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Sarcopenia is a progressive muscle wasting condition often associated with hyperammonemia. However, no approved animal models of sarcopenia with hyperammonemia were reported. This study aimed to provide a surgical modelling of sarcopenia with hyperammonemia. Male Wistar rats were assigned by the method of random numbers ( n  = 6 per group) into experimental group with ligation of portal and pyloric veins or control group with sham surgery. Blood ammonia levels were measured directly after the surgery (20 min), after 1 h to observe acute damage in functioning shunts, and at the final endpoint (30 days). Rats were sacrificed with histological study of the liver, spleen, cerebral cortex, and skeletal muscles. Experimental rats revealed hyperammonemia at 30 days compared to controls, 70 µmol/L versus 38 µmol/L, p <0.05. No significant changes were observed in liver morphology between the groups, approving hyperammonemia without liver damage. Splenomegaly and Gamna-Gandy bodies in the spleen of experimental rats indirectly evidenced functionable portosystemic shunting after the ligation. Cerebral cortex showed a significant decrease in neurons of experimental animals, 7.6 ± 2.5 NeuN + cells vs 13 ± 2 in controls, p <0.05. Skeletal muscles revealed a significant difference of muscle fiber diameter between the groups, 20.2 ± 2.1 µm in the experimental group vs 30.7 ± 4.3 µm in controls, at p < 0.001. A model of sarcopenia with hyperammonemia was established with concomitant changes in cerebral histology revealed. This model may be a valuable tool for studies of sarcopenia and related therapeutic options.

Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. The brain is much more susceptible to the deleterious effects of ammonium in childhood than in adulthood. Hyperammonemia provokes irreversible damage to the developing central nervous system: cortical atrophy, ventricular enlargement and demyelination lead to cognitive impairment, seizures and cerebral palsy. The mechanisms leading to these severe brain lesions are still not well understood, but recent studies show that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress and signal transduction pathways. All in all, at the cellular level, these are associated with alterations in neuronal differentiation and patterns of cell death. Recent advances in imaging techniques are increasing our understanding of these processes through detailed in vivo longitudinal analysis of neurobiochemical changes associated with hyperammonemia. Further, several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase. Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches.

Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.

Many theories have been advanced to explain the encephalopathy associated with chronic liver disease and with the less common acute form. A major factor contributing to hepatic encephalopathy is hyperammonemia resulting from portacaval shunting and/or liver damage. However, an increasing number of causes of hyperammonemic encephalopathy have been discovered that present with the same clinical and laboratory features found in acute liver failure, but without liver failure. Here, we critically review the physiology, pathology, and biochemistry of ammonia (i.e., NH3 plus NH4+) and show how these elements interact to constitute a syndrome that clinicians refer to as hyperammonemic encephalopathy (i.e., acute liver failure, fulminant hepatic failure, chronic liver disease). Included will be a brief history of the status of ammonia and the centrality of the astrocyte in brain nitrogen metabolism. Ammonia is normally detoxified in the liver and extrahepatic tissues by conversion to urea and glutamine, respectively. In the brain, glutamine synthesis is largely confined to astrocytes, and it is generally accepted that in hyperammonemia excess glutamine compromises astrocyte morphology and function. Mechanisms postulated to account for this toxicity will be examined with emphasis on the osmotic effects of excess glutamine (the osmotic gliopathy theory). Because hyperammonemia causes osmotic stress and encephalopathy in patients with normal or abnormal liver function alike, the term “hyperammonemic encephalopathy” can be broadly applied to encephalopathy resulting from liver disease and from various other diseases that produce hyperammonemia. Finally, the possibility that a brain glutamine synthetase inhibitor may be of therapeutic benefit, especially in the acute form of liver disease, is discussed.

Adults and children with cholestatic liver disease are at risk for type C hepatic encephalopathy (HE) and may present lifelong neurocognitive impairment. While the underlying cellular and molecular mechanisms are still incompletely understood, ammonium and bile acids (BAs) seem to play a key role in this pathology, by crossing the blood-brain-barrier and modifying neuronal homeostasis and synaptic plasticity. This experimental study aimed to investigate the effects of ammonium and BAs on dendritic spines of rat hippocampal CA1 neurons. Taking advantage of the bile duct ligated (BDL) in vivo rat model and a hippocampal organotypic rat ex vivo slice model, we analyzed dendritic spine density in both models and spine turnover ex vivo. BDL rats showed decreased dendritic spine densities after 8 weeks, paralleled with increased concentrations of blood ammonium. In organotypic hippocampal slices, exposure to ammonium, tauro-α-muricholic and taurocholic acid induced a decrease in dendritic spine density during the first 3 days, followed by an increase in dendritic spinogenesis during days 4–5, resulting in an increased number of dendritic spines. These observations provide new insights into the effects of ammonium and BAs on dendritic spines and consequently synaptic plasticity in chronic cholestatic liver disease.

Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known. To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis. More than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%. In conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.

Hyperargininemia is caused by deficiency of arginase 1, which catalyzes the hydrolysis of L-arginine to urea as the final enzyme in the urea cycle. In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life and hepatic pathology, such as neonatal cholestasis, acute liver failure, or liver fibrosis. Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. This article provides an update on the first patients ever described, gives an overview of the distinct clinical characteristics, biochemical as well as genetical background and discusses treatment options.

Purpose: Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB). Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates. This study aimed to test for CAVA or CAVB deficiencies in a group of 96 patients with early-onset hyperammonemia and to prove the disease-causing role of the CAVA variants found. Methods: We performed CA5A and CA5B sequencing in the described cohort and developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues. Results: In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B . Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect. Conclusion: CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs. It seems to be more common than other rare metabolic diseases, and early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae. Genet Med 18 10, 991–1000.

Two different diets able to induce dietary hyperammonaemia (a methionine-choline-deficient (MCD) diet and a methionine-deficient diet enriched with ammonium acetate (MAD + 20% ammonium acetate)) were tested in a rat model. The diets were shown to have different modes of action, inducing significant hyperammonaemia (HA) and growth retardation in the rats, with different metabolic consequences. The MCD diet resulted in the development of endogenous HA, with a decrease in bilirubin levels and an increase in hepatic fat content. In contrast, the MAD + 20% ammonium acetate diet increased circulating ALP and haptoglobin levels and decreased liver mass. The above results suggest that the MCD diet deteriorated the liver function of the rats, resulting in the development of endogenous HA, while the MAD diet caused moderate changes in liver metabolism, resulting in the development of exogenous HA. Interestingly, the commonly used oral treatments Lactulose and Rifaximin did not ameliorate hyperammonaemia during or after the treatment period. In conclusion, even though the diets used in the current study caused somewhat similar hyperammonaemia, they seemed to provoke different metabolic consequences. The latter can have an impact on the severity of the resulting hyperammonaemia and thus on the hyperammonaemia-induced encephalopathy, resulting in the development of distinguishing cognitive and metabolic (liver) effects compared to other forms of encephalopathy. We hypothesized that these rat models, with significantly increased serum ammonia levels, along with different liver injuries, could serve as a suitable double animal model for the testing of new, oral enzyme therapies for hepatic encephalopathy in future studies.

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFα and PKA in these mechanisms. EV were isolated from primary cultures of CD4 lymphocytes or monocytes from control or hyperammonemic rats and added to hippocampal slices from control rats to assess induction of neuroinflammation and changes in neurotransmission. To assess the role of TNFα and protein kinase A (PKA) in the production of pathological EV by monocytes from hyperammonemic rats, we blocked TNFα with anti-TNFα or inhibited PKA. Lysosomal-autophagy dysfunction was assessed with LysoTracker and by analyzing cathepsin L, LAMP2, and LC3. In hyperammonemic rats, monocytes but not CD4 lymphocytes release pathological EV. Hyperammonemia increases the EV release by monocytes and their content of TNFR1 and TNFα. These EV induce activation of glia and of the TNFα-TNFR1-S1PR2-IL-1β-CCL2-BDNF-TrkB pathway and alterations in membrane expression of NMDA and AMPA receptors in hippocampal slices from control rats. Hyperammonemia increases TNFα levels in monocytes, which increases cAMP and PKA activity and reduces LC3 content. This leads to autophagy-lysosome dysfunction, with altered LC3, cathepsin L, and LAMP2 content and pH that increases the release of EV and their TNFR1 and TNFα content. All these changes are reversed by blocking TNFα with anti-TNFα or inhibiting PKA with an inhibitor. These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE.