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Background: Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect, defined by an increased alveolar-arterial oxygen gradient, induced by pulmonary vascular dilatations in the context of liver disease. The pathogenesis of HPS is poorly understood. Morphologic changes associated with HPS are unknown. This study aimed at describing imaging and pathology changes associated with HPS.Methods: We performed a case-control study in candidates for transplant with suspicion of cirrhosis. Each patient with HPS (Pao2 ≤ 70 mm Hg) was matched to three control subjects for age, cause, and liver disease severity. Pretransplant thoracic and abdominal imaging and explanted livers were reviewed.Results: CT scans and Doppler ultrasounds from 21 patients with HPS were compared with those from 63 control subjects. HPS was associated with a two- to threefold higher prevalence of obstructed intrahepatic portal branches, of slowed or hepatofugal portal blood flow, and of large abdominal portosystemic shunts. Hepatic artery diameter was also larger in patients with HPS. Explanted livers from 19 patients with HPS were compared with those from 57 control subjects. HPS was associated with a fourfold higher prevalence of portal venule thrombosis and a ninefold higher prevalence of extensive vascular proliferation within fibrous septa. Obstruction of centrilobular venules, sinusoidal dilatation, and liver parenchymal extinction were also more common in patients with HPS.Conclusions: HPS is associated with intrahepatic vascular changes and with features suggesting severe portal hypertension. These results raise the hypothesis that intrahepatic vascular changes precipitate the development of HPS, opening new therapeutic perspectives for HPS. [ABSTRACT FROM AUTHOR]

Bacterial DNA (bactDNA) has been found in serum and ascitic fluid (AF) of 30-40% of hospitalized patients with cirrhosis and non-neutrocytic ascites, but its prevalence in outpatients is unknown. The aim of this prospective study was to investigate the presence of bactDNA in AF and serum among cirrhotic outpatients with non-neutrocytic ascites. Thirty-one consecutive patients with cirrhosis and non-neutrocytic ascites, who underwent therapeutic paracentesis in our outpatient clinic, were enrolled over a 13-week period. Of these patients, 13 had a single paracentesis and 18 patients had several consecutive paracenteses (2-10) over the study period. Overall, 98 serum and non-neutrocytic AF specimens were obtained and tested for the presence of bactDNA by polymerase chain reaction amplification of the 16S ribosomal RNA gene. The main causes of cirrhosis were alcohol (53.5%) and hepatitis C (30%). The median MELD score was 16 and there were 54.8% Child-Pugh C patients. BactDNA was negative in all samples from 28 of the 31 patients, including 15 patients with several paracentesis. One patient had a single AF sample culture positive and bactDNA positive for Streptococcus mitis, whereas the simultaneous blood sample was negative. For each of the last two patients, DNA from Lactococcus lactis was detected in a single blood sample but not in the simultaneous AF sample. In contrast to that reported previously in hospitalized patients, bactDNA is rarely detected in serum and AF of outpatients with cirrhosis and non-neutrocytic ascites. [ABSTRACT FROM AUTHOR]

Background/Aim: In cirrhosis, systemic nitric oxide (NO) overproduction and hepatic NO hypoproduction lead to arterial vasodilatation and portal hypertension. The mechanisms involved in these alterations in endothelial NO synthase (eNOS)-derived NO production in hepatic and systemic vasculature remain unknown. The aim of this study was to evaluate the regulation of eNOS and its major modulators in the liver and aorta during the development of cirrhosis in rats. Methods: Activated eNOS and Akt and expressions, and caveolin-1 (Cav-1) and scavenger receptor class B type I (SR-BI) expressions were measured before and 1, 2, 3 and 4 weeks after bile duct ligation. Plasma high-density lipoprotein (HDL) levels were measured. Results: Activated aortic eNOS increased at week 1, whereas it began to decrease at week 3 in the liver. Aortic expression of Cav-1 decreased at week 3 while hepatic expression increased by four-fold. Activated aortic Akt increased progressively while in the liver it gradually decreased during the development of cirrhosis. HDL levels decreased during the first week and decreased thereafter. The hepatic expression of SR-BI decreased. Conclusion: This study shows that the modulation of Akt and Cav-1 is inverted in the liver and the aorta during the development of cirrhosis. In addition, decreased HDL levels may play a role in reduced hepatic eNOS activity. [ABSTRACT FROM AUTHOR]

Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or α1-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In patients with cirrhosis, acute renal failure is due to prerenal failure (a result of decreased renal perfusion) and tubular necrosis. There are 3 main causes of prerenal failure: ‘true hypovolemia’ (which complicates hemorrhage, gastrointestinal or renal fluid losses), sepsis, and type 1 hepatorenal syndrome (HRS). Prerenal failure may also be due to the administration of non-steroidal antiinflammatory drugs, or intravascular radiocontrast agents. Prerenal failure is reversible after restoration of renal blood flow. Treatments target the cause of hypoperfusion, and fluid replacement is used to treat ‘non-HRS’ prerenal failure. In patients with type 1 HRS with very low short-term survival rate, liver transplantation is the ideal treatment. Systemic vasoconstrictor therapy with terlipressin (combined with intravenous human albumin), noradrenaline (combined with albumin and furosemide) or midodrine (combined with octreotide and albumin) may improve renal function in patients with type 1 HRS waiting for liver transplantation. MARS (for Molecular Adsorbent Recirculating System) and the transjugular intrahepatic portosystemic shunt may also improve renal function in these patients. In patients with cirrhosis, acute tubular necrosis is mainly due to an ischemic insult to the renal tubules. Studies are needed on the natural course and treatment (e.g., renal-replacement therapy) of acute tubular necrosis in patients with cirrhosis. [Copyright &y& Elsevier]

The question of which colloid (albumin or synthetic colloids) used for plasma expansion following paracentesis or other complications requiring fluid loading in patients with cirrhosis remains controversial. Aims: To compare outcome and hospital-related cost in patients with cirrhosis treated with 20% human albumin with those treated with a synthetic colloid (3.5% polygeline). Methods: The primary end point was occurrence of a first liver-related complication. Results: When the trial was prematurely discontinued because of safety concerns about bovine-derived products, 30 patients were assigned to receive albumin and 38 were assigned to receive a synthetic colloid. Sixty-three patients were included for ascites removal by paracentesis and five patients for ascites removal by paracentesis and renal impairment. The median time to first liver-related complication was not significantly longer in the albumin group (20 vs. 7 days). However, the total number of liver-related complications adjusted to a 100-day period was significantly lower in the albumin group. The median hospital cost for a 30-day period was significantly lower in the albumin group (1915 euros vs. 4612 euros). Conclusions: In patients with cirrhosis and ascites, human albumin appears to be more effective in preventing liver-related complications than synthetic colloid. This may be associated with decreased hospital costs. [ABSTRACT FROM AUTHOR]

Background: Bacterial translocation, that is, extra-intestinal dissemination of gut bacteria, occurs in approximately 50% of humans and rats with cirrhosis and plays a significant role in enhanced tumor necrosis factor-α (TNF-α) production. The authors’ previous studies have indicated that prevention of bacterial translocation with norfloxacine or inhibition of TNF-α with pentoxifylline treatment decreased both the incidence and severity of hepatopulmonary syndrome by attenuating the induction of pulmonary intravascular macrophages in cirrhotic rats. In the present study the hypothesis was tested that the cirrhotic rats with bacterial translocation had higher TNF-α production, higher level of sequestration of macrophages in pulmonary vessels, and increased incidence and severity of hepatopulmonary syndrome. Methods: Rats were studied 5 weeks after common bile duct ligation or sham operation. Bacterial translocation was defined by positive mesenteric lymph node cultures. Hepatopulmonary syndrome was assessed by measurements of alveoloarterial oxygen difference (AaPO2) and intrapulmonary shunt. The TNF-α concentration in plasma was measured by ELISA. Pulmonary intravascular macrophage sequestration was assessed by lung morphometric analysis. Results: Bacterial translocation occurred in 48% of cirrhotic rats. Plasma concentrations of TNF-α and the percentage of vessels with pulmonary intravascular macrophages were higher in the cirrhotic rats with bacterial translocation. Rats with bacterial translocation also had a higher incidence (9% vs 63%, P < 0.01) and severity of hepatopulmonary syndrome, as indicated by higher levels of both AaPO2 and intrapulmonary shunt. Conclusions: These results suggest that bacterial translocation may play a role in the pathogenesis of hepatopulmonary syndrome by inducing pulmonary intravascular macrophages through TNF-α upregulation. [ABSTRACT FROM AUTHOR]

Plessier A, Denninger M-H, Consigny Y, Pessione F, Francoz C, Durand F, Francque S, Bezeaud A, Chauvelot-Moachon L, Lebrec D, Valla D-C, Moreau R. Coagulation disorders in patients with cirrhosis and severe sepsis. Liver International 2003: 23: 440–448. © Blackwell Munksgaard, 2003 In patients with cirrhosis, severe sepsis may stimulate the extrinsic coagulation pathway resulting in thrombin generation and fibrin formation. To compare 23 patients with severe sepsis to 13 infected patients without severe sepsis and 18 patients without infection. Zymogen forms of clotting factors involved in the extrinsic pathway (i.e., factors VII+X, V, prothrombin), and the presence of soluble fibrin were assessed. Zymogen forms of clotting factors were significantly lower, while Child–Pugh score and the proportion of patients with soluble fibrin were higher in the severe-sepsis group than in the other groups. Decreased zymogen levels were independently correlated with an elevated Child–Pugh score and the presence of severe sepsis. In the severe-sepsis group, after adjustment for the severity of cirrhosis, decreased zymogen levels were associated with significant increases in the relative risk ratios of in-hospital death. Cirrhotic patients with severe sepsis have decreased blood levels of zymogen forms of factors VII+X, V, and prothrombin, which may be due not only to the severity of cirrhosis but also, at least in part, to the consumption of these zymogens by the extrinsic coagulation pathway. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim: Hypoxemia is common in patients with cirrhosis but the natural history of this syndrome is unknown. The aim of this study was to follow a series of patients with cirrhosis and to compare patients with and without hypoxemia to determine their risk of complications and survival rate. Methods: Fifty-eight consecutive Child–Pugh C patients with cirrhosis were included and followed up for 1–18 months. Blood gas measurements and plasma endothelin levels were measured in all patients. Blood gas measurements were repeated in 34 patients. Results: Hypoxemia was present in 35 patients (60%) (alveolar-arterial oxygen (AaO2 ) gradient > 20 mmHg) but none had pulmonary symptoms. There was no significant difference in liver tests and plasma endothelin levels between hypoxemic and non-hypoxemic patients. The occurrence of variceal bleeding and survival rate was not significantly different between the two groups. The AaO 2 gradient worsened in nine patients and normalized in six of the hypoxemic patients. The AaO 2 gradient increased to more than 20 mmHg in seven non-hypoxemic patients. There was no relationship between AaO 2 gradient changes and Child–Pugh score grade changes. Conclusion: Asymptomatic hypoxemia is common in patients with severe cirrhosis but it is not a predictive factor of short-term complications or mortality. These results should be considered when deciding on liver transplantation. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim: Terlipressin has been proposed to treat renal failure in patients with type 1 hepatorenal syndrome (HRS). However, the predictive factors for improved renal function and survival are unknown in patients with type 1 HRS treated with terlipressin. The aim of the present retrospective study was to investigate the predictive factors and prognosis of patients with type 1 HRS treated with terlipressin. Methods: The clinical charts of 18 consecutive patients with cirrhosis and type 1 HRS treated with terlipressin were studied. The predictive factors for improved renal function and survival were identified using univariate analyses. Results: Improved renal function, indicated by a significant decrease in serum creatinine (61 ± 4%), occurred in 11 (60%) patients. The only predictive factor for improved renal function was a Child–Pugh's score ≤13 at the time of diagnosis of HRS (P = 0.02). Fifteen patients (83%) died at 45 days and the median survival was 24 days. Of the three patients who survived, two underwent successful orthotopic liver transplantation. Three predictive factors for survival were identified: absence of a precipitating factor for HRS ( P = 0.012); improved renal function during terlipressin therapy ( P = 0.05); and a dose of terlipressin ≥3 mg/day ( P = 0.04). Conclusions: In patients with type 1 HRS treated with terlipressin, patients with improved renal function had less severe cirrhosis (Child–Pugh >10 but ≤13) than patients without. The predictive factors for survival were the absence of a precipitating factor for HRS, the terlipressin-induced improvement in renal function and a dose of terlipressin of at least 3 mg/day. These findings suggest that a randomized controlled trial investigating the effect of terlipressin on survival in patients with type 1 HRS should be performed. © 2002 Blackwell Publishing Asia Pty Ltd. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims: Cirrhosis is associated with a hyperdynamic syndrome and arterial vasodilation that is related to nitric oxide (NO) synthase 3 overactivity. Septic shock is frequently associated with cirrhosis and with a vascular induction of NO synthase 2. The aims of this study were to compare the effects of lipopolysaccharide (LPS) in normal and cirrhotic rats, and to test the effects of a-non-steroidal anti-inflammatory drug (NSAID) coupled with a (NO) donor. Methods: Cirrhotic rats received NO-flurbiprofen, flurbiprofen or vehicle followed by LPS or placebo 15 min later. The heart rate and mean arterial pressure of rats were monitered for 5 h. Thoracic aortic rings were removed and contracted with the use of norepinephrine. Nitric oxide synthase activity was measured in the aorta and stomach of cirrhotic rats. Results: Arterial pressure decreased in cirrhotic rats in the vehicle/LPS and flurbiprofen/LPS groups. After LPS administration, the heart rate of rats increased in all groups. In the aortic rings, LPS induced hyporeactivity to norepinephrine in all groups except the NO-flurbiprofen group. This hyporeactivity was abolished after preincubation with Nw-nitro-L-arginine (L-NNA). Nw-nitro-L-arginine had no effect on norepinephrine-induced vasoconstriction in the NO-flurbiprofen/LPS group. Nitric oxide synthase 2 activity in the stomach and aorta of cirrhotic rats was increased in each group except in the NO-flurbiprofen group after LPS administration. Pretreatment with NO–NSAID prevented aortic hyporeactivity to norepinephrine in cirrhotic rats treated with LPS as it probably inhibited the NO synthase 2 induction. Conclusions: These findings suggest that NO-flurbiprofen has a beneficial hemodynamic effect in cirrhotic rats and may help to prevent LPS aortic hyporeactivity. [ABSTRACT FROM AUTHOR]

ABSTRACT- Aims/Backgrounds: The aim of this prospective study was to evaluate the influence of transjugular portosystemic intrahepatic shunts (TIPS) on tissue oxygenation in patients with cirrhosis and refractory ascites. Methods: Five shunted patients were included in the study. The blood and tissue oxygenation values were analyzed 12 days and 4 months after TIPS procedure. The results were compared with those observed in patients treated by paracentesis. Results: Unlike patients treated by paracentesis, PaO2 values remained unchanged throughout follow-up in shunted patients. After the TIPS procedure, there was a transient increase in systemic O2 transport and O2 uptake and a transient decrease in O2 saturation of hepatic oxyhemoglobin. After 4 months, TIPS resulted in an increase in PCO2 values and bicarbonate concentrations. Conclusions: The TIPS procedure seems to prevent the decrease in PaO2 observed in patients treated by paracentesis and may improve the respiratory alkalosis of cirrhosis. [ABSTRACT FROM AUTHOR]

Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg · kg-1 · min-1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356±50 vs 166±30 pg/ml, p=0.04) than in normal rats (186±23 vs 86±31 pg/ml, p=0.06) and rats with portal vein stenosis (103±37 vs 93±5 pg/ml, p=0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg · kg-1 · min-1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (-25±2%) than in normal rats (-11±1%) and in rats with portal vein stenosis (-13±2%) ( p=0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis. [ABSTRACT FROM AUTHOR]

Among diVerent substances which decrease the degree of portal hypertension, only β-adrenoceptor antagonists are used to prevent recurrent hemorrhage in patients with cirrhosis [1]. Controlled trials comparing endoscopic sclerotherapy with or without β-adrenoceptor antagonists have also been performed. [ABSTRACT FROM AUTHOR]

Background & Aims: The MELDNa score was developed to improve the prognostic value of the MELD score in cirrhosis and was built for serum sodium concentrations numerically capped between 125 and 140mmol/L. This model is not validated in a well-defined population of patients with cirrhosis and refractory ascites in whom severe hyponatremia (⩽125mmol/L) is frequent. This study assessed the prognostic value of severe hyponatremia and the MELDNa score in these patients. Methods: A consecutive, single-centre, observational, prospective study was performed in patients with cirrhosis and refractory ascites defined according to the International Ascites Club criteria. The prevalence of low serum sodium was assessed in this population. Predictive factors of mortality were analyzed and compared. Results: One hundred seventy-four patients were included. Sixty-six (37.9%) had low serum sodium (<130mmol/L). Sixty-one (35.1%) had diuretic-intractable ascites due to severe hyponatremia (⩽125mmol/L). The median MELDNa score was 23 (10–33). The 1-year cumulative incidence of death was 55% (95% CI: 55–56%). The best predictive factors of mortality were the following: severe hyponatremia (⩽125mmol/L) as an underlying cause of refractory ascites, a higher Child–Pugh score, beta-blocker therapy, and a high frequency of large-volume paracentesis. The Child–Pugh score had a higher area under receiver operating curve to predict mortality than MELDNa. Conclusions: In patients with cirrhosis and refractory ascites, severe hyponatremia and Child–Pugh score are better predictors of mortality than MELDNa. [Copyright &y& Elsevier]

Background & Aims: In decompensated cirrhosis, the early innate immune response to the Toll-like receptor 4 (TLR4) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine IL-10. In LPS-stimulated non-cirrhotic immune cells, the constitutively active glycogen synthase kinase (GSK) 3 favors pro- vs. anti-inflammatory cytokines, by acting on gene induction. However, in these cells, TLR4 dampens its own pro-inflammatory response by inducing early (within minutes) AKT-mediated phosphorylation of GSK3β (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3β (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases IL-10. Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from patients with advanced cirrhosis and normal subjects. Methods: Cells were pre-incubated with or without GSK3 inhibitor (SB216763 or lithium chloride) for 1h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1h and ELISA at 20h, respectively. GSK3β phosphorylation was assessed using Western blotting. Results: In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-α and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3β on Ser9 found in normal monocytes, was abolished in cirrhotic cells. Conclusions: GSK3 is involved in the early TLR4-mediated pro-inflammatory response in patients with decompensated cirrhosis. This was associated with a defect in AKT-mediated GSK3β phosphorylation resulting in unrestricted ‘pro-inflammatory’ activity of the enzyme. [Copyright &y& Elsevier]

Background & Aims: In patients with cirrhosis and refractory ascites the role of beta-blockers in the development of paracentesis-induced circulatory dysfunction (PICD) is unknown. The aim of this study was to investigate the incidence of PICD before and after discontinuation of beta-blockers in patients with cirrhosis and refractory ascites. A self control cross-over study was performed. Methods: Patients with cirrhosis and refractory ascites treated with beta-blockers were selected. Heart rate, arterial pressure, and plasma renin concentrations (PRC) were collected before, immediately after and 1week after large-volume paracentesis associated with intravenous albumin administration. Beta-blocker therapy was progressively discontinued after complete endoscopic eradication of varices. The clinical and biological evaluation was then repeated. The presence of PICD was defined as an increase in PRC of at least 50% above baseline 1week after paracentesis. Results: Ten patients were included (nine men, mean age 59.1±10.7years old). The MELD score was 17.7±4.4 and eight patients were Child–Pugh C. When patients were given beta-blockers, the heart rate did not change immediately after paracentesis while mean arterial pressure significantly decreased; PICD developed in eight patients. After beta-blockers were discontinued, the heart rate significantly increased immediately after paracentesis and mean arterial pressure significantly decreased; PICD only developed in one patient; the difference in the incidence of PICD was significant when these same patients were treated with beta-blockers. Conclusions: The use of beta-blockers may be associated with a high risk of PICD in patients with cirrhosis and refractory ascites. [Copyright &y& Elsevier]

Background/Aims: Endoplasmic reticulum (ER)-related unfolded protein response (UPR) is mediated by PKR-like ER kinase (PERK), ATF6 and IRE1. PERK phosphorylates eukaryotic translation initiation factor-2α (eIF2α) to attenuate protein synthesis, including in NF-κB-dependent antiapoptotic proteins. We hypothesized that an altered UPR in the liver may sensitize cirrhotic livers to LPS-induced, TNFα-mediated apoptosis. Thus, we examined in vivo UPR and NF-κB activity in livers from cirrhotic and normal LPS-challenged rats. Methods: Livers were harvested in rats that did or did not receive LPS. Results: Under baseline conditions, no UPR was found in normal livers while PERK/eIF2α and ATF6 pathways were activated in cirrhotic livers. After LPS, in normal livers, the PERK/eIF2α pathway was transiently activated. ATF6 and IRE1 were activated. In cirrhotic livers, the PERK/eIF2α pathway remained elevated. ATF6 and IRE1 pathways were altered. LPS-induced, NF-κB-dependent antiapoptotic proteins increased in normal livers whereas their expression was blunted at the posttranscriptional level in cirrhotic livers. Conclusions: Cirrhotic livers exhibit partial UPR activation in the basal state and full UPR, although altered, after LPS challenge. Sustained eIF2α phosphorylation, a hallmark of cirrhotic liver UPR, is associated with a lack of LPS-induced accumulation of NF-κB-dependent antiapoptotic proteins which may sensitize cirrhotic livers to LPS/TNFα-mediated apoptosis. [Copyright &y& Elsevier]

Background/Aims: In cirrhosis, tumor necrosis factor (TNF)-alpha overproduction is involved in both the systemic complications and progression of liver injury. Since monocytes from patients with advanced cirrhosis have an increase in lipopolysaccharide (LPS)-induced TNF-alpha production, we hypothesized that an upregulation of TNF-alpha production pathways and/or alteration of constitutive and inducible suppressor of TNF-alpha hyperproduction (protein kinase B (Akt) and interleukin-1 receptor-associated kinase (IRAK)-M, respectively) should be found in monocytes of these patients. Thus, we investigated ex vivo the signaling pathways of TNF-alpha production before and after LPS incubation in monocytes from noninfected Child-Pugh C patients with advanced cirrhosis and healthy subjects. Methods: TNF-alpha production, expressions of intracellular TNF-alpha, toll-like receptor-4 (TLR4), IkappaB-alpha, IRAK-1, IRAK-M, mitogen-activated protein (MAP) kinases and Akt activity were measured in monocytes. Results: Cirrhotic monocytes without LPS have less TLR4 expression, less IkappaB-alpha protein levels, more TNF-alpha expression, higher MAP kinase activities and decreased Akt activity than control monocytes. In cirrhotic monocytes, LPS-induced TNF-alpha hyperproduction and signaling upregulation were associated with a lack of IRAK-M induction. Conclusions: Upregulated signaling pathways of the TNF-alpha production, decreased Akt activity and a lack of IRAK-M induction may be involved in the process of cirrhotic monocyte sensitization to produce TNF-alpha. [Copyright &y& Elsevier]