Hyperammonaemia induces hepatic injury with alteration of gene expression profiles

Jia, Bin; Yu, Zujiang; Duan, Zhenfeng; Lu, Xinquan; Li, Jingjing; Liu, Xiao-rui; Sun, Ran; Gao, Xiaojuan; Wang, Yanfang; Yan, Jingya; Kan, Quancheng

doi:10.1111/liv.12365

Cited by 46 publications

(34 citation statements)

References 30 publications

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“…In addition to the impact on HSC contraction, elevated ammonia has been shown to promote liver injury through up-regulation of toll-like receptor genes, generation of oxidative stress through activation of resident macrophages and neutrophils and activation of NFκB and iNOS. In addition, ammonia promotes increased hepatocyte apoptosis and changes in cell cycle with higher cyclin D1, thereby further promoting liver injury as liver disease evolves (Jia et al, 2014). It is possible that impaired urea cycle metabolism and reduced liver clearance of ammonia primes the liver and other organs to the impact of acute inflammation and further oxidative stress, as occurs in conditions such as acute-on-chronic liver failure, though this assertion requires mechanistic evaluation.…”

Section: Livermentioning

confidence: 99%

Ammonia toxicity: from head to toe?

et al. 2016

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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.

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Section: Livermentioning

confidence: 99%

Ammonia toxicity: from head to toe?

et al. 2016

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“…The toxicity of ammonia is a result of its direct effect on pH, membrane potential and metabolism which independently or collectively cause cell dysfunction (Lai and Cooper 1991;Bosoi and Rose 2009). As the effects of ammonia are not brain-specific (Lai and Cooper 1991;Norenberg 2003), it has been shown that elevated concentrations of ammonia can also affect other organs and tissues (Kubota et al 2004;Jia et al 2014;Rose 2014).…”

Section: +Hsdwlf Hqfhskdorsdwk\ Dqrwkhu Frpsolfdwlrq Ri Olyhu Glvhdvhmentioning

confidence: 99%

The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis

et al. 2016

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Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham-operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss.

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“…In addition to the well‐known neurotoxic effects, hyperammonemia has a deleterious effect on several organ systems, which may augment inflammation and/or organ injury . Hyperammonemia may directly induce hepatic injury, potentiate immune dysfunction and hepatic stellate cell activation, and contribute to the pathogenesis of sarcopenia, which is an independent predictor of mortality in cirrhosis …”

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confidence: 99%

Prognostic Role of Ammonia in Patients With Cirrhosis

et al. 2019

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Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in patients with cirrhosis and acute decompensation is unknown. The aims of this study were to determine the relationship between ammonia levels and severity of HE and its association with organ dysfunction and short‐term mortality. We identified 498 patients from two institutions as part of prospective observational studies in patients with cirrhosis. Plasma ammonia levels were measured on admission and Chronic Liver Failure‐Sequential Organ Failure Assessment criteria were used to determine the presence of organ failures. The 28‐day patient survival was determined. Receiver operating characteristic analysis was used to identify the cutoff points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. The 28‐day mortality was 43.4%. Plasma ammonia correlated with severity of HE (P < 0.001), was significantly higher in nonsurvivors (93 [73‐121] versus 67 [55‐89] µmol/L, P < 0.001), and was an independent predictor of 28‐day mortality (hazard ratio, 1.009, P < 0.001). An ammonia level of 79.5 µmol/L had sensitivity of 68.1% and specificity of 67.4% for predicting 28‐day mortality. An ammonia level of ≥79.5 µmol/L was associated with a higher frequency of organ failures (liver [P = 0.004], coagulation [P < 0.001], kidney [P = 0.004], and respiratory [P < 0.001]). Lack of improvement in baseline ammonia at day 5 was associated with high mortality (70.6%). Conclusion: Ammonia level correlates with not only the severity of HE but also the failure of other organs and is an independent risk factor for mortality; lack of improvement in ammonia level is associated with high risk of death, making it an important biomarker and a therapeutic target.

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Hyperammonaemia induces hepatic injury with alteration of gene expression profiles

Abstract: This study demonstrates that hyperammonaemia can directly induce hepatic injury via the hepatocyte apoptosis. Gene expression profile may provide the possible explanations and mechanisms for the hepatic injury induced by hyperammonaemia.

Cited by 46 publications

References 30 publications

Ammonia toxicity: from head to toe?

Ammonia toxicity: from head to toe?

The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis

Prognostic Role of Ammonia in Patients With Cirrhosis

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