A morphological method for ammonia detection in liver

Gutiérrez-de-Juan, Virginia; Davalillo, Sergio López de; Fernández‐Ramos, David; Barbier-Torres, Lucía; Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Simón, Jorge; Lopitz‐Otsoa, Fernando; Heras, Javier de las; Iruzubieta, Paula; Arias-Loste, María Teresa; Villa, Erica; Crespo, Javier; Andrade, Raúl J.; Lucena, M. Isabel; Varela‐Rey, Marta; Lu, Shelly C.; Mato, José M.; Delgado, Teresa C.; Martínez-Chantar, María-Luz

doi:10.1371/journal.pone.0173914

Cited by 40 publications

(37 citation statements)

References 28 publications

(28 reference statements)

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“…It has been proposed that the application of a novel morphological method for the detection of increased hepatic concentrations of ammonia that was shown to correlate well with the severity of chronic liver disease could afford a useful method for the prediction of patient outcome in fatty liver disease [3]. Further elucidation of ammonia-related signaling pathways and their intermediates identified in this report has the potential not only for the identification of pathophysiological mechanisms in these disorders but also for the design of novel therapeutic strategies and the provision of biomarkers for risk stratification in relation to NAFLD/NASH.…”

Section: Discussionmentioning

confidence: 99%

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Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

Butterworth

Canbay

2018

Dig Dis

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Background: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. Summary: L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6–9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA’s ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.

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Section: Discussionmentioning

confidence: 99%

“…Given the key role of the liver in the removal of excess ammonia, it is not surprising that patients with NASH are hyperammonemic [2] and hepatic accumulation of ammonia has been confirmed in both patients and animal models of fatty liver disease [3].…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

Butterworth

Canbay

2018

Dig Dis

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“…The sections were then washed briefly twice in distilled water, counterstained with hematoxylin (Sigma-Aldrich), washed with running tap water, dehydrated in graded alcohol, and mounted with DPX permanent mounting medium. (22) otC enzyme activity. In brief, liver samples were incubated in the presence of excessive amounts of l-ornithine and carbamoyl phosphate under optimal enzyme conditions (triethanolamine solution).…”

Section: Markers Of Hepatic Cell Deathmentioning

confidence: 99%

“…Macroscopically, the livers from HC and HFHC animals were progressively enlarged compared to NC animals (21 [19][20][21][22], 36 [33][34][35][36][37][38] g versus 17 [15][16][17][18] g at 16 weeks, P = 0.003) (Supporting Fig. S1B; Table 1).…”

Section: Progressive Urea Cycle Dysfunction and Hyperammonemia In An mentioning

confidence: 99%

Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease

et al. 2019

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Background and Aims In nonalcoholic fatty liver disease (NAFLD), fibrosis is the most important factor contributing to NAFLD‐associated morbidity and mortality. Prevention of progression and reduction in fibrosis are the main aims of treatment. Even in early stages of NAFLD, hepatic and systemic hyperammonemia is evident. This is due to reduced urea synthesis; and as ammonia is known to activate hepatic stellate cells, we hypothesized that ammonia may be involved in the progression of fibrosis in NAFLD. Approach and Results In a high‐fat, high‐cholesterol diet–induced rodent model of NAFLD, we observed a progressive stepwise reduction in the expression and activity of urea cycle enzymes resulting in hyperammonemia, evidence of hepatic stellate cell activation, and progressive fibrosis. In primary, cultured hepatocytes and precision‐cut liver slices we demonstrated increased gene expression of profibrogenic markers after lipid and/or ammonia exposure. Lowering of ammonia with the ammonia scavenger ornithine phenylacetate prevented hepatocyte cell death and significantly reduced the development of fibrosis both in vitro in the liver slices and in vivo in a rodent model. The prevention of fibrosis in the rodent model was associated with restoration of urea cycle enzyme activity and function, reduced hepatic ammonia, and markers of inflammation. Conclusions The results of this study suggest that hepatic steatosis results in hyperammonemia, which is associated with progression of hepatic fibrosis. Reduction of ammonia levels prevented progression of fibrosis, providing a potential treatment for NAFLD.

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“…Та же группа авторов еще в одном исследовании отмечает «раннее увеличение аммиакаособенность неалкогольной жировой болезни печени, выбор агента для понижения аммиака позволяет уменьшить прогрессию НАЖБП и уровень фиброза» [37]. Еще одна группа авторов разработала методику определения внутрипеченочного аммиака как маркера и потенциального фактора повреждения печени при НАЖБП на доклинической стадии, они сделали вывод, что «накопление аммиака увеличивается у пациентов при НАЖБП с повышенной степенью лобулярного воспаления и гомоцистеина плазмы» [38].…”

Section: таблица постпрандиальные показатели кровотока и первичных мunclassified

Different types of hyperammonemia in clinical practice

Плотникова¹,

Сухих

2018

Med. sov.

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Hyperammonemia is a metabolic disorder, which is caused as a result of high levels of ammonia present in the blood. Hyperammonemia is related to severe liver diseases, primarily to cirrhosis in 90% of cases. Non-cirrhotic causes should be considered in the remaining 10%. The article describes various causes and clinical features of hyperammonemia related to the pre-cirrhotic stages of liver disease, especially to non-alcoholic fatty dystrophy. The authors also provide other etiologies that cause hyperammonemia of varying severity, from minimal to very severe, leading to fatal outcome. The paper provides an analysis of the efficacy of L-ornithine-L-aspartate in hyperammonemia, and the results of own original author’s pharmaceutical equivalence study of the original and generic drug L-ornithine-L-aspartate.

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A morphological method for ammonia detection in liver

Cited by 40 publications

References 28 publications

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease

Different types of hyperammonemia in clinical practice

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