of
vessels, portal venous blood and its toxic by-products by-pass the liver and directly mix into the systemic circulation. It is a well-known congenital
cause of encephalopathy which is characterized by high ammonium levels. Our case; a two-year-old male dog was brought to our clinic with
tonic-clonic epileptic seizures and allotriophagia presenting for the last four months.Diagnosis of portosystemic shunt was made, and a surgical
operation was planned. After the operation, ammonium levels decreased sharply. However, ammonium levels have started to rise again the month
following the procedure and leaded to more severe symptoms. Consequently, the patient was euthanized after three months.
... Another explanation for steatosis occurring secondary to CPSS could be plasma ammonia levels. CPSS are the most frequent cause of hyperammonemia in dogs which, when left untreated, results in hepatic encephalopathy [35]. In case of hyperammonemia, the ammonia is postulated to accumulate in lysosomes. ...
Non-alcoholic fatty liver disease (NAFLD) is a poorly understood multifactorial pandemic disorder. One of the hallmarks of NAFLD, hepatic steatosis, is a common feature in canine congenital portosystemic shunts. The aim of this study was to gain detailed insight into the pathogenesis of steatosis in this large animal model. Hepatic lipid accumulation, gene-expression analysis and HPLC-MS of neutral lipids and phospholipids in extrahepatic (EHPSS) and intrahepatic portosystemic shunts (IHPSS) was compared to healthy control dogs. Liver organoids of diseased dogs and healthy control dogs were incubated with palmitic- and oleic-acid, and lipid accumulation was quantified using LD540. In histological slides of shunt livers, a 12-fold increase of lipid content was detected compared to the control dogs (EHPSS P<0.01; IHPSS P = 0.042). Involvement of lipid-related genes to steatosis in portosystemic shunting was corroborated using gene-expression profiling. Lipid analysis demonstrated different triglyceride composition and a shift towards short chain and omega-3 fatty acids in shunt versus healthy dogs, with no difference in lipid species composition between shunt types. All organoids showed a similar increase in triacylglycerols after free fatty acids enrichment. This study demonstrates that steatosis is probably secondary to canine portosystemic shunts. Unravelling the pathogenesis of this hepatic steatosis might contribute to a better understanding of steatosis in NAFLD.
... In dogs, UCED are extremely rare 25,26 and CPSS is the most common cause of hyperammonemia and HE 27,28 . CPSS result in severe reduction of ureagenesis, reduced expressions of urea cycle enzymes and consequently hyperammonemia 29,30 . Clinical symptoms of hyperammonemia in dogs (e.g. ...
... To our knowledge, this is the first randomized, placebo controlled study for the safety and efficacy of SB and SPA treatments of hyperammonemia. Due to the similarities of ammonia metabolism, dogs are considered a valid model for hyperammonemia in man 29,31 . In our study, SB and SPA treatments were safe and well-tolerated in both healthy dogs (SB + SPA) and dogs with CPSS (SB). ...
Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series. Canine congenital portosystemic shunting (CPSS) is a naturally occurring model for hyperammonemia. Here, we performed cross-over, randomized, placebo-controlled studies in healthy dogs to assess safety and pharmacokinetics of SB and SPA (phase I). As follow-up safety and efficacy of SB was evaluated in CPSS-dogs with hyperammonemia (phase II). Pharmacokinetics of SB and SPA were comparable to those reported in humans. Treatment with SB and SPA was safe and both nitrogen scavengers were converted into their respective metabolites hippuric acid and phenylacetylglutamine or phenylacetylglycine, with a preference for phenylacetylglycine. In CPSS-dogs, treatment with SB resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste. Consequentially, treatment of hyperammonemia justifies additional/placebo-controlled trials in human medicine.
... These processes actually secure energy production that is important to provide adequate energy supply to maintain the astroglial capacity for Glu uptake. In context, we discuss sub-second-to-minute timescale processes such as the fast astroglial release of the inhibitory GABA (Héja et al., 2009(Héja et al., , 2012Kardos et al., 2015;Kersanté et al., 2013;Kirischuk et al., 2015;Lee et al., 2011;Unichenko et al., 2013), ATP, Glu and D-serine (Halassa and Haydon, 2010;Henneberger et al., 2010;Parpura et al., 2014; for discussions of gliotransmission see Bazargani and Attwell, 2016;Sloan and Barres, 2014;Van Horn et al., 2013;Verkhratsky et al., 2016). These processes can be modulated by protein synthesis-and traffickingrelated processes, including up-and down-regulation of astroglial Glu transporter expression by epidermal growth factor (EGF) (Zelenaia et al., 2000), transforming growth factor-b (TGF-b) (Lee et al., 2012), insulin like growth factor type I (IGF-I) (Yin et al., 2013), and tumor necrosis factor-a (TNF-a) (Pickering et al., 2005). ...
... Specifically, ammonia from the gut is detoxified by two major pathways, urea synthesis and Gln formation. Urea synthesis is responsible for the disposal of over 90% of surplus nitrogen from dietary or endogenous nitrogen sources (van Straten et al., 2014). The crucial role of hepatic GS in the maintenance of ammonia homeostasis was demonstrated in liver-specific GS knockout mice exhibiting increased blood ammonia levels, induction of oxidative stress in brain tissue, and behavioral abnormalities (Qvartskhavaa et al., 2015). ...
