Relationship between tumor necrosis factor‐alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure

Odeh, Majed; Sabo, Edmond; Srugo, Isaac; Oliven, Arie

doi:10.1080/07853890500317414

Cited by 72 publications

(80 citation statements)

References 41 publications

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“…It has recently been suggested that inflammatory mediators might play a crucial role in the pathogenesis of this syndrome (27,42,51). Serum levels of inflammatory cytokines have been shown to correlate with the severity of encephalopathy in patients with cirrhosis (43,44). Both the presence of hepatic encephalopathy and the reduction in HRV have negative prognostic value in this patient population (7,17).…”

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confidence: 99%

Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy

Mani¹,

Montagnese²,

Jackson³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

111

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Mani AR, Montagnese S, Jackson CD, Jenkins CW, Head IM, Stephens RC, Moore KP, Morgan MY. Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 296: G330 -G338, 2009. First published November 20, 2008 doi:10.1152/ajpgi.90488.2008.-Heart rate variability (HRV) is reduced in several clinical settings associated with either systemic inflammation or neuropsychiatric impairment. The possibility that the changes in HRV observed in patients with neuropsychiatric impairment might relate to the overproduction of inflammatory cytokines does not seem to have been considered in the studies undertaken to date. HRV is decreased in patients with liver cirrhosis but its relationship to the impairment of neuropsychiatric performance, commonly observed in these patients, is unknown. The aim of this study was to investigate the relationship between HRV, hepatic encephalopathy, and production of inflammatory cytokines in patients with cirrhosis. Eighty patients with cirrhosis [53 men, 27 women; mean (Ϯ1SD) age 54 Ϯ 10 yr], classified as neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy, and 11 healthy subjects were studied. HRV was assessed by applying Poincaré plot analysis to the R-R interval series on a 5-min ECG. Inflammatory cytokines (TNF-␣, IL-6, IL-10, and IL-12) were measured in a subgroup of patients. Long-term R-R variability was significantly decreased in the patients with cirrhosis, in parallel with the degree of neuropsychiatric impairment (P Ͻ 0.01) and independently of the degree of hepatic dysfunction (P ϭ 0.011). The relative risk of death increased by 7.7% for every 1-ms drop in this variable. Plasma levels of IL-6 significantly correlated with indexes of both HRV and neuropsychiatric performance. The changes observed in HRV and in neuropsychiatric status in patients with cirrhosis are significantly correlated, most likely reflecting a common pathogenic mechanism mediated by inflammatory cytokines.

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confidence: 99%

Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy

Mani¹,

Montagnese²,

Jackson³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

111

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“…[51][52][53] The production of TNF-␣, a central player in inflammatory reactions, has been shown to be markedly elevated in cirrhosis. 51,54,55 TNF-␣ substantially reduces the expression of 11␤-HSD2, a contention supported by several lines of evidence. First, Takahashi et al reported a decreased 11␤-HSD2 expression in the mineralocorticoid responsive colonic mucosa of patients with inflammatory bowel disease.…”

Section: Biology Of 11␤-hsd2mentioning

confidence: 54%

Impaired 11β-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact?

Frey

2006

Hepatology

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Exaggerated renal sodium retention with concomitant potassium loss is a hallmark of cirrhosis and contributes to the accumulation of fluid as ascites, pleural effusion, or edema. This apparent mineralocorticoid effect is only partially explained by increased aldosterone concentrations. I present evidence supporting the hypothesis that cortisol confers mineralocorticoid action in cirrhosis. The underlying molecular pathology for this mineralocorticoid receptor (MR) activation by cortisol is a reduced activity of the 11␤-hydroxysteroid dehydrogenase type 2, an enzyme protecting the MR from promiscuous activation by cortisol in healthy mammalians. (HEPATOLOGY 2006;44:795-801.) R enal sodium retention and potassium loss are observed in many patients suffering from cirrhosis. Traditionally, this abnormality is attributed to secondary hyperaldosteronism as a consequence of renal hypoperfusion related to intra-abdominal fluid sequestration. 1 This concept has been questioned for 2 reasons. First, patients with cirrhosis accumulating ascites can show renal sodium retention in the presence of normal plasma aldosterone concentration and increased circulating concentrations of natriuretic peptides 2-8 and second, renal sodium retention precedes intra-abdominal fluid sequestration in some situations, and therefore a secondary hyperaldosteronism does not explain the abnormal renal handling of sodium and potassium. 2-4 Many of these patients have a normal renal plasma flow and glomerular filtration rate. Therefore, sodium retention cannot be explained on the basis of an impaired renal perfusion or a decreased filtered sodium load 7 and an unknown mechanism might induce sodium retention. 9 Because this type of renal sodium avidity is linked with enhanced renal potassium loss and blocked by aldosterone antagonists, one is tempted to speculate that the underlying mechanism is an activation of mineralocorticoid receptor (MR). Several independent groups of investigators demonstrated that for a given renal sodium excretion the values for aldosterone were too low in patients with cirrhosis and therefore hypothesized that these findings are explained by an increased renal tubular sensitivity to aldosterone. [10][11][12] Here, the evidence is given for another hypothetical mechanism, which might mimic the presumed increased renal tubular sensitivity to aldosterone, i.e., the presence of a MRactivating ligand other than aldosterone. This ligand is most likely cortisol. MR activation by cortisol is not explained by an enhanced adrenal production rate and/or increased serum concentrations of cortisol in these patients, but by a reduced activity of the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2), which allows promiscuous activation of MR by the glucocorticoid cortisol. Activation of MR by CortisolInitially identified in the classic mineralocorticoid-responsive tissues including the aldosterone-sensitive part of the distal nephron, colon, or salivary glands, MR acts as a ligand-inducible transcription factor. 13,14 The cor...

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“…The "TNF theory" of HA/HE pathogenesis [8] emphasizes significant roles of TNF-α and other cytokines in HE up to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13]. Obviously, TNF-α could be considered a suitable target for therapeutic intervention, however, with limited information on its responsiveness towards RSV in neuroinflammation and neuroexcitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…During recent past, "TNF theory" (Tumor necrosis factor) of HE pathogenesis could draw much attention due to a close association between the level of TNF-α and ammonia in the brain of CLF patients with HE [8]. Later studies have also emphasized significant involvement of TNF-α and other cytokines in HE to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…The information, mainly derived from the cell culture system and from animal models with acute HE, suggest that the increased brain ammonia level mainly drives astrocytes to undergo significant morpho-pathological changes and also over activates glutamate-NMDA receptor (N-Methyl-D-Aspartate Receptor) pathway in the post-synaptic neurons [1,[5][6][7]. Moreover, NMDAR inhibition could not be translated into prevention of ammonia neurotoxicity, mainly because threshold glutamate-NMDAR activation is necessary for normal neurological functions including higher order brain functions and normal synaptic activity.During recent past, "TNF theory" (Tumor necrosis factor) of HE pathogenesis could draw much attention due to a close association between the level of TNF-α and ammonia in the brain of CLF patients with HE [8]. Later studies have also emphasized significant involvement of TNF-α and other cytokines in HE to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13].…”

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confidence: 99%

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Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

Khanna¹,

Trigun²

2016

IJCAM

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Research ArticleInt J Complement Alt Med 2016, 4(2): 00115 IntroductionAmmonia neurotoxicity is considered responsible for development of a serious nervous system disorder called hepatic encephalopathy (HE). This situation arises mainly due to liver dysfunction led hyperammonemia (HA). HE is characterized by the neuropsychiatric manifestations related to motor dysfunction, memory impairment, and deranged sleep-awake cycle [1,2]. Since HE affects the quality of life of the patients, it is important to develop effective therapeutic strategy against HE. This necessitates understanding the neuro-chemistry of HA pathogenesis.Since ammonia crosses the blood brain barrier easily, prolonged HA condition, a common situation during chronic liver failure (CLF), is likely to maintain increased ammonia concentration in brain [3,4]. The information, mainly derived from the cell culture system and from animal models with acute HE, suggest that the increased brain ammonia level mainly drives astrocytes to undergo significant morpho-pathological changes and also over activates glutamate-NMDA receptor (N-Methyl-D-Aspartate Receptor) pathway in the post-synaptic neurons [1,[5][6][7]. Moreover, NMDAR inhibition could not be translated into prevention of ammonia neurotoxicity, mainly because threshold glutamate-NMDAR activation is necessary for normal neurological functions including higher order brain functions and normal synaptic activity.During recent past, "TNF theory" (Tumor necrosis factor) of HE pathogenesis could draw much attention due to a close association between the level of TNF-α and ammonia in the brain of CLF patients with HE [8]. Later studies have also emphasized significant involvement of TNF-α and other cytokines in HE to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13].It is now evident that the microglia and astroglia cells in brain synthesize TNF-α to regulate higher order brain functions and astrocyte induced synaptic strengthening [14][15][16][17]. However, when produced in higher amounts during neuropathology, they are known to potentiate glutamate induced cytotoxicity by inhibiting glutamate transport to the glial cells from the synaptic cleft [12,[16][17][18][19]. Even development of MHE has been described to be dependent more on enhanced inflammatory markers than the severity of CLF or HA in the CLF patients [20]. Moreover, some findings from in vitro studies suggest that resveratrol treatment could prevent ammonia toxicity in astroglial cells by normalizing ROS/RNS level [12,21,22]. Thus, hinting towards a significant role of resveratrol in ameliorating ammonia toxicity. However, the mechanism by which resveratrol does so is unclear.Resveratrol (3, 3, 4'-trihydroxy-Trans stilbene), a natural polyphenol, is found in a number of dietary sources such as grapes, berries, and red wine [23][24][25]. It acts as an effective cardioprotector, AbstractChronic liver failure (CLF) led hyperammonemia (HA) is known to develop a metabolic brain disorder known a...

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Relationship between tumor necrosis factor‐alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure

Cited by 72 publications

References 41 publications

Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy

Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy

Impaired 11β-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact?

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

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