Pablo Bellot

Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study.

An 80% dysfunction rate at 2 years limits the use of transjugular intrahepatic portosystemic shunts (TIPS) in the treatment of complications of portal hypertension. The use of covered stents could improve shunt patency; however, long‐term effect and safety remain unknown. Eighty patients randomized to be treated by TIPS either with a covered stent (Group 1) or an uncovered prosthesis (Group 2) were followed‐up for 2 years. Doppler US was performed every 3 months. Angiography and portosystemic pressure gradient measurement were performed every 6 months or whenever dysfunction was suspected. Actuarial rates of primary patency in Groups 1 and 2 were 76% and 36% respectively (P=0.001). Clinical relapse occurred in four patients (10%) in Group 1 and 12 (29%) in Group 2 (P<0.05). Actuarial rates of being free of encephalopathy were 67% in Group 1 and 51% in Group 2 (P<0.05). Probability of survival was 58% and 45% at 2 years, respectively, in Groups 1 and 2 (NS). The mean Child–Pugh score improved only in Group 1 (from 8.1±1.6 to 7±2.2 at 2 years –P<0.05). We also compared the Doppler‐US parameters between patent and dysfunctioning shunts. In patent shunts, the mean velocity within the portal vein was significantly higher but the performance of Doppler‐US was not accurate enough to predict shunt dysfunction. In conclusion, the improvement in TIPS patency by using covered prostheses is maintained over time with a decreased risk of encephalopathy, while the risk of death was not increased.

A New Scoring System for Prognostic Stratification of Patients With Alcoholic Hepatitis

OBJECTIVES:u2003Prognostic stratification of patients with alcoholic hepatitis (AH) may improve the clinical management and facilitate clinical trials. We aimed at developing a scoring system capable of providing prognostic stratification of patients with AH.METHODS:u2003Patients with biopsy-proven AH were prospectively included between 2000 and 2006. The biochemical, clinical, portal hemodynamic and histological parameters were evaluated. A Cox regression model was used for univariate and multivariate analyses. A predictive score was built using variables obtained at admission identified in the multivariate analysis. The resulting score was validated in an independent prospective cohort.RESULTS:u2003In total, 103 patients with biopsy-proven AH were included in the study cohort. Age, serum bilirubin, serum creatinine, and international normalized ratio (INR) independently predicted 90-day mortality. We generated the Age, serum Bilirubin, INR, and serum Creatinine (ABIC) score: (age × 0.1) + (serum bilirubin × 0.08) + (serum creatinine × 0.3) + (INR × 0.8). The area under the curve (AUC) was 0.82. Using the Kaplan-Meier analysis with the cutoff values of 6.71 and 9.0, we identified patients with low, intermediate, and high risk of death at 90 days (100%, 70%, and 25% of survival rate, respectively). Using the same cutoff values, the ABIC score also stratified patients according to their risk of death at 1 yr. These results were validated by a confirmatory cohort (N = 80).CONCLUSIONS:u2003The ABIC score is a new tool that allows the stratification of risk of death in patients with AH at 90 days and 1 yr. This score can help improve the management of these patients and also help to perform clinical trials.

Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis

Bacterial infections and severity of associated inflammatory reaction influence prognosis in patients with advanced cirrhosis. We compared the innate immune response to bacterial DNA (bactDNA) translocation with that caused by viable bacteria translocation in patients with spontaneous bacterial peritonitis and the relationship between the cytokine response and serum levels of bactDNA. The bactDNA translocation was investigated in 226 patients with cirrhosis and noninfected ascites, 22 patients with spontaneous bacterial peritonitis, and 10 patients with ascites receiving continuous norfloxacin. Serum and ascitic fluid tumor necrosis factor α, interferon‐γ, interleukin‐12, and nitric oxide metabolites were measured via enzyme‐linked immunosorbent assay. Bacterial genomic identifications were made via amplification and sequencing of the 16S ribosomal RNA gene and digital quantization with DNA Lab‐on‐chips. The bactDNA was present in 77 noninfected patients (34%) and in all cases of spontaneous bacterial peritonitis, even in those with culture‐negative ascitic fluid. No patient receiving norfloxacin showed bactDNA translocation. Levels of all cytokines were similar in patients with bactDNA translocation or spontaneous bacterial peritonitis and significantly higher than in patients without bactDNA or in those receiving norfloxacin. Serum bactDNA concentration paralleled levels of all cytokines and nitric oxide in a series of patients with bactDNA translocation or spontaneous bacterial peritonitis followed during 72 hours. Antibiotic treatment in the series of patients with spontaneous bacterial peritonitis did not abrogate bactDNA translocation in the short term. Conclusion: bactDNA translocation‐associated cytokine response is indistinguishable from that in patients with spontaneous bacterial peritonitis and is dependent on bactDNA concentration. Norfloxacin abrogates bactDNA translocation and cytokine response. (HEPATOLOGY 2008;47:978–985.)

Serum and ascitic fluid bacterial DNA: A new independent prognostic factor in noninfected patients with cirrhosis

We tested the hypothesis that the presence of bacterial DNA (bactDNA) in ascitic fluid and serum is associated with decreased survival in patients with cirrhosis. In a prospective, multicenter study, we analyzed the clinical evolution of 156 patients with cirrhosis and ascites (first or recurrence) with lower than 250 polymorphonuclear cells (PMN)/μL, negative ascites bacteriological culture, and absence of other bacterial infections being admitted for evaluation of large‐volume paracentesis, according to the presence of bactDNA at admission. Survival, causes of death, and successive hospital admissions were determined during a 12‐month follow‐up period. BactDNA was detected in 48 patients. The most prevalent identified bactDNA corresponded to Escherichia coli (n = 32/48 patients, 66.6%). Patients were followed for 12 months after inclusion and in this period 34 patients died: 16 of 108 (15%) bactDNA negative versus 18 of 48 (38%) bactDNA positive (P = 0.003). The most frequent cause of death was acute‐on‐chronic liver failure in both groups (7/16 and 9/18 in patients without or with bactDNA, respectively), although more prevalent in the first month of follow‐up in patients with presence of bactDNA (0 versus 4/7). When considering patients with model for end‐stage liver disease (MELD) score less than 15, mortality was significantly higher in those with presence of bactDNA. Spontaneous bacterial peritonitis developed similarly in patients with or without bactDNA at admission. Conclusion: The presence of bactDNA in a patient with cirrhosis during an ascitic episode is an indicator of poor prognosis. This fact may be related to the development of acute‐on‐chronic liver failure at short term and does not predict the development of spontaneous bacterial peritonitis. (HEPATOLOGY 2008;48:1924‐1931.)

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial‐DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial‐DNA(−) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial‐DNA(+) as compared with bacterial‐DNA(−) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. Conclusion: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction. (HEPATOLOGY 2010;.)

Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension

Patients with cirrhosis show intrahepatic endothelial dysfunction, characterized by an impaired flow‐dependent vasorelaxation. This alteration is responsible for the marked postprandial increase in portal pressure and is attributed to an insufficient release of nitric oxide (NO). Ascorbic acid reverts endothelial dysfunction in other vascular disorders, via the increase of NO bioavailability through the neutralization of superoxide anions, thus preventing the scavenging of NO by superoxide. This study examined whether acute ascorbic acid administration might improve endothelial dysfunction in cirrhosis. Thirty‐seven portal hypertensive patients with cirrhosis had measurements of hepatic and systemic hemodynamics, ascorbic acid, and malondialdehyde (MDA). Patients were randomly allocated to receive ascorbic acid (3 g, intravenously, n = 15) or placebo (n = 12) followed by a liquid meal. A third group received ascorbic acid followed by a sham meal (n = 10). Measurements were repeated after 30 minutes (hepatic venous pressure gradient at 15 and 30 minutes). Patients with cirrhosis had significantly lower ascorbic acid levels and higher MDA than healthy controls. Ascorbic acid significantly reduced MDA levels and markedly attenuated the postprandial increase in the hepatic venous pressure gradient (4% ± 7% vs. 18% ± 10% in placebo at 30 minutes, P < .001). Ascorbic acid followed by sham meal did not modify hepatic or systemic hemodynamics. In conclusion, patients with cirrhosis exhibited intrahepatic endothelial dysfunction, associated with decreased levels of ascorbic acid and increased levels of MDA. Ascorbic acid improved intrahepatic endothelial dysfunction, blunting the postprandial increase in portal pressure. These results encourage the performance of further studies testing antioxidants as adjunctive therapy in the treatment of portal hypertension. (HEPATOLOGY 2006;43:485–491.)

Translocación de productos de origen bacteriano en la cirrosis

Bacterial translocation (BT) is defined as the passage of viable bacteria through the intestinal barrier toward the mesenteric lymph nodes, where they may disseminate toward other systems. The pathogenesis of BT in cirrhosis involves three main factors: bacterial overgrowth, increased intestinal permeability, and immune system alterations. Recent findings indicate that the concept of BT could be broadened to include the presence of bacterial products (bacterial DNA and endotoxin) in mesenteric lymph nodes and other territories. Both bacterial DNA and endotoxin provoke sustained activation of the immune system with release of proinflammatory cytokines and effectors such as nitric oxide, which aggravate the hemodynamic alterations present in patients with cirrhosis. This article provides a detailed description of the abnormalities present in patients with cirrhosis that allow the existence of TB and the immune and clinical repercussions of this phenomenon.

Evaluation of regional hepatic perfusion (RHP) by contrast-enhanced ultrasound in patients with cirrhosis

BACKGROUND & AIMSnUltrasonographic contrast agents allow the assessment of myocardial and renal perfusion through the analysis of refill kinetics after microbubbles rupture. This study evaluated the feasibility of contrast-enhanced ultrasonographic (CEUS) estimations of regional hepatic perfusion in patients with cirrhosis, and its correlation with clinical and hemodynamic parameters.nnnMETHODSnFifty-five patients with cirrhosis undergoing hepatic vein catheterization were included. Hepatic perfusion was studied by CEUS (using Contrast Coherent Imaging) during a continuous i.v. infusion of microbubbles (SonoVue®); after their rupture (high insonation power), tissue refill was digitally recorded and time-intensity curves were electronically calculated on a region of interest of the right hepatic lobe. Regional hepatic perfusion (RHP) was calculated as microbubbles velocity×microbubble concentration. During hepatic vein catheterization, we measured hepatic blood flow by indocyanine green (ICG) infusion, hepatic venous pressure gradient (HVPG), and cardiac output (Swan-Ganz catheter).nnnRESULTSnRHP was higher in patients than in healthy controls (5.1±3.7 vs. 3.4±0.7, p=0.003), and correlated with MELD (R=0.403, p=0.002), Child-Pugh score (R=0.348, p=0.009), and HVPG (R=0.279, p=0.041). RHP inversely correlated with ICG extraction (R=-0.346, p=0.039), ICG intrinsic clearance (R=-0.327, p=0.050), and ICG clearance (R=0.517, p=0.001), and directly correlated with hyperdynamic syndrome markers (cardiac index R=0.422, p=0.003; mean arterial pressure R=-0.405, p=0.004; systemic vascular resistance R=-0.496, p=0.001).nnnCONCLUSIONSnRHP increases in patients with cirrhosis and correlates with the degree of liver failure and hyperdynamic syndrome. RHP increases along with liver functional reserve decrease, suggesting that RHP increase occurs mainly through anatomical/functional shunts. RHP by CEUS is a feasible novel, objective, quantitative, non-invasive tool, potentially useful for the estimation of hepatic perfusion in patients with cirrhosis.

Norfloxacin Modulates the Inflammatory Response and Directly Affects Neutrophils in Patients With Decompensated Cirrhosis

BACKGROUND & AIMSnPatients with cirrhosis undergoing selective intestinal decontamination with norfloxacin show a reduction in serum cytokine levels, probably because of a combined effect of norfloxacin on bowel flora and neutrophils.nnnMETHODSnThirty-one patients with cirrhosis receiving norfloxacin (400 mg/day) were included. Blood samples were collected at 0.5-4 hours (peak samples group, n = 47) and at 22-24 hours (trough samples group, n = 84) after dose. Fifty-nine ascitic fluid samples were obtained. Single doses of norfloxacin and trimethoprim/sulfamethoxazole were administered to 13 and 5 patients, respectively, (temporal profile group) and samples were collected at 0, 0.5, 1, 1.5, 2, 4, and 24 hours. Norfloxacin, trimethoprim/sulfamethoxazole, cytokines, nitric oxide, expression levels of nuclear factor (NF)-kappaB and inhibitor of NF-kappaB (IkB-alpha), neutrophil oxidative burst, and rate of apoptotic events were determined.nnnRESULTSnAll samples were bacterial DNA negative and had no significant levels of lipopolysaccharide. Serum and ascitic levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-12, and nitric oxide were significantly lower in peak than in trough samples. A correlation was present between serum norfloxacins concentrations and tumor necrosis factor-alpha (r = -0.68; P < .001), interferon-gamma (r = -0.66; P < .001), interleukin-12 (r = -0.66; P < .001), and nitric oxide (r = -0.68; P < .001). Serum norfloxacins highest concentrations (1 +/- 0.5 microg/mL) were achieved at 1-2 hours and concurred in time with the lower levels of cytokines and nitric oxide. Intracellular norfloxacins highest levels (2 +/- 1 microg/mL/10(7) cells) were observed at 2 hours and concurred with a lower NF-kappaB expression, a reduced anion superoxide generation, and apoptotic rate in response to phorbol myristate acetate. Trimethoprim/sulfamethoxazole did not significantly modulate cytokine expression.nnnCONCLUSIONSnNorfloxacin but not trimethoprim/sulfamethoxazole modulates inflammatory response and directly affects neutrophils in patients with cirrhosis.

Systemic hemodynamics, vasoactive systems, and plasma volume in patients with severe Budd‐Chiari syndrome

Budd‐Chiari syndrome (BCS) causes postsinusoidal portal hypertension, which leads to complications similar to those observed in cirrhosis. However, no studies have investigated whether patients with BCS develop the hyperdynamic circulatory syndrome present in patients with cirrhosis who have portal hypertension. We evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with BCS admitted for complications of portal hypertension. BCS patients had mean systemic and cardiopulmonary pressures and cardiac indices that were within the normal range but were significantly different from those of a group of patients with cirrhosis matched by sex, body surface, and liver function (cardiac index 3.1 ± 0.7 vs. 4.9 ± 1.2 L · min−1 · m−2; P < .001; systemic vascular resistance [SVR] index, 2,189 ± 736 vs. 1,377 ± 422 dyne · s · cm−5 · m−2, P < .001). Despite normal systemic vascular resistance, BCS patients had activation of the neurohumoral vasoactive systems, as evidenced by increased plasma renin activity, aldosterone and norepinephrine levels (15.0 ± 21.5 ng/mL · h, 76.7 ± 106.8 ng/dL, 586 ± 868 pg/mL; respectively) and plasma volume expansion. The analysis of individual BCS patients identified that 7 of the 21 patients actually had reduced SVR index. These patients had the greatest plasma volume expansion. A significant inverse correlation between plasma volume and SVR index was observed. In conclusion, patients with BCS had activation of vasoactive neurohumoral systems and expanded plasma volume. This outcome was observed even though most of these patients did not exhibit systemic vasodilation and cardiac output was not increased, in marked contrast with what is observed in patients with cirrhosis. (HEPATOLOGY 2006;43:27–33.)