Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure

Bernal, William; Donaldson, Peter; Underhill, James A.; Wendon, Julia; Williams, Roger

doi:10.1016/s0168-8278(98)80178-5

Cited by 59 publications

(34 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ALF 6,45 and polymorphisms of the TNFa gene are known to influence the clinical outcome in ALF. 46 The etiology of liver disease and, in the case of toxic liver injury, the nature of the hepatotoxin appear to determine the systemic cytokine profile of the pro-inflammatory response in ALF. 47 However, whether or not the systemic inflammatory response in ALF is transmitted to the brain and, if so, by what mechanism remains, to be established.…”

Section: Microglia/neuroinflammationmentioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

114

View full text Add to dashboard Cite

Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepatoprotective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. ( J CLIN EXP HEPATOL 2015;5:S96-S103) A cute liver failure (ALF), also referred to as fulminant hepatic failure, invariably leads to central nervous system dysfunction that may include encephalopathy, seizures and brain edema, a major cause of intracranial hypertension and brain herniation, a leading cause of mortality in ALF. An increase in cerebral blood flow frequently accompanies the onset of brain edema. 1Neuropathological assessments of the brain in both human and experimental ALF reveals significant changes to neuroglia in general and to astrocytes and microglia, in particular. Astrocytes in brain sections from patients who died in ALF are swollen 2 as are their mitochondria (Figure 1). Based upon these observations, it is generally assumed that the brain edema that accompanies ALF is primarily, if not exclusively, cytotoxic in nature. Studies in experimental animals with ALF due to toxic liver injury show a similar pattern of changes as well as alterations in expression of genes coding for key astrocytic proteins. 3Although gross alterations of the blood-brain barrier (BBB) are not generally a feature of ALF, alterations of cerebrovascular endothelial cell function have occasionally been described. 2,4 On the other hand, material from ALF animals in which edema and encephalopathy were precipitated by infection manifest clear alterations of both BBB function and of expression of BBB tight junction proteins.5 These latter findings suggest that, in ALF accompanied by significant infection/inflammation, brain edema may comprise both cytotoxic and vasogenic components. BRAIN METABOLISM IN ACUTE LIVER FAILUREALF leads to severe compromise of cerebral metabolism and includes increases of cerebral blood flow, decrea...

show abstract

Section: Microglia/neuroinflammationmentioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

114

View full text Add to dashboard Cite

show abstract

“…[13][14][15] The presence of TNF-␣ polymorphisms appears to influence the prognosis of hepatic diseases with various causes (autoimmune and alcoholic). 14,[16][17][18][19][20][21][22] Macrophages from patients with HHC have repeatedly been reported to have a defect in iron metabolism, since a low iron content is usually found in circulating monocytes, their precursors, and Kupffer cells. In addition, monocytes from patients with HHC release an increased amount of ferritin after erythrophagocytosis because they are unable to store iron.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor α promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis

Fargion

Valenti

Dongiovanni

et al. 2001

Blood

View full text Add to dashboard Cite

Severe iron overload usually develops in patients with hereditary hemochromatosis (HHC), but variability in the phenotypic expression of the disease has been reported. This study assessed whether tumor necrosis factor ␣ (TNF-␣) plays a role in phenotypic expression of HHC. Sixty-four patients with HHC and 172 healthy volunteers (controls) were studied. Release of TNF-␣ from stimulated peripheral blood monocytes was measured by enzyme-linked immunosorbent assay, and 308 and 238 TNF-␣ polymorphisms were detected with polymerase chain reaction and restriction fragmentlength polymorphism analysis. The relation between TNF-␣ polymorphisms and clinical expression of HHC was evaluated. Patients with HHC released less TNF-␣ than controls, but the difference was significant only in homozygotes for the C282Y mutation. The prevalence of the 308 TNF-␣ polymorphism was similar in patients and controls, whereas the prevalence of the 238 polymorphic allele was significantly lower in patients (3% versus 16%; P ‫؍‬ .002). A lower prevalence of cirrhosis was observed in patients with TNF-␣ polymorphism than in those without it (4 of 15 [27%] versus 28 of 49 [57%]), but the difference was not significant (P ‫؍‬ .07). In nonhomozygotes for the C282Y mutation, severe liver siderosis was less prevalent in patients with the 308 polymorphism than in those without it (P ‫؍‬ .05). Alanine aminotransferase (ALT) values were significantly lower in patients with TNF-␣ polymorphism (P ‫؍‬ .006), even when patients with other hepatotoxic factors were excluded. Multivariate analysis showed that TNF-␣ polymorphism was independently associated with ALT values (P ‫؍‬ .0008 and P ‫؍‬ .045, respectively, in homozygotes and nonhomozygotes for the C282Y mutation) and siderosis in nonhomozygotes (P ‫؍‬ .047). Thus, TNF-␣ appears to play a role in HHC by modulating the severity of liver damage. (Blood. 2001;97:3707-3712)

show abstract

“…This may have an as yet unexplained effect on individual patient survival. 132 It is clear that precise end-points are required for such a trial. Design of a multicentre controlled trial will be a dif®cult task, the results will take time to accrue and must in the ®rst instance be carefully interpreted.…”

Section: Resultsmentioning

confidence: 99%

Review article: liver support systems in acute hepatic failure

Rahman¹,

Hodgson²

1999

Aliment Pharmacol Ther

View full text Add to dashboard Cite

The treatment of acute hepatic failure has developed rapidly over the last 40 years, reducing morbidity and mortality from this syndrome. Whilst this has been partly attributed to significant improvements in the specialist medical management of these patients, advances in surgical techniques and pharmaceutical developments have led to the establishment of successful liver transplantation programmes, which have improved mortality significantly.This review will examine the clinical impact of alternative methods that have been used to provide extra‐corporeal hepatic support. Non‐biological, bio‐ logical and hybrid hepatic extra‐corporeal support will be explored, offering a comprehensive historical overview and an appraisal of present and future advances.

show abstract

Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure

Cited by 59 publications

References 30 publications

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Tumor necrosis factor α promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis

Review article: liver support systems in acute hepatic failure

Contact Info

Product

Resources

About