Increased Plasma Tumor Necrosis Factor in Severe Alcoholic Hepatitis

Bird, George; Sheron, Nick; Goka, A.K.J.; Alexander, Graeme; Williams, Roger

doi:10.7326/0003-4819-112-12-917

Cited by 433 publications

(184 citation statements)

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“…This includes the correlation beween mortality and plasma levels of TNF-a observed in patients with A allele were cirrhotic compared with 106/137 (77%) TNFA-G homozygotes. Neither this difference nor that between alcoholic steatohepatitis 11,14 and the hepatotoxicity of TNFa shown in various experimental models of liver cell injury. 8 cirrhotics and controls was significant.…”

Section: We Have Examined the Frequency Of The Two Recently De-mentioning

confidence: 97%

“…No differences were observed for the polymoranimal models of alcoholic liver injury. tors have shown increased plasma levels of TNF-a activity in patients with ASH [11][12][13][14][15] and some have shown a correlation In common with other end-organ complications of alcohol with liver function and mortality. 11,14 TNF-a is cytotoxic to abuse, severe liver disease develops in only a minority of sensitized hepatocytes and has been implicated as a proximal heavy drinkers.…”

Section: We Have Examined the Frequency Of The Two Recently De-mentioning

confidence: 99%

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Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis

et al. 1997

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bility to ALD have thus far focused primarily on genes encod-SEE EDITORIAL ON PAGE 232 ing ethanol metabolizing enzymes. 3 Results have been conflicting, but it would appear that the known polymorphisms of genes encoding the alcohol and aldehyde dehydroTwin concordance studies suggest that genetic factors play genase enymes and the ethanol-inducible cytochrome P450, a role in determining why only a minority of heavy drinkers CYP2E1, play only a minor role in the Caucasian populadevelop hepatitis and cirrhosis. Tumor necrosis factor a tion. [5][6][7] These results have led to a search for alternative ''can-(TNF-a) has emerged as the ''final common pathway'' in the didate genes'' potentially involved in determining individual pathogenesis of alcohol-related hepatic necro-inflammation.susceptibility to advanced ALD. We have examined the frequency of the two recently de-The cytokine tumor necrosis factor a (TNF-a) has recently scribed polymorphisms of the TNF-a promoter in 150 paemerged as an important mediator of hepatic necro-inflamtients with biopsy-proven alcoholic liver disease and 145 mation associated with excessive alcohol intake. 8 Investigahealthy volunteers. There was a significant excess of the rare tion of the role of TNF-a and other cytokines in alcoholic allele (TNFA-A; G 0238 r A) at position 0238 in patients with steatohepatitis was first stimulated by the striking similarity steatohepatitis compared with controls or patients without observed between the metabolic complications of ASH and this lesion. This is consistent with previous suggestions that the metabolic effects of cytokines, including TNF-a. 8 Inthe TNFA-A allele, which falls within a putative Y regulation creased TNF-a production by peripheral blood monocytes box of the TNF-a promoter, is associated with increased TNFand Kupffer cells has been shown in patients with ASH and a expression. No differences were observed for the polymoranimal models of alcoholic liver injury. 9,10 Several investigaphism at position 0308. (HEPATOLOGY 1997;26:143-146.)tors have shown increased plasma levels of TNF-a activity in patients with ASH 11-15 and some have shown a correlation In common with other end-organ complications of alcohol with liver function and mortality. 11,14 TNF-a is cytotoxic to abuse, severe liver disease develops in only a minority of sensitized hepatocytes and has been implicated as a proximal heavy drinkers. In several biopsy studies alcoholic steatohepmediator in experimental liver injury induced by Propionibacatitis (ASH), characterized by steatosis and necroinflammaterium acnes, galactosamine, lead and endotoxin, and ischtion, is present in 6% to 30% of heavy drinkers, with estabemia-reperfusion. 8 In humans, reversible hepatitis is one of lished cirrhosis in less than 20%. 1 Although some evidence the toxicities of human recombinant TNF-a administered for supports a dose-response relationship between alcohol contherapy to cancer patients. 16 sumption and risk of disease, 2 it is clear that factors other Recently, two polymorphi...

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Section: We Have Examined the Frequency Of The Two Recently De-mentioning

confidence: 97%

Section: We Have Examined the Frequency Of The Two Recently De-mentioning

confidence: 99%

Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis

et al. 1997

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“…In addition, endotoxin-induced stimulation of Kupffer cells has been proposed to be an important initiating event leading to the production of proinflammatory cytokines and oxygen free radicals in alcoholic liver disease, which shares histologic similarities with NASH. 30,34,35 On the other hand, Yang et al 14 suggested that systemic endotoxinemia contributes to TNF-␣ production and steatohepatitis in genetically obese rats. Wigg et al 32 found that patients with NASH have a higher prevalence of small-intestinal bacterial overgrowth, the potential source of higher endotoxinemia levels.…”

Section: Discussionmentioning

confidence: 99%

Gene expression of tumor necrosis factor α and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients

et al. 2001

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The main objective of this study was to analyze the pathogenic role of the tumor necrosis factor ␣ (TNF-␣) system in the development of nonalcoholic steatohepatitis (NASH). Fifty-two obese patients were studied. We investigated: (1) the expression of mRNA of TNF-␣ and their p55 and p75-receptors by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in hepatic and adipose tissues; and (2) the relationship between TNF-␣, p55, and p75 and the severity of NASH. Obese patients without NASH were the control group. A remarkable increase in the expression of mRNA of TNF-␣ was found in patients with NASH in hepatic tissue (0.65 ؎ 0.54) and in peripheral fat (0.43 ؎ 0.45); in the control samples, the mRNA expression was 0.28 ؎ 0.32, P < .007, and 0.26 ؎ 0.22, P < .018, respectively. Furthermore, we found a significant increase in the mRNA levels of p55 receptor (2.42 ؎ 1.81 vs. 1.56 ؎ 1.17; P < .05); however, the mRNA expression of the p75 receptor was similar in both patients. Those patients with NASH with significant fibrosis presented an increase in the expression of mRNA TNF-␣ in comparison with those with a slight or nonexistent fibrosis. An overexpression of TNF-␣ mRNA is found in the liver and in the adipose tissue of NASH patients. The levels of mRNA-p55 are increased in the liver tissue of NASH patients. This overexpression is more elevated in patients with more advanced NASH. These findings suggest that the TNF-␣ system may be involved in the pathogenesis of NASH.

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“…In clinical studies, plasma endotoxin levels in alcoholic patients with cirrhosis often do not correlate with circulating levels of proinflammatory cytokines. 44,45 Moreover, 30% to 50% of cases of ALD demonstrate undetectable levels of endotoxin in the plasma. 18,29 The present study presents a clear and important message that the alcoholic liver injury that is associated with LPS exposure may occur in an episodic mode, but in the absence of high, sustained plasma levels of endotoxin.…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Alcoholic Liver Injury by Enteral Endotoxin in Rats

et al. 2000

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Increased gut permeability (leaky gut) and endotoxin-mediated Kupffer cell activation are proposed as the mechanisms of alcoholic liver injury. Although ethanol feeding is shown to sensitize the liver for injury induced by parental administration of lipopolysaccharide (LPS), how enteral LPS loading affects alcoholic liver injury is yet to be tested. The present study provides direct evidence for enhanced entrance to portal circulation of LPS enterally administered to the intragastric ethanol infusion model. Portal and systemic blood endotoxin levels increased to 43.0 ؎ 4.1 and 6.2 ؎ 4.3 pg/mL at 2 hours following enteral LPS administration (5 mg/kg) in alcohol-fed animals, while no such increases were observed in pair-fed controls. However, endotoxin levels in systemic blood of alcohol-fed rats were reduced to 0 to 1.5 pg/mL 16 hours after LPS administration. Development of effective therapies for alcoholic liver disease (ALD) depends on the understanding of the mechanisms that contribute to the disease process. Experimental and clinical findings to date suggest that endotoxin and proinflammatory cytokines constitute the main effector molecules in alcohol-induced liver injury. 1-5 Endotoxin (lipopolysaccharide [LPS]), a prominent agonist of Kupffer cells, interacts with its specific carrier, LPS-binding protein (LBP) to stimulate hepatic macrophages via binding of the LPS-LBP complex to the CD14 receptor. [6][7][8] This stimulation results in the release of proinflammatory mediators by the macrophages and consequent immunological and cytotoxic events leading to development of liver injury.In rats given continuous infusion of ethanol and a high-fat diet, focal hepatic inflammation and necrosis may be evident after 4 weeks 9 and are accompanied by the pretranslational induction of proinflammatory cytokine expression in Kupffer cells. 10 Hepatic expression of tumor necrosis factor ␣ (TNF-␣) mRNA is induced when pathological changes in the liver become evident. 11 Simultaneous increases in the plasma endotoxin level and mRNA expression of proinflammatory cytokines are noted in ethanol-fed rats. 12,13 Taken together, these results suggest that induction of progressive alcoholic liver injury may require increased plasma endotoxin levels as a mechanism of proinflammatory cytokine induction. In support of this notion, alcoholic patients with chronic liver disease exhibit increased intestinal permeability. 14,15 Patients with alcoholic cirrhosis have higher endotoxin levels than heavy drinkers without cirrhosis and healthy controls. 16 Peripheral blood mononuclear cells isolated from patients with alcoholic cirrhosis secrete more interleukin-6, interleukin-8, and TNF-␣ than those from healthy controls. 17,18 In the intragastric infusion model, plasma endotoxin levels and enhanced LBP and CD14 expression are correlated with the presence of liver necrosis, [19][20][21][22] and the treatment of the animals with lactobacillus 23 or antibiotics 24 ameliorates alcoholic liver injury. Furthermore, intestinal permeability is als...

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Increased Plasma Tumor Necrosis Factor in Severe Alcoholic Hepatitis

Abstract: Elevations in tumor necrosis factor in alcoholic hepatitis are most marked in severe cases, suggesting that tumor necrosis factor plays a role in the pathogenesis.

Cited by 433 publications

References 15 publications

Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis

Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis

Gene expression of tumor necrosis factor α and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients

Exacerbation of Alcoholic Liver Injury by Enteral Endotoxin in Rats

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