Feline hyperammonemia associated with functional cobalamin deficiency: A case report.

Ammonia is a major neurotoxic substance associated with the complex pathogenesis of hepatic encephalopathy. Although several primary and secondary conditions have been reported to cause hyperammonemia, in veterinary medicine this condition is considered primarily associated with hepatic disease or portosystemic shunting. Only a few cases of inherited urea cycle enzyme deficiency and organic acid metabolic disorders have been reported in cats with hyperammonemia. To the best of our knowledge, this is the first report of hyperammonemia in a cat caused by accumulation of methylmalonic acid (MMA) secondary to functional cobalamin deficiency. A 2-year-old spayed female Turkish Angora cat exhibited postprandial depression with a 3-month history of hyperammonemia. Serum protein C and bile acid concentrations were normal. Plasma amino acid analysis revealed a deficiency of urea cycle amino acids. Although the serum cobalamin concentration was markedly high, there was no evidence of inflammatory, hepatic, or renal disease or neoplasia on blood, ultrasonographic, and computed tomographic examination. Gas chromatography-mass spectrometry revealed a high MMA concentration in the urine. Based on the results, functional cobalamin deficiency was diagnosed. Following oral amino acid supplementation and initiation of a low-protein diet, the serum ammonia level returned to normal and the postprandial depression improved. Urea cycle amino acid deficiency secondary to functional cobalamin deficiency presumably caused hyperammonemia due to MMA accumulation in this case.

Hyperammoniémie féline associée à un déficit fonctionnel en cobalamine : rapport de cas. L'ammoniac est une substance neurotoxique majeure associée à la pathogenèse complexe de l'encéphalopathie hépatique. Bien que plusieurs affections primaires et secondaires aient été signalées comme étant à l'origine d'une hyperammoniémie, en médecine vétérinaire, cette affection est considérée comme principalement associée à une maladie hépatique ou à un shunt porto-systémique. Seuls quelques cas de déficit héréditaire en enzymes du cycle de l'urée et de troubles métaboliques des acides organiques ont été signalés chez des chats atteints d'hyperammoniémie. À notre connaissance, il s'agit du premier rapport d'hyperammoniémie chez un chat causée par une accumulation d'acide méthylmalonique (MMA) secondaire à un déficit fonctionnel en cobalamine.Une chatte angora turque stérilisée âgée de 2 ans a présenté une dépression postprandiale avec une histoire d'hyperammoniémie depuis 3 mois. Les concentrations sériques de protéine C et d'acides biliaires étaient normales. L'analyse plasmatique des acides aminés a révélé une déficience en acides aminés du cycle de l'urée. Bien que la concentration sérique de cobalamine ait été nettement élevée, il n'y avait aucun signe de maladie inflammatoire, hépatique ou rénale ou de néoplasie à l'examen sanguin, échographique et tomodensitométrique. La chromatographie en phase gazeuse-spectrométrie de masse a révélé une forte concentration de MMA dans l'urine. Sur la base des résultats, un déficit fonctionnel en cobalamine a été diagnostiqué. Après une supplémentation orale en acides aminés et la mise en place d'un régime pauvre en protéines, le taux sérique d'ammoniac est revenu à la normale et la dépression postprandiale s'est améliorée. Une carence en acides aminés du cycle de l'urée secondaire à une carence en cobalamine fonctionnelle a vraisemblablement causé une hyperammoniémie due à l'accumulation de MMA dans ce cas.(Traduit par Dr Serge Messier).

Resolution of neurologic signs presumed to be associated with hyperammonemia in 2 endurance horses.

This case report describes 2 endurance horses with non-hepatic hyperammonemia. The animals were competing in a 160-km endurance competition in extreme heat conditions and were presented for obtundation. One of the horses also had evidence of blindness. The blood ammonia concentration was elevated (196 µmol/L and 249 µmol/L) and both horses improved following treatment with intravenous fluids and supportive care. These are the first documented cases of clinical signs presumed to be associated with hyperammonemia in endurance horses. Despite the severity of the clinical presentation, both horses made a full recovery. Key clinical message: Non-hepatic hyperammonemia should be considered as a potential cause of blindness and obtundation in competing endurance horses. Horses appear to respond well to treatment with intravenous fluids.

Fin des signes neurologiques présumés être associés avec de l'hyperammoniémie chez deux chevaux d'endurance. Le présent rapport de cas décrit la situation de deux chevaux d'endurance avec une hyperammoniémie non-hépatique. Les animaux compétitionnaient dans une course d'endurance de 160 km dans des conditions de chaleur extrême et furent présentés pour confusion. Un des chevaux avait également des évidences de cécité. Les concentrations d'ammoniaque sanguin étaient élevées (196 µmol/L et 249 µmol/L) et les deux chevaux s'améliorèrent à la suite du traitement avec des fluides intraveineux et des soins de support. Ces cas représentent les premiers cas documentés de signes cliniques présumés être associés avec de l'hyperammoniémie chez des chevaux d'endurance. Malgré la sévérité de la présentation clinique, les deux chevaux ont récupéré complètement.Message clinique clé :L'hyperammoniémie non-hépatique devrait être considérée comme une cause potentielle de cécité et de confusion chez des chevaux d'endurance en compétition. Les chevaux semblent bien répondre à un traitement avec des fluides intraveineux.(Traduit par Dr Serge Messier).

Necrotizing Enteritis and Hyperammonemic Encephalopathy Associated With Equine Coronavirus Infection in Equids.

Equine coronavirus (ECoV) is a Betacoronavirus recently associated clinically and epidemiologically with emerging outbreaks of pyrogenic, enteric, and/or neurologic disease in horses in the United States, Japan, and Europe. We describe the pathologic, immunohistochemical, ultrastructural, and molecular findings in 2 horses and 1 donkey that succumbed to natural infection with ECoV. One horse and the donkey (case Nos. 1, 3) had severe diffuse necrotizing enteritis with marked villous attenuation, epithelial cell necrosis at the tips of the villi, neutrophilic and fibrinous extravasation into the small intestinal lumen (pseudomembrane formation), as well as crypt necrosis, microthrombosis, and hemorrhage. The other horse (case No. 2) had hyperammonemic encephalopathy with Alzheimer type II astrocytosis throughout the cerebral cortex. ECoV was detected by quantitative polymerase chain reaction in small intestinal tissue, contents, and/or feces, and coronavirus antigen was detected by immunohistochemistry in the small intestine in all cases. Coronavirus-like particles characterized by spherical, moderately electron lucent, enveloped virions with distinct peplomer-like structures projecting from the surface were detected by negatively stained transmission electron microscopy in small intestine in case No. 1, and transmission electron microscopy of fixed small intestinal tissue from the same case revealed similar 85- to 100-nm intracytoplasmic particles located in vacuoles and free in the cytoplasm of unidentified (presumably epithelial) cells. Sequence comparison showed 97.9% to 99.0% sequence identity with the ECoV-NC99 and Tokachi09 strains. All together, these results indicate that ECoV is associated with necrotizing enteritis and hyperammonemic encephalopathy in equids.

Treatment of portal vein thrombosis using vascular access port implantation in a Dalmatian dog: A case report.

Background: Portal vein thrombosis is a disease with potentially deleterious outcomes including portal vein hypertension and intestinal infarction. The factors contributing is various; however, dogs with with acute portal vein thrombosis or multiple thromboses are less likely to survive. Therefore, acute development of portal hypertension has a requires an immediate treatment. Case Description: A 10-year-old Dalmatian was referred for syncope and azotemia, hyperammonemia. After each examinations including computed tomography scan, we diagnosed with acute portal vein thrombosis with unknown cause. A portal vein port was inserted to prevent and control the portal vein thrombus. The port was placed in abdomen subcutaneously after the position of the catheter were stabilized. Low-molecular-weight heparin was injected from the port to manage thrombosis after the operation. This case responded well to this treatment. Syncope and azotemia, hyperammonemia resolved and no relapse of thrombosis was found 6 months after the operation. Conclusion: Implantable vascular access port is a drug delivery system with the advantage of dealing with treatment-resistant acute portal vein thrombosis.

Putative intestinal hyperammonaemia in horses: 36 cases.

REASONS FOR PERFORMING THE STUDY: Intestinal hyperammonaemia (HA) has been infrequently reported in individual horses; however, there have been no studies describing clinical and laboratory data as well as short- and long-term outcome in a larger number of cases. OBJECTIVES: To describe clinical and laboratory data and short- and long-term outcome in a large group of horses with intestinal HA. METHODS: Multi-centred, retrospective study; case records of horses with HA were reviewed and any horse with a clinical or post mortem diagnosis of intestinal HA was included. Hyperammonaemia was defined as a blood ammonium (NH(4) (+)) concentration ≥60 µmol/l and horses with a diagnosis of primary hepatic disease were excluded. Relevant data were recorded and, if appropriate, data from survivors were compared to nonsurvivors to identify potential prognostic indicators. RESULTS: Thirty-six cases, 26 mature horses and 10 foals with intestinal HA were identified. Case histories included diarrhoea, colic and neurological signs and the most common clinical diagnosis was colitis and/or enteritis. The most common clinical and laboratory abnormalities included tachycardia, increased packed cell volume, hyperlactataemia and hyperglycaemia. Fourteen horses (39%) survived to discharge; NH(4) (+) concentration on admission was the only parameter significantly associated with survival. All surviving horses and foals for which follow-up information was available recovered completely and returned to their intended use without further complications. CONCLUSIONS AND POTENTIAL RELEVANCE: Intestinal HA occurs in mature horses and foals and can be associated with severe clinical and laboratory abnormalities; further studies are required to investigate predisposing factors and delineate possible differences in aetiologies.

Hyperammonemia in azotemic cats.

OBJECTIVES: Hyperammonemia occurs in cats with hepatobiliary and nutritional (cobalamin and arginine deficiency) disorders, and has also been documented in four cats with renal azotemia. We hypothesized that in cats with renal azotemia, fasting hyperammonemia would correlate with indices of worsening kidney function, and would be independent of cobalamin, potassium, systemic inflammation or urinary tract infection (UTI) with urease-producing bacteria. METHODS: A fasted blood sample was prospectively collected for ammonia and cobalamin analysis from 18 client-owned cats with renal azotemia (creatinine [Cr] ⩾1.6 mg/dl, urine specific gravity <1.030 or documentation of historical chronic kidney disease [CKD]). Correlations between blood ammonia and selected biochemical parameters were analyzed using Pearson's correlation coefficient. RESULTS: Seven castrated males and 11 spayed females with a median age of 12 years (range 4-19 years) were enrolled. Ten of 18 (56%) cats presented for acute kidney injury (AKI) or acute on chronic kidney disease (AoCKD), and 8/18 (44%) presented for progressive CKD. The median Cr was 5.9 mg/dl (range 1.9-24.7 mg/dl). Hyperammonemia was documented in 4/18 (22%) cats, with a median of 95 µmol/dl (range 85-98 µmol/dl), and all four of these cats were classified as AKI/AoCKD. Blood ammonia concentrations had a significant moderate positive correlation between blood urea nitrogen (BUN) (r = 0.645, P = 0.003), Cr (r = 0.578, P = 0.012) and serum phosphorus (r = 0.714, P = 0.0009) but not with cobalamin, potassium or white blood cell count. No cats had UTIs with urease-producing bacteria. CONCLUSIONS AND RELEVANCE: A correlation exists between blood ammonia and BUN, Cr and phosphorus in cats with renal azotemia. Future studies are warranted in a larger population of cats to determine the true prevalence, etiology and potential therapeutic effect of medical management of hyperammonemia on long-term prognosis in cats with kidney disease.

Koi sleepy disease as a pathophysiological and immunological consequence of a branchial infection of common carp with carp edema virus.

Gills of fish are involved in respiration, excretion and osmoregulation. Due to numerous interactions between these processes, branchial diseases have serious implications on fish health. Here, "koi sleepy disease" (KSD), caused by carp edema virus (CEV) infection was used to study physiological, immunological and metabolic consequences of a gill disease in fish. A metabolome analysis shows that the moderately hypoxic-tolerant carp can compensate the respiratory compromise related to this infection by various adaptations in their metabolism. Instead, the disease is accompanied by a massive disturbance of the osmotic balance with hyponatremia as low as 71.65 mmol L-1, and an accumulation of ammonia in circulatory blood causing a hyperammonemia as high as 1123.24 µmol L-1. At water conditions with increased ambient salt, the hydro-mineral balance and the ammonia excretion were restored. Importantly, both hyponatremia and hyperammonemia in KSD-affected carp can be linked to an immunosuppression leading to a four-fold drop in the number of white blood cells, and significant downregulation of cd4, tcr a2 and igm expression in gills, which can be evaded by increasing the ion concentration in water. This shows that the complex host-pathogen interactions within the gills can have immunosuppressive consequences, which have not previously been addressed in fish. Furthermore, it makes the CEV infection of carp a powerful model for studying interdependent pathological and immunological effects of a branchial disease in fish.

Transient hyperammonaemia following epileptic seizures in cats.

OBJECTIVES: The aim of this study was to determine whether transient postictal hyperammonaemia exists in cats. METHODS: The medical records of all feline patients that presented at a Swedish veterinary hospital between 2008 and 2018 were retrospectively reviewed to find those that had a recent or ongoing epileptic seizure. To qualify for inclusion, the medical record had to include information on at least one ammonia value taken in close proximity to, or during, an active seizure, the cat must have exceeded the normal upper limit of blood ammonia concentration on initial testing (reference interval 0-95 µmol/l), and there needed to be a follow-up ammonia value available within a maximum of 3 days. RESULTS: Five cats were included in the study, and they had blood ammonia concentrations on initial testing ranging from 146 to 195 µmol/l. They were all retested within a period of 2 h to 3 days of the original reading. All five cats had a spontaneous decrease in ammonia levels without any specific treatment for hyperammonaemia. CONCLUSIONS AND RELEVANCE: Pursuant to the findings of this retrospective study, transient hyperammonaemia may be noted after epileptic seizure in cats. Consequently, a differential diagnostic list in feline patients with hyperammonaemia could, depending on the context, include non-hepatic-related pathologies, such as epileptic seizures.

Comparative accuracy and precision of two commercial laboratory analyzers for the quantification of ammonia in cerebrospinal fluid.

BACKGROUND: Hyperammonemia is one of the contributing factors of hepatic encephalopathy (HE). Although blood ammonia concentrations are frequently measured in patients suspected of HE, systemic levels do not necessarily reflect the amount of ammonia in the central nervous system. Measuring ammonia in cerebrospinal fluid (CSF) can help to understand HE better and potentially improve the diagnosis and follow-up of patients with HE. OBJECTIVES: The objectives of this technical report were to evaluate the accuracy and precision of two commercial blood ammonia analyzers (Catalyst Dx, CatDX and Pocket Chem BA, PocBA) to measure CSF ammonia concentrations. METHODS: A pool of normal equine CSF was spiked with concentrated ammonia, and a series of six spiked samples were measured in parallel with both CatDx and PocBA. RESULTS: CatDx and PocBA data correlated excellently with but differed significantly from the spiked ammonia concentrations. These differences were smaller when ammonia CSF concentrations were measured with the PocBA than with the CatDx. In addition, values obtained with the PocBA were more precise than those measured with the CatDx, especially for low ammonia concentrations. CONCLUSION: This in-house comparative study shows that ammonia concentrations in spiked equine CSF correlate well with those measured by two commercial blood ammonia analyzers. Nevertheless, concentrations obtained with the PocBA are more accurate and more precise than those obtained with the CatDx, making the former device the preferred choice for clinical veterinary applications.

Efficacy of orally administered sodium benzoate and sodium phenylbutyrate in dogs with congenital portosystemic shunts.

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.

TLR5 silencing reduced hyperammonaemia-induced liver injury by inhibiting oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals.

BACKGROUND: Liver injury is a serious threat for human health and life. Toll-like receptor 5 (TLR5) has reported to be a vital mediator in flagellin or tetrachloride (CCl4)-induced liver injury. However, the roles and etiology of TLR5 in hyperammonaemia (HA)-induced liver injury are poor defined. METHODS: HA rats were generated by intragastric administration using ammonium chloride solution. Liver status was assessed by haematoxylin and eosin (H&E) staining and measuring serum levels of liver injury markers. Immunohistochemistry (IHC) assay was used to visualize protein expression in tissues. Apoptotic index in tissues was determined by TUNEL assay. RT-qPCR assay was employed to test mRNA expression. Oxidative stress responses was assessed by detecting levels of reactive oxygen species (ROS) and related indicators. NF-κB activity was examined by TransAM NF-κB colorimetric kit. RESULTS: TLR5 was highly expressed in liver tissues of HA rats. TLR5 knockdown ameliorated HA-induced liver injury by inhibiting liver cell apoptosis. TLR5 depletion inhibited HA-induced pro-inflammatory cytokine expression in liver tissues, but had no effect on the infiltration of T and macrophage cells into liver tissues. TLR5 silencing impaired HA-induced oxidative stress responses in hepatocytes, but not in hepatic stellate cells (HSCs). TLR5 downregulation inhibited HA-induced activation on TLR5/NF-κB and TLR5/MAPK signaling pathways. CONCLUSION: TLR5 silencing reduced HA-induced liver injury by inhibiting hepatocyte apoptosis, oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals, deepening our understanding on the molecular mechanism of HA-induced liver injury and providing a potential therapeutic target for alleviating liver injury.

Clinical investigation of a point-of-care blood ammonia analyzer.

BACKGROUND: Hyperammonemia has frequently been implicated in the pathogenesis of hepatic encephalopathy. Blood ammonia determination requires minimal delay between sampling and analysis for accurate results. OBJECTIVES: The aim of this study was to investigate the PocketChem BA, a new point-of-care (POC) blood ammonia analyzer for clinical use by determining machine precision, linearity, repeatability, and accuracy. METHODS: Coefficients of variation were determined by repeated measurement of 2 control solutions. Linearity was investigated by testing serial dilutions of a stock solution. For accuracy, samples from clinical cases were used to compare the results on the PocketChem BA with those obtained using an enzymatic reference method for canine plasma. Canine and feline patients were consecutively enrolled if blood ammonia was assayed and samples could be analyzed shortly after collection. Classification of results (as normal or high, using 100 micromol/L as a cutoff value), Bland-Altman and Deming regression plots, and intraclass correlation coefficients were used to compare the methods. Stability of samples and test strips also was assessed over time. RESULTS: Coefficients of variation were 10.6% and 4.8% for low and high controls, respectively. Concentrations of ammonia in diluted stock solutions correlated positively with mean measured concentrations (Pearson coefficient 0.988, P<.001). Of the 54 samples obtained from 38 dogs and 4 cats, 41 had ammonia concentrations within the readable range. Results from the POC analyzer and the reference method were correlated positively (intraclass coefficient 0.800, 95% confidence interval 0.655-0.888), with the POC analyzer having negative constant and proportional biases. The methods agreed in the classification of 45/54 (83.3%) samples, with 7 false negative results on the POC analyzer. Results of repeated sample and strip analyses at 1 and 24 hours were significantly different (P<.05) from those at 0 hour. CONCLUSIONS: The PocketChem BA has acceptable precision, adequate linearity, and satisfactory agreement with a reference method, but negative constant and proportional biases. The POC analyzer may be suitable for clinical use in patients suspected of having hepatic encephalopathy, using a lower reference limit of 60 mumol/L to decrease false negative results.

Transient hyperammonemia due to urea cycle enzyme deficiency in Irish wolfhounds.

BACKGROUND: Irish Wolfhounds frequently have a congenital portosystemic shunt, but a considerable proportion of the 6- to 8-wk-old pups has hyperammonemia in the absence of portosystemic shunting. This hyperammonemia causes no signs and is transient, normalizing at the age of 3-4 months. HYPOTHESIS: Transient hyperammonemia has a metabolic basis in Irish Wolfhounds. ANIMALS: Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied. METHODS: Integrity of the portal circulation was examined by ultrasonography and scintigraphy. Absence of parenchymal liver disease was verified by liver biopsy. Amino acid profiles were measured in 4 pups and repeated in 2 of these pups when ammonia concentrations had normalized. The amino acid profiles were compared with those of healthy Irish Wolfhound pups. RESULTS: Fasting venous ammonia concentrations were high (113-622 microg/dL, 65-345 micromol/L) in all pups, whereas bile acids were within reference range in all but 1. The ammonia and bile acid concentrations from all parents were within reference range. Portosystemic shunting was excluded in all but 1 pup. Liver biopsy excluded significant lesions in all 10 pups examined. Hypercitrullinemia was found and persisted even when ammonia had normalized, at the expense of an increase in glutamine and asparagine. CONCLUSIONS AND CLINICAL IMPORTANCE: Citrulline concentrations are controlled by the urea cycle enzymes argininosuccinase and argininosuccinate synthetase, and a defect in either of these enzymes may be responsible for the transient hyperammonemia in Irish Wolfhounds. Resolution of the hyperammonemia is associated with increased activity of alternative metabolic pathways forming glutamine and asparagine. Confirmation requires measurement of enzyme activities in liver tissue.

Postmortem diagnosis of idiopathic hyperammonemia in a horse.

A 6-year-old Quarter Horse stallion was referred to Oklahoma State University Veterinary Medical Teaching Hospital for evaluation of abdominal pain that developed after breeding activity earlier in the day. The horse developed diarrhea and progressively worsening neurologic signs (circling, ataxia, head pressing) within 22 hours of presentation and was subsequently euthanized due to severe self-destructive behavior. Antemortem biochemical and hematologic abnormalities included hypocalcemia but no evidence of hepatic disease. Idiopathic hyperammonemia and encephalopathy were suspected; cerebrospinal fluid (CSF) and aqueous humor were collected 10 hours postmortem for ammonia analysis using a colorimetric assay. Results were compared with those of 6 horses that also had been euthanized, for diseases unrelated to encephalopathy. Ammonia also was measured in plasma samples obtained antemortem. Ammonia concentrations in plasma (958 micromol/L), CSF (1566 micromol/L) and aqueous humor (1018 micromol/L) samples from the stallion were markedly increased compared to those in the 6 unaffected horses (plasma, 9-43 micromol/L; CSF, 370-532 micromol/L; aqueous humor, 70-483 micromol/L). Since the acute nature of hyperammonemic encephalopathy often does not provide sufficient time for an antemortem diagnosis, postmortem analysis of CSF and aqueous humor ammonia concentrations may be a useful alternative for documenting hyperammonemia in horses.

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.

Neurologic signs and hyperammonemia in a horse with colic.

A 23-year-old Thoroughbred gelding was referred for the evaluation of acute onset of ataxia and depression, and a 2-day history of fever. On physical examination, the gelding was profoundly depressed and 10-12% dehydrated. The horse appeared very unstable, with a wide-based stance in the hind limbs, severe symmetric ataxia in all 4 limbs, and proprioceptive deficits in both hind limbs. Nasogastric intubation produced 4 L of brown, fetid reflux, and rectal examination revealed mild small intestinal and cecal distention. Hematologic abnormalities included neutropenia with toxic change, compatible with acute inflammation and endotoxemia, and prolonged coagulation times. Serum biochemical abnormalities included prerenal azotemia. metabolic acidosis, and electrolyte abnormalities consistent with enteritis. Blood ammonia concentration was markedly increased (406 micromol/L; reference interval 4-49 micromol/L), however, serum bile acids concentration and hepatic enzyme activities were within reference intervals. Histopathologic examination of a liver biopsy revealed no abnormalities and results of tests for several infectious agents were negative. Clinical signs resolved with correction of the dehydration and electrolyte abnormalities and with antibiotic therapy. The horse was diagnosed with hyperammonemic neuropathy associated with gastrointestinal disease. In such cases, hyperammonemia is caused by increased production of ammonia by organisms in the gastrointestinal tract in combination with increased gut permeability that facilitates ammonia absorption.

Hyperammonemic hepatic encephalopathy management through L-ornithin-L-aspartate administration in dogs.

Seventeen dogs were treated with L-ornithin-L-aspartate (LOLA; experimental group). Three dogs were treated with lactulose recognized therapy (control group). Following LOLA administration, 15 dogs experienced a significant decrease in ammonia level (p ＜ 0.05) and showed clinical signs of improvement. However, there were no clinical signs of improvement in two dogs, even though the ammonia level decreased. Conversely, the clinical signs of the control group also improved and the ammonia level decreased, although these changes were not significant (p ＞ 0.05). These results suggest that LOLA is an effective drug to treat hyperammonemia in veterinary medicine.

Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie.

An eight-month-old Border collie was presented with anorexia, cachexia, failure to thrive and stupor. Laboratory tests demonstrated a mild anaemia, neutropenia, proteinuria and hyperammonaemia. Serum bile acid concentrations were normal, but an ammonia tolerance test (ATT) was abnormal. The dog responded to symptomatic therapy for hepatoencephalopathy. When a low serum cobalamin (vitamin B12) concentration and methylmalonic aciduria were noted, the dog was given a supplement of parenteral cobalamin. Two weeks later, a repeat ATT was normal. Cobalamin supplementation was continued every two weeks, and all clinical signs, except for proteinuria, resolved despite withdrawing all therapy for hepatoencephalopathy. A presumptive diagnosis of hereditary selective cobalamin malabsorption was made, based on the young age, Border collie breed, low serum cobalamin concentration and methylmalonic aciduria. Although hereditary selective cobalamin malabsorption in Border collies, giant schnauzers, Australian shepherd dogs and beagles has previously been reported in North America, to the authors' knowledge this is the first report of the condition in the UK and the first to document an abnormal ATT in a cobalamin-deficient dog.

Hyperammonaemia in four cats with renal azotaemia.

Hyperammonaemia is well reported in animals with advanced hepatic disease and portosystemic shunts, but is unreported in cats with renal disease. This case series describes four cats with severe renal azotaemia in which elevated ammonia levels were detected during the course of treatment. In two cases hyperammonaemia was detected at a time when neurological signs consistent with encephalopathy had developed. This raises the possibility that hyperammonaemia may play a role in the development of encephalopathy in cats with renal azotaemia.

The effect of hyperammonemia on myostatin and myogenic regulatory factor gene expression in broiler embryos.

Myogenesis is facilitated by four myogenic regulatory factors and is significantly inhibited by myostatin. The objective of the current study was to examine embryonic gene regulation of myostatin/myogenic regulatory factors, and subsequent manipulations of protein synthesis, in broiler embryos under induced hyperammonemia. Broiler eggs were injected with ammonium acetate solution four times over 48 h beginning on either embryonic day (ED) 15 or 17. Serum ammonia concentration was significantly higher (P<0.05) in ammonium acetate injected embryos for both ED17 and ED19 collected samples when compared with sham-injected controls. Expression of mRNA, extracted from pectoralis major of experimental and control embryos, was measured using real-time quantitative PCR for myostatin, myogenic regulatory factors myogenic factor 5, myogenic determination factor 1, myogenin, myogenic regulatory factor 4 and paired box 7. A significantly lower (P<0.01) myostatin expression was accompanied by a higher serum ammonia concentration in both ED17 and ED19 collected samples. Myogenic factor 5 expression was higher (P<0.05) in ED17 collected samples administered ammonium acetate. In both ED17 and ED19 collected samples, myogenic regulatory factor 4 was lower (P⩽0.05) in ammonium acetate injected embryos. No significant difference was seen in myogenic determination factor 1, myogenin or paired box 7 expression between treatment groups for either age of sample collection. In addition, there was no significant difference in BrdU staining of histological samples taken from treated and control embryos. Myostatin protein levels were evaluated by Western blot analysis, and also showed lower myostatin expression (P<0.05). Overall, it appears possible to inhibit myostatin expression through hyperammonemia, which is expected to have a positive effect on embryonic myogenesis and postnatal muscle growth.