Angelo Gatta

Nutrition and survival in patients with liver cirrhosis

Although the effect of malnutrition on survival has been demonstrated by a number of studies, it is not clear whether malnutrition represents an independent risk factor in patients with liver disease. We studied 212 hospitalized patients with liver cirrhosis who were followed clinically for 2 y or until death. Body fat and muscle mass were evaluated by triceps skinfold thickness (TSF) and midarm muscle circumference (MAMC), respectively. Multivariate analysis according to Coxs model assessed the predictive power of nutritional parameters on survival. Thirty-four percent of patients had severe malnutrition as determined by MAMC and/or TSF below the 5th percentile and 20% had moderate malnutrition (MAMC and/or TSF < 10th percentile). Twenty-six percent of patients were overnourished (MAMC and/or TSF > 75th percentile). Severely and moderately malnourished patients had lower survival rates than normal and overnourished patients. When analyzed with Coxs regression analysis, severe depletion of muscle mass and body fat were found to be independent predictors of survival. The inclusion of MAMC and TSF in the Child-Pugh score, the prognostic score used most with liver disease, improved its prognostic accuracy. The prognostic power of MAMC was higher than that of TSF. These data demonstrate that malnutrition is an independent predictor of survival in patients with liver cirrhosis. The inclusion of anthropometric measures in the assessment of these patients might provide better prognostic information.

Renal failure and bacterial infections in patients with cirrhosis: Epidemiology and clinical features

The aim of the study was to investigate the prevalence and clinical course of renal failure that was induced by the various types of bacterial infections in patients with cirrhosis and ascites. Three hundred and nine patients, who were consecutively admitted to the 3 major hospitals of Padova, Italy, during the first 6 months of 2005, were studied prospectively. Of these, 233 patients (75.4%) had evidence of ascites. In 104 patients with cirrhosis and ascites (44.6%) a bacterial infection was diagnosed. A bacterial infection‐induced renal failure was observed in 35 of 104 patients (33.6%). The prevalence of renal failure was higher in biliary or gastrointestinal tract infections and in spontaneous bacterial peritonitis (SBP) and in than in other types of infections. In addition, the progressive form of renal failure was only precipitated by biliary or gastrointestinal tract infections, SBP, and urinary tract infections (UTI). In a multivariate analysis only MELD score (P = 0.001), the peak count of neutrophil leukocyte in blood (P = 0.04), and the lack of resolution of infection (P = 0.03) had an independent predictive value on the occurrence of renal failure. Conclusion: The results of the study show that the development of bacterial‐induced renal failure in patients with cirrhosis and ascites is related to the MELD score, and to both the severity and the lack of resolution of the infection. A progressive form of renal failure occurs only as a consequence of biliary or gastrointestinal tract infections, SBP, and UTI. (HEPATOLOGY 2007;45:223–229.)

Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients

BACKGROUND/AIMS The electroencephalogram (EEG) is frequently altered in cirrhotic patients. We, therefore, performed a study to ascertain the features and the prognosis of cirrhotic patients without current overt hepatic encephalopathy (OHE) who have EEG alterations. METHODS A series of 296 consecutive cirrhotic patients who had undergone quantified-EEG was studied. The median follow-up was 442 days, 128 patients had bouts of OHE and 78 patients died from liver-related causes. Another group of 124 cirrhotic patients with a median follow-up of 223 days was examined to validate the prognostic model. RESULTS EEG alterations were detected in 38% of the patients. The prevalence of EEG alterations was associated with the severity of cirrhosis (class B: odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.2-4.7; class C: OR = 3.5, 95% CI = 1.6-7.7), but not with the aetiology (alcoholic vs. non-alcoholic: OR = 0.9; 95% CI = 0.5-1.5). The EEG predicted the occurrence of OHE (chi2 = 26; P < 0.001) and mortality (chi2 = 34; P < 0.001), also adjusting for Child-Pugh class by a multivariate analysis. In the patients with a Child-Pugh score of > or = 8, the EEG discriminated between those patients with a higher 1-year risk of OHE (hazard ratio (HR) = 3.3, 95% CI = 1.8-6.1) and death (HR = 3.1, 95% CI = 1.7-5.6). CONCLUSIONS In conclusion, quantified-EEG had a prognostic value for the occurrence of bouts of OHE and mortality in cirrhotic patients.

Chronic hepatitis B in children after e antigen seroclearance: Final report of a 29‐year longitudinal study

Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long‐term prognosis remains unsettled. This report describes the results of a 29‐year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg‐positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 ± 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg‐negative hepatitis and the other 84 became inactive carriers. During a mean follow‐up of 14.5 ± 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg‐negative hepatitis at the last follow‐up. Of the 8 initially HBeAg‐negative children, 2 had HBeAg‐negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg‐negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow‐up, 15 of the 89 initially HBeAg‐positive patients and 2 of 8 initially HBeAg‐negative children had cleared hepatitis B surface antigen. In conclusion, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg‐negative hepatitis. Long‐term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse. (HEPATOLOGY 2006;43:556–562.)

Prognostic Usefulness of Hepatic Vein Catheterization in Patients With Cirrhosis and Esophageal Varices

Clinical and anamnestic data, Pugh score, and size of esophageal varices were obtained in 129 cirrhotics. Hepatic vein catheterization was performed to measure hepatic venous pressure gradient (HVPG), indocyanine green (ICG) intrinsic hepatic clearance, and hepatic plasma flow. During a follow-up period of up to 60 months, 44 patients experienced gastrointestinal bleeding and 54 died. Applying Cox regression analysis, ICG intrinsic hepatic clearance, Pugh score, previous variceal bleeding, and HVPG were the only significant prognostic determinants of survival. In addition, Coxs regression analysis showed that HVPG, Pugh score, size of varices, and previous variceal bleeding all contained significant prognostic information regarding risk of gastrointestinal bleeding. The models were validated using a split-sample technique, and prognostic indexes for death and gastrointestinal bleeding were calculated. The prognostic index predicting death had significantly improved prognostic accuracy over a prognostic index calculated excluding the data obtained from hepatic vein catheterization (P less than 0.05). In conclusion, prognostic accuracy in cirrhosis with portal hypertension is significantly improved by information obtained from hepatic vein catheterization.

Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection

Context Many persons infected with hepatitis C virus (HCV) are asymptomatic. The extent of liver disease in these persons is unclear. Contribution The researchers tested 4820 apparently healthy persons in Italy for hepatitis C virus. Among the 116 (2.4%) who tested positive, 85 were viremic; only about half of these 85 patients had elevated alanine aminotransferase (ALT) levels. Liver biopsy showed substantial inflammation or fibrosis in 19% of persons with normal ALT levels and 61% of persons with abnormal ALT levels. Implications The substantial prevalence of abnormal liver histology among asymptomatic persons is a provocative but incomplete rationale for screening for HCV. The prevalence of infection and the effectiveness of treatment are also important considerations. The Editors Although new hepatitis C virus (HCV) infections have declined during the past decade in most developed countries (1), hepatitis C remains a major health problem because of the many persons infected before serologic testing became available (2, 3). Many persons with HCV infection are asymptomatic and unaware that they are infected. While it is clear that HCV contributes greatly to end-stage liver disease, the natural history of hepatitis C in asymptomatic individuals is poorly defined. Published studies indicate that the natural history of hepatitis C is heterogeneous. Several factors, including age at infection, alcohol use, and co-infection with hepatitis B virus or HIV, increase the risk for cirrhosis (4-8). Independent of these cofactors, prognosis is related to hepatic histopathology, particularly the type and amount of liver necroinflammation and fibrosis (9-11). Our understanding of the histology of hepatitis C in asymptomatic persons comes mainly from studies of blood donors (a selected population) (12-14). We report an investigation of the prevalence, histologic activity, and stage of HCV infection in 4820 otherwise apparently healthy adults living in northeastern Italy. Methods Patients We tested for serum anti-HCV in 4820 adults (2132 men and 2688 women; age range, 16 to 60 years) who were undergoing a screening program for cardiovascular risk factors. To be eligible for this program, persons had to be free of acute or chronic illness (based on history and clinical symptoms) at the time of evaluation. Telecom Italy proposed and promoted the screening program to employees and their relatives. Participation was voluntary. Participants lived in one of three regions (Veneto, Trentino-Alto-Adige, and Friuli-Venezia-Giulia) in northeastern Italy and included a wide range of socioeconomic strata (from employees in lower positions to senior managers and their relatives). All 4820 persons (1210 employees and 3610 relatives) gave written informed consent and underwent clinical evaluation and testing for anti-HCV by enzyme-linked immunosorbent assay (ELISA) (Ortho Diagnostic Systems, Raritan, New Jersey) at the initial visit. Within 1 month, we retested persons who were positive for anti-HCV by ELISA. Serum that was confirmed to be HCV positive was tested for HCV RNA by polymerase chain reaction (PCR) (Amplicor HCV Monitor test, Roche Diagnostics, Indianapolis, Indiana). We retested serum for HCV RNA after 1 and 3 months in confirmed anti-HCVpositive persons whose initial test results for HCV RNA had been negative. We monitored serum alanine aminotransferase (ALT) levels 1, 3, 6, and 12 months after anti-HCV detection. We proposed liver biopsy for all viremic persons. These biopsies were done 6 to 14 months after detection of anti-HCV; patients provided informed consent. Liver biopsy specimens were evaluated according to the METAVIR scoring system (15). We classified patients with METAVIR scores of F2 and higher or A2 and higher as having significant liver disease according to international guidelines (16). Statistical Analysis Prevalences of HCV infection and of liver disease were compared by using the Fisher exact test for 2 2 tables. The chi-square test for linear trend was used to compare prevalences in age subgroups. Role of the Funding Source The study protocol was developed by a Scientific Committee of the Italian National Research Council (CNR), approved by a National Ethical Committee, and directly funded by the Italian National Research Council. The Italian National Research Council had no role in the collection, analysis, and reporting of the study or in the decision to publish the manuscript. Results Prevalence of HCV Infection in the Screened Population Of the 4820 persons tested, 116 (2.4% [CI, 1.97% to 2.84%]) were repeatedly positive for anti-HCV by ELISA and 12 additional persons were initially positive but were negative on repeated testing. Samples confirmed to be anti-HCV positive were tested for HCV RNA; 75 of these were positive. The 41 persons who were initially positive for anti-HCV but negative for HCV RNA were tested for serum HCV RNA 1 and 3 months after anti-HCV detection; 10 were positive in both (n = 8) or one (n = 2) follow-up test. Thus, 85 of 116 anti-HCVpositive persons (73.3%), or 85 of 4820 screened individuals (1.76 % [CI, 1.39% to 2.14%]) were positive for HCV RNA. Among the 85 HCV RNApositive individuals, ALT levels were normal (<50 U/L) at all times (at 0, 1, 3, 6, and 12 months) in 39 persons (46%), elevated at all times in 37 persons (43.5%), and abnormal at least once in 9 patients (10.5%). The 10 persons with intermittent HCV RNA positivity had persistently normal ALT levels during follow-up. Liver Histology in HCV-Infected Persons Seventy-eight of the 85 persons who were positive for HCV RNA had liver biopsies; these 78 patients included 32 of 39 persons with persistently normal ALT levels and all 46 persons with elevated ALT levels. The Figure summarizes the histopathologic characteristics of the 78 HCV-positive persons according to the ALT profile during the observation period. Overall, 52% of patients with elevated ALT levels and 19% of patients with normal ALT levels had significant fibrosis (F2 to F4), whereas 24% of patients with elevated ALT levels and none with normal ALT levels had significant necroinflammatory activity (A2 to A3). Thus, on the basis of a fibrosis score of 2 or higher or an activity score of 2 or higher, moderate to severe chronic hepatitis was seen in 28 of 46 (61% [CI, 45.4% to 74.9%]) patients with elevated ALT levels and in 6 of 32 (19% [CI, 7.21% to 36.4%]) patients with normal ALT levels (P < 0.001). Both mean and peak ALT values during the 12-month follow-up period correlated with activity and fibrosis stage (Table). The percentage of patients with significant activity or fibrosis increased with increasing ALT levels (data not shown). Figure. Histologic activity and fibrosis stage of the 78 persons with normal or elevated alanine aminotransferase levels who were positive for hepatitis C virus. Table. Liver Histology during the 12-Month Follow-up Period in 78 Hepatitis C VirusPositive Persons Prevalence of HCV Infection and Liver Disease by Age Prevalence of HCV RNA positivity increased with age: 0.67% (CI, 0.23% to 1.57%) in persons age 16 to 30 years, 1.4% (CI, 0.93% to 2.08%) in persons age 31 to 45 years, and 2.4% (CI, 1.8% to 3.2%) in persons age 46 to 60 years (P = 0.003). The percentage of persons with persistently normal ALT levels was similar in the three age groups, but severity of liver disease increased with age. The prevalence of significant fibrosis (F2) was 20% in the persons age 16 to 30 years and 48% in the persons age 46 to 60 years. When only patients with abnormal ALT levels were considered, the corresponding figures were 33% in persons age 16 to 30 years, 50% in the persons age 31 to 45 years, and 79% in the persons age 46 to 60 years. HCV Genotypes Among the 85 persons positive for HCV RNA, 52 (61.2%) were infected with HCV genotype 1b, 5 (5.8%) with genotype 1a, 20 (23.5%) with genotype 2a/2c, and 8 (9.4%) with genotype 3. Four of 5 patients age 16 to 30 years were infected with genotype 3, and the fifth was infected with genotype 1a. Genotype in persons age 31 to 45 years and 46 to 60 years did not differ significantly. The HCV genotypes were not significantly associated with ALT levels or histologic features after adjustment for age (data not shown). Discussion It has been difficult to estimate precisely how many asymptomatic HCV-infected persons are at significant risk for progressive liver disease. This is a result of the limited available information on the actual burden of HCV in the general population and uncertainty about the natural course of HCV infection in asymptomatic individuals (16). Previous studies mainly considered blood donors screened for anti-HCV and rarely reported systematic data on liver histology. Our survey was conducted in a less highly selected population and might therefore better represent the burden of HCV in the general population. Limitations of our study include the uncertain generalizability to other geographic areas, the inclusion of only working adults and their relatives, and the lack of detailed information on risk factors in the screened population and of cofactors known to influence hepatitis C progression (use of alcohol or drugs; co-infection with hepatitis B virus or HIV) in the HCV-positive persons. Our data may underestimate the prevalence of HCV because of a healthy worker effect. Despite these limitations, our data indicate that progressive liver disease can be detected in a substantial proportion of apparently healthy, asymptomatic persons with HCV infection. Of note, almost 40% of individuals positive for HCV RNA, representing 0.70% of the general population cohort screened, had active inflammatory lesions or advanced fibrosis (as shown by liver biopsy results). These histologic features are considered the hallmark of progressive HCV infection and indications for antiviral therapies (16). Our findings would suggest that broader screening for HCV in the general population might be indi

Hepatic arterial resistance in cirrhosis with and without portal vein thrombosis: Relationships with portal hemodynamics☆

BACKGROUND/AIMS Little information is available on hepatic arterial hemodynamics in cirrhosis because of the invasiveness of methods. Hepatic arterial resistance indexes were evaluated noninvasively by Doppler ultrasonography and were correlated with portal hemodynamics evaluated both noninvasively and invasively. METHODS Hepatic arterial resistance indexes, portal blood flow velocity and volume, and portal vein congestion index were evaluated in 31 controls and 171 cirrhotic patients with (n = 13) or without (n = 158) portal vein thrombosis. Resistance to portal blood flow was also calculated in 15 patients from hepatic venous pressure gradient, measured by hepatic vein catheterization, and portal blood flow. RESULTS Resistance indexes were significantly higher in cirrhotics without portal thrombosis than in controls (pulsatility index, 1.30 +/- 0.29 vs. 0.89 +/- 0.09; P < 0.001; resistive index, 0.71 +/- 0.07 vs. 0.59 +/- 0.04; P < 0.001). In patients with portal thrombosis, the pulsatility index (1.86 +/- 0.39) and resistive index (0.81 +/- 0.06) were significantly higher than in controls (P < 0.001) and in patients without thrombosis (P < 0.001). Resistance indexes directly correlated with portal resistance (P < 0.01), the congestion index (P < 0.01), and the degree of esophageal varices (P < 0.01). CONCLUSIONS Hepatic arterial resistance indexes increase in cirrhosis, particularly with portal vein thrombosis. The pathophysiology of the increase in hepatic arterial resistance seems to be parallel to that of portal resistance.

Spectral versus visual EEG analysis in mild hepatic encephalopathy

OBJECTIVE Spectral EEG analysis has been claimed to reduce subjective variability in EEG assessment of hepatic encephalopathy and to allow the detection of mild encephalopathy. METHOD To test such assumptions, 43 digital EEG were recorded in 32 cirrhotics without overt encephalopathy or with grade 1 overt encephalopathy; 7 patients were re-tested (2-5 times) in their follow up. All patients underwent psychometric assessment. Nineteen controls were considered. EEG were blindly evaluated by two electroencephalographers and by spectral EEG analysis performed according to 3 different techniques. RESULTS The reliability of the classification based on spectral analysis (biparietal technique) was higher than that based on a three-degree qualitative visual reading (concordance/discordance = 58/4 versus 46/16 P < 0.01) and comparable with that of semiquantitative visual assessment based on posterior basic rhythm (concordance/discordance = 55/7 P = 0.5). The accuracy of spectral EEG analysis was higher than that of qualitative visual EEG readings alone (90 versus 75%) and comparable to semi-quantitative visual assessment (87%), however, statistical significance was not reached. In the follow-up, the variations of theta and delta relative power were found to be significantly correlated with psychometric variations. CONCLUSIONS In conclusion, spectral EEG analysis may improve the assessment of mild hepatic encephalopathy by decreasing inter-operator variability and providing reliable parameters correlated with mental status.

Randomised trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis

BACKGROUND The risk of having a first cirrhosis-associated variceal bleed is lowered by about 50% by beta-blockers. Use of beta-blockers is currently recommended for patients with cirrhosis and oesophageal varices that are at risk of bleeding. We aimed to test the effectiveness of isosorbide mononitrate as an adjunct to the beta-blocker nadolol in the prophylaxis of first variceal bleeding in these patients. METHODS We did a randomised multicentre study to compare the non-selective beta-blocker, nadolol, with nadolol plus isosorbide mononitrate in 146 relatively well (Child-Pugh score < or = 11) patients who had oesophageal varices at risk of bleeding. Patients on nadolol alone received a single oral 40 mg daily dose. Every second day the dose was titrated to achieve 20-25% decrease in resting heart rate (maximum dose 160 mg daily). Patients receiving both drugs received nadolol as above then isosorbide mononitrate was added starting with 10 mg orally twice daily, which was increased to 20 mg unless hypotension or severe headache occurred. The main endpoint was the occurrence of variceal bleeding of any severity. Patients were followed up for up to 40 months. FINDINGS During the study period 11 of 74 patients from the nadolol alone group and four of 72 from the nadolol plus isosorbide mononitrate group had variceal bleeding (log-rank test p = 0.03). Cumulative risk of variceal bleeding was 18% in the nadolol group and 7.5% in the combined treatment group (95% CI for difference 1-25%). Two patients in each group had a non-variceal bleed related to portal hypertension. 14 patients from the nadolol only group and eight from the combined treatment group died during the study period (log-rank test p = 0.09). Four and eight patients, respectively, had to discontinue one of the drugs because of side-effects. INTERPRETATION Nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the primary prophylaxis of variceal bleeding in relatively well patients with cirrhosis, and has few side-effects.

Role of spleen enlargement in cirrhosis with portal hypertension

The possible relationships between splenomegaly and portal hypertension have been analysed in patients with cirrhosis. In this condition, splenomegaly is not only caused by portal congestion, but it is mainly due to tissue hyperplasia and fibrosis. The increase in spleen size is followed by an increase in splenic blood flow, which participates in portal hypertension actively congesting the portal system.