Gennaro D'Amico

Infections in Patients With Cirrhosis Increase Mortality Four-Fold and Should Be Used in Determining Prognosis

BACKGROUND & AIMS A staged prognostic model of cirrhosis based on varices, ascites, and bleeding has been proposed. We analyzed data on infections in patients with cirrhosis to determine whether it is also a prognostic factor. METHODS Studies were identified by MEDLINE, EMBASE, COCHRANE, and ISI Web of Science searches (1978-2009); search terms included sepsis, infection, mortality, and cirrhosis. Studies (n = 178) reporting more than 10 patients and mortality data were evaluated (225 cohorts, 11,987 patients). Mortality after 1, 3, and 12 months was compared with severity, site, microbial cause of infection, etiology of cirrhosis, and publication year. Pooled odds ratio of death was compared for infected versus noninfected groups (18 cohorts, 2317 patients). RESULTS Overall median mortality of infected patients was 38%: 30.3% at 1 month and 63% at 12 months. Pooled odds ratio for death of infected versus noninfected patients was 3.75 (95% confidence interval, 2.12-4.23). In 101 studies that reported spontaneous bacterial peritonitis (7062 patients), the median mortality was 43.7%: 31.5% at 1 month and 66.2% at 12 months. In 30 studies that reported bacteremia (1437 patients), the median mortality rate was 42.2%. Mortality before 2000 was 47.7% and after 2000 was 32.3% (P = .023); mortality was reduced only at 30 days after spontaneous bacterial peritonitis (49% vs 31.5%; P = .005). CONCLUSIONS In patients with cirrhosis, infections increase mortality 4-fold; 30% of patients die within 1 month after infection and another 30% die by 1 year. Prospective studies with prolonged follow-up evaluation and to evaluate preventative strategies are needed.

Survival and prognostic indicators in compensated and decompensated cirrhosis

Six-year survival of cirrhosis was assessed in a series of 1155 consecutive patients (751 men, 404 women). Among the men, 33% were alcoholics and 18% were HBsAg positive; corresponding figures for the women were 15% and 6%, respectively. Features of decompensation at first presentation were observed in 63% of the patients. Six-year survival was 54% in compensated and 21% in decompensated patients. No significant differences in survival were found between alcoholics and nonalcoholics. Leading causes of death were liver failure (49%), hepatocellular carcinoma (22%), and bleeding (13%). The prognostic role of 21 variables was evaluated separately in compensated and decompensated patients by the Coxs regression model. The following variables were found to be significant predictors of death risk in compensated patients: male sex, HBsAg positivity, age, prothrombin time prolongation, and esophageal varices. In decompensated disease the significant indicators of death risk were: hepatocellular carcinoma, encephalopathy, hemorrhage, SGOT, esophageal varices, gamma globulins, prothrombin time prolongation, continued abuse of alcohol, HBsAg positivity, gamma glutamyl transpeptidase, and cholinesterase. A simple prognostic index based upon the relative risk coefficient of the significant variables is suggested.

Hepatocellular carcinoma : a worldwide problem and the major risk factors

Male sex, age, cirrhosis, and HBsAg are the major risk factors for hepatocellular carcinoma (HCC). The geographic distribution of HCC is highly uneven, such that three distinct incidence areas are recognized. To clarify the reason(s) for this geographic variability of HCC, the risk factors in earch incidence area were assessed. In parallel with the geographic distribution of HCC, HBsAg prevalence was highest in both HCC patients and in general population in Africa and Asia, where mothers of HCC patients are frequently HBsAg-positive, suggesting that hepatitis B virus hyperendemicity and perinatal infection account for the high HCC incidence in these areas. Cirrhosis, which is found on autopsy in 80% of the cases of HCC patients worldwide, is the most prevalent risk factor for HCC in areas where hepatitis B virus infection is less common. However, HBsAg carriage adds to the HCC risk carried by cirrhosis and explains the higher incidence of HCC in cirrhotics from Africa and Asia as well as elsewhere. Available data suggest that chronic HCV infection is a risk factor for cirrhosis and HCC. HBV vaccination should decrease HCC incidence rates worldwide; however, HCC prevention in regions where HBsAg carriage is infrequent may also require prevention of the other causes of cirrhosis in order for HCC rates to decline.

Prevention of First Bleeding in Cirrhosis: A Meta-Analysis of Randomized Trials of Nonsurgical Treatment

OBJECTIVE To assess the effectiveness of beta-blockers and endoscopic sclerotherapy in the prevention of first bleeding and reduction of mortality in patients with cirrhosis and esophagogastric varices. DATA SOURCES Pertinent studies were selected using MEDLINE (1980 to 1990), reference lists from published articles or reviews, and congress abstract lists. STUDY SELECTION Randomized trials comparing beta-blockers or sclerotherapy with a nonactive treatment. Nine randomized clinical trials of beta-blockers and 19 trials of sclerotherapy were reviewed. Seven trials of beta-blockers and 15 of sclerotherapy were published as full papers. DATA EXTRACTION Crude rates of bleeding and death in treated and control groups were extracted from each trial by three independent observers according to the intention-to-treat principle. The quality of published papers was systematically assessed and scored. DATA SYNTHESIS The Mantel-Haenszel-Peto method was used for statistical evaluation of heterogeneity and for pooling of the results. No substantial heterogeneity was found, and the incidence of bleeding in trials of beta-blockers was significantly reduced (pooled odds ratio, 0.54; 95% CI, 0.39 to 0.74), particularly in patients with large or medium-sized varices or in those with varices and a hepatic vein pressure gradient above 12 mm Hg; however, only a trend toward reduced mortality was obtained. Sclerotherapy trials were highly heterogeneous in the direction of the treatment effects on both bleeding (pooled odds ratio, 0.6; CI, 0.49 to 0.74) and mortality (pooled odds ratio, 0.76; CI, 0.61 to 0.94). The quality of the trials and the rate of bleeding in the untreated groups were the major sources of heterogeneity. The favorable results of sclerotherapy were obtained in trials with high bleeding rates among controls; several of these trials had a low quality score. CONCLUSIONS Beta-blockers may be recommended for prevention of first bleeding in cirrhotic patients with varices who have a high risk for bleeding. The effectiveness of sclerotherapy remains undetermined. Further trials in high-risk patients may prove useful if improved criteria to predict bleeding risk become available.

Natural history of congestive gastropathy in cirrhosis

In a prospective study of the natural history of congestive gastropathy, 212 consecutive cirrhotic patients (75 treated with sclerotherapy) were included. Mean follow-up was 46 months. Mild gastropathy (mosaiclike pattern) was found in 110 patients and severe gastropathy (granular mucosa with cherry spots) was found in 20. Prevalence of Helicobacter pylori, formerly Campylobacter pylori, was 50% in patients without, 43% in those with mild, and 28% in those with severe gastropathy. Congestive gastropathy was significantly more frequent in patients treated with sclerotherapy (83% vs. 50%, P less than 10(-5)). Sixty-month actuarial proportions of patients free of anemia (in the absence of hematemesis or melena), were 17% with severe, 62% with mild, and 93% without gastropathy (P less than 10(-8]. Corresponding figures for overt bleeding were 25%, 73%, and 87% (P less than 10(-7], whereas those for survival were 46%, 72%, and 85% (P = 0.0005), respectively. A multivariate regression analysis supported the following conclusions: (a) sclerotherapy and the presence of large esophageal varices significantly increase the risk of congestive gastropathy, which (b) is a significant risk indicator of both chronic and overt bleeding but does not independently affect survival.

Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial

A beneficial effect of recombinant activated factor VII (rFVIIa) in Child‐Pugh class B and C patients with cirrhosis who have variceal bleeding has been suggested. This randomized controlled trial assessed the efficacy and safety of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child‐Pugh > 8; Child‐Pugh B = 26%, C = 74%) were randomized equally to: placebo; 600 μg/kg rFVIIa (200 + 4× 100 μg/kg); or 300 μg/kg rFVIIa (200 + 100 μg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hours after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24‐hour bleeding, or failure to prevent rebleeding or death at day 5. Secondary endpoints included adverse events and 42‐day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (P = 0.37). There was no significant difference in 5‐day mortality between groups; however, 42‐day mortality was significantly lower with 600 μg/kg rFVIIa compared with placebo (odds ratio 0.31, 95% confidence interval = 0.13–0.74), and bleeding‐related deaths were reduced from 12% (placebo) to 2% (600 μg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. Conclusion: Treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Therefore, decision on the use of this hemostatic agent in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting. Adverse events were comparable across groups. (HEPATOLOGY 2008.)

Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding

Promoting the development of oesophageal varices and ascites, portal hypertension dominates the clinical course of cirrhosis. Varices appear in patients with portal pressure gradient above 10 mmHg and enlarge in 10-20% within 1-2 years of their detection. Bleeding occurs in patients with portal pressure gradient above 12 mmHg when the wall tension causes the rupture of varices, with an incidence of about 10% per year. Indicators of bleeding risk are portal pressure gradient, variceal pressure, large varices and liver dysfunction. Mortality per bleeding episode is 30-50%. Among survivors 60% will rebleed and 30% will die in the following year. The risk of rebleeding decreases in patients with spontaneous or treatment induced reduction of portal pressure gradient or variceal pressure. Ascites develops in almost all patients along the course of the disease. Median survival after its appearance is less than 2 years. Less than 5% of cirrhotic patients die without ascites or without a previous bleeding. Thus portal hypertension is a major determinant of survival in cirrhosis.

Reliability of endoscopy in the assessment of variceal features: The Italian Liver Cirrhosis Project

In order to evaluate the reliability of the endoscopic assessment of variceal features, 6 skilled endoscopists separately examined 28 patients with liver cirrhosis and varices. Definitions of variceal features were set up on the basis of the classification of the Japanese Research Society for Portal Hypertension. A new item, i.e. oesophageal lumen occupancy, and a semiquantitative rating system of endoscopic findings were introduced. Beyond chance agreement (Kappa index) was poor on the assessment of the extension of blue colour (0.33) and prevalence of cherry red spots or red weal marking (0.17) whereas was fair to good (0.40-0.66; P less than 10(-5)) on the following: location, size, lumen occupancy, presence of blue colour, presence and extension of red colour sign, haematocystic spot. We conclude that the endoscopic assessment of oesophageal varices based on these features is reliable; their prognostic value as predictors of bleeding risk should be prospectively assessed.

Noninvasive markers of esophageal varices: Another round, not the last†

Esophageal varices are a serious consequence of portal hypertension. They appear only after the hepatic venous pressure gradient (HVPG) has increased to at least 10 to 12 mm Hg.1,2 In patients with cirrhosis the incidence of esophageal varices increases by nearly 5% per year, and the rate of progression from small to large varices is approximately 5 to 10 % per year.3,4 Increasing size of varices is associated with an increase in variceal-wall tension to a critical level at which varices rupture and cause life-threatening bleeding. The mortality rate from variceal bleeding is about 20% when patients are treated optimally in hospital.5 However, an appreciable proportion of patients with variceal bleeding die before reaching the hospital.6 Thus, the true mortality rate from bleeding varices is considerably higher than relatively optimistic estimates based on hospitalized patients. Because nonselective -blockers and banding ligation prevent bleeding in more than half of patients with medium or large varices,7,8 practice guidelines for the treatment of portal hypertension in the United States9 and Europe10 have recommended endoscopic screening of patients with cirrhosis for varices, and treatment of patients with medium or large varices to prevent bleeding. It has been suggested that all patients should undergo endoscopic screening for varices at the time that cirrhosis is diagnosed, and every 2 to 3 years thereafter in those with compensated disease and no varices; the recommended time intervals between endoscopies for those with small varices was 1 to 2 years,11 and 1 year for those with decompensated disease, with or without varices.9,11 These recommendations imply a considerable burden of endoscopies and related costs; they require that patients repeatedly undergo an unpleasant procedure, even though up to 50% of them may still not have developed esophageal varices 10 years after the diagnosis of cirrhosis.4 Therefore, these guidelines might not be ideal for clinical practice. This inference is supported by recent studies from the United States12 and Italy5 suggesting that the guidelines are not being fully adopted. Moreover, the guidelines were based largely on studies of patients with cirrhosis due to viral hepatitis or alcohol abuse; accordingly, it is unclear to what extent the guidelines may apply to patients with other causes of portal hypertension. To reduce the number of unnecessary endoscopies in patients with cirrhosis but without varices, several studies have evaluated possible noninvasive markers of esophageal varices in patients with cirrhosis.13–21 The conclusion from most of these studies is that by selecting patients for endoscopic screening based on a few laboratory and/or ultrasonographic variables (usually the platelet count and the diameter of the portal vein), an appreciable number of endoscopies may be avoided, while keeping the rate of undiagnosed varices, which are at risk of bleeding, acceptably low (Table 1). However, the predictive accuracy of such noninvasive markers is still considered to be unsatisfactory, and none of them has been recommended for use in clinical practice so far.11 Prevention of bleeding from esophageal varices is further complicated by uncertainty about whether nonselective -blockers can prevent the development of varices or the progression of small varices to larger varices that may bleed. Multicenter, randomized, controlled trials to address this issue are ongoing in the United States and Europe. However, two recent analyses of costeffectiveness22,23 suggested that the strategy of treating all cirrhotic patients without a history of bleeding with nonselective -blockers, irrespective of the presence or size of varices (i.e., avoiding endoscopy) is more cost-effective than the strategy of treating only patients with endoscopically proven risk-varices with -blockers or banding ligation. A third analysis, however, confirmed that this strategy is most cost-effective only for patients who have decompensated disease; for patients who have compensated disease screening and treating only those with large varices is more cost-effective.24 In this issue of HEPATOLOGY, Zein and colleagues at the Mayo Clinic report a study of potential noninvasive markers of esophageal varices in a consecutive series of 183 patients with primary sclerosing cholangitis (PSC).25 The results of the study show that a platelet count of 150 103/dL is associated with an odds ratio of 6.3 (95% Abbreviations: HVPG, hepatic venous pressure gradient; PSC, primary sclerosing cholangitis; ROC, receiver operating characteristic. From the 1Division of Gastroenterology, Ospedale V Cervello, Palermo, Italy; and the 2Institute of Biometry, University of Milan, Milan, Italy. Received November 4, 2003; accepted November 10, 2003. Address reprint requests to: Gennaro D’Amico, Division Gastroenterology, Ospedale V Cervello, Via Trabucco 180, 901146 Palermo, Italy. E-mail: gedamico@libero.it; fax: 39-91-688-5111. Copyright

Research PaperReliability of endoscopy in the assessment of variceal features: The Italian Liver Cirrhosis Project*

In order to evaluate the reliability of the endoscopic assessment of variceal features, 6 skilled endoscopists separately examined 28 patients with liver cirrhosis and varices. Definitions of variceal features were set up on the basis of the classification of the Japanese Research Society for Portal Hypertension. A new item, i.e. oesophageal lumen occupancy, and a semiquantitative rating system of endoscopic findings were introduced. Beyond chance agreement (Kappa index) was poor on the assessment of the extension of blue colour (0.33) and prevalence of cherry red spots or red weal marking (0.17) whereas was fair to good (0.40-0.66; P less than 10(-5)) on the following: location, size, lumen occupancy, presence of blue colour, presence and extension of red colour sign, haematocystic spot. We conclude that the endoscopic assessment of oesophageal varices based on these features is reliable; their prognostic value as predictors of bleeding risk should be prospectively assessed.