Jaime Guardia

Transmission of Hepatitis C Virus by a Cardiac Surgeon

BACKGROUND In the course of a study conducted in 1992 through 1994 of the efficacy of screening blood donors for antibodies to hepatitis C virus (HCV), we found that two patients had acquired hepatitis C after cardiac surgery, with the transmission apparently unrelated to blood transfusions. Because their surgeon had chronic hepatitis C, we sought to determine whether he was transmitting the virus to his patients. METHODS Of 222 of the surgeons patients who participated in studies of post-transfusion hepatitis between 1988 and 1994, 6 contracted postoperative hepatitis C, despite the use of only seronegative blood for transfusions. All six patients had undergone valve-replacement surgery. Analyses were performed to compare nucleotide sequences encompassing the hypervariable region at the junction between the coding regions for envelope glycoproteins E1 and E2 in the surgeon, the patients, and 10 controls infected with the same HCV genotype. RESULTS The surgeon and five of the six patients with hepatitis C unrelated to transfusion were infected with HCV genotype 3; the sixth patient had genotype 1 and was considered to have been infected from another source. Thirteen other patients of the surgeon had transfusion-associated hepatitis C and were also infected with genotype 1. The average net genetic distance between the sequences from the five patients with HCV genotype 3 and those from the surgeon was 2.1 percent (range, 1.1 to 2.5 percent; P < 0.001), as compared with an average distance of 7.6 percent (range, 6.1 to 8.3 percent) between the sequences from the patients and those from the controls. The results of phylogenetic-tree analysis indicated a common epidemiologic origin of the viruses from the surgeon and the five patients. CONCLUSIONS Our findings provide evidence that a cardiac surgeon with chronic hepatitis C may have transmitted HCV to five of his patients during open-heart surgery.

Evaluation of Antibodies to Hepatitis C Virus in a Study of Transfusion-Associated Hepatitis

BACKGROUND The hepatitis C virus (HCV) is now known to be the chief cause of transfusion-associated non-A, non-B hepatitis, but the prevalence of HCV among blood donors and the frequency of transmission by blood transfusion are unknown. METHODS To assess the sensitivity and specificity of a test for antibody to HCV, we tested serum samples from participants in a large study of transfusion-associated hepatitis. Samples were obtained prospectively from consecutive adults undergoing open-heart surgery in Spain, but were tested retrospectively, after the antibody enzyme immunoassay for anti-HCV became available. RESULTS Of 280 transfusion recipients given a total of 1109 units of blood, 27 (9.6 percent) had transfusion-associated non-A, non-B hepatitis (mean follow-up, 52 weeks) and 24 of the 27 seroconverted to anti-HCV-positive, whereas only 2 (0.8 percent) of the remaining transfusion recipients seroconverted. Among the 1044 donor specimens available for testing, 16 (1.5 percent) had anti-HCV antibody. Only 1 additional seropositive donor was found when 44 implicated donors who had been seronegative were retested 9 to 12 months later. Of the 16 recipients of anti-HCV-positive blood, 14 (88 percent) had transfusion-associated hepatitis and seroconverted to anti-HCV-positive. The remaining two recipients had neither hepatitis nor anti-HCV antibody. Among 25 patients with non-A, non-B hepatitis for whom all transfused blood was tested, 14 had received blood positive for anti-HCV. CONCLUSIONS About 90 percent of blood donors with antibody to HCV have infectious virus in their blood. The screening of blood donors for anti-HCV antibody should prevent about half the cases of transfusion-associated hepatitis, but the donors with infectious virus who are anti-HCV-negative may remain seronegative for prolonged periods.

High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus.

OBJECTIVE To determine the epidemiologic, clinical, serologic, and histologic importance of antibodies to hepatitis C virus (anti-HCV) in blood donors. DESIGN Cross-sectional identification and prospective evaluation of seropositive donors; retrospective assessment of infectivity; and nested case-control study for risk factors. SETTING Liver unit of a referral-based university hospital. SUBJECTS Of 30,231 consecutive donors, 368 (1.2%) were found to be anti-HCV-reactive by enzyme-linked immunosorbent assay (ELISA). Two hundred and fifty-four of these 368 donors were evaluated for risk factors by comparison with 284 age- and sex-matched controls. Eighty-six spouses of seropositive donors were also evaluated. MEASUREMENTS AND MAIN RESULTS Twenty-four percent of the seropositive donors had a history of percutaneous exposure to blood. This rate increased to 45% when only those donors confirmed to be anti-HCV positive by a second-generation recombinant immunoblot assay (RIBA-2) were considered. A family history of liver disease (odds ratio, 2.8; 95% Cl, 1.6 to 4.8), previous blood transfusion (odds ratio, 6.1; 95% Cl, 3 to 12.5), and a history of tattooing or intravenous drug abuse (odds ratio, 8.4; 95% Cl, 2.3 to 31) were associated with anti-HCV seropositivity. An elevated alanine aminotransferase (ALT) level was found in 58% of the seropositive donors. Of the 150 donors tested, 104 (69%; Cl, 62% to 77%) were confirmed by RIBA-2 to be anti-HCV positive. Of the 105 donors who had a biopsy, 16% had normal histologic findings, 11% had minimal changes, 21% had chronic persistent hepatitis, 45% had chronic active hepatitis, and 7% had active cirrhosis. All 77 donors with RIBA-2-confirmed seropositivity had histologic abnormalities. Of 43 donors evaluated in an infectivity study, 82% were implicated in previous HCV transmission. Only 2.3% of the spouses were anti-HCV positive. The ELISA, RIBA-2, and ALT results correlated with infectivity and abnormal histologic findings. CONCLUSIONS In our geographic area, almost 70% of donors who are anti-HCV positive by ELISA are confirmed to be positive by RIBA-2; most of these donors appear to be chronic carriers of HCV and have substantial liver disease.

Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis

Objective: Nitric oxide has been proposed as a mediator of hyperdynamic circulation in cirrhosis. Endotoxin and cytokines induce the synthesis of nitric oxide. The aim of this study was to investigate the relationship between endotoxemia, cytokines, and nitric oxide in patients with cirrhosis, and to correlate these findings with clinical, biochemical, and hemodynamic parameters. Methods: Clinical, biochemical, and hemodynamic parameters were assessed in 66 patients with cirrhosis and 15 controls. Levels of antidiuretic hormone, plasma renin activity, aldosterone, interferon γ, interleukin-1, interleukin-6, tumor necrosis factor α, endotoxin, and nitrates-nitrites were determined. Results: Mean arterial pressure was lower and interleukin-6, tumor necrosis factor α, nitrites-nitrates levels, and endotoxin positivity rates were higher in cirrhotics than in controls (p < 0.005). Mean arterial pressure decreased and interleukin-6 levels increased with worsening of Child score (p < 0.005). Patients with ascites had higher levels of interleukin-6, tumor necrosis factor α, and nitrates-nitrites than patients without ascites (p < 0.01). Elevated levels of interleukin-6 were found in patients with encephalopathy grade I, compared with patients without (p < 0.001); this association was independent of the severity of liver disease. In patients with low mean arterial pressure, interleukin-6 levels were higher than in patients with high mean arterial pressure (p= 0.001), whereas tumor necrosis factor α and nitrates-nitrites levels were not different. By multivariate analysis, high interleukin-6 levels showed independent associations with the presence of ascites, encephalopathy, and low mean arterial pressure. Only interleukin-6 levels had significant correlations with Child score, plasma renin activity, serum and urinary sodium, and mean arterial pressure (r ≥ 0.4, p < 0.005). Conclusions: Although the activity of the nitric oxide pathway is increased in patients with cirrhosis and might contribute to the hemodynamic alteration, other factors are involved. Interleukin-6, possibly through nitric oxide-independent mechanisms, also might play a role in the vasodilatation of cirrhosis and the pathogenesis of hepatic encephalopathy.

Long-Term Immunogenicity and Efficacy of Hepatitis B Vaccine in Hemodialysis Patients

Although the efficacy of hepatitis B vaccines in patients under chronic hemodialysis treatment has been well documented, the persistence of immunity in this population remains largely unknown. In this study we have followed 60 hemodialysis patients up to 3 years after primary hepatitis B vaccination (four doses of recombinant hepatitis B vaccine; Engerix B, 20 mg/dose) to evaluate the persistence of immunity (as indicated by serum levels of antibody to hepatitis B surface antigen-anti-HBs-higher than or equal to 10 mIU/ml). Fourty-four (73%) patients developed anti-HBs levels above 10 mIU/ml after vaccination; the remaining 16 (27%) vaccinees were considered nonresponders and were given a booster dose that again failed to elicit an immunoresponse. After 3 years of follow-up, 18 out of 44 (41%) responders had no detectable anti-HBs levels in the serum (antibody loss occurring within 8 and 12 months in 3 cases, within 1 and 2 years in 13, and within 2 and 3 years in 2 other cases). When compared with the responders that lost their antibodies during the follow-up period, those who remained immunoreactive 3 years after vaccination was initiated were younger and had higher anti-HBs levels at 8 months of follow-up. Two hepatitis B virus infections were detected among nonresponders during the follow-up period. Based on these data, we conclude that patients undergoing chronic hemodialysis therapy not only have lower response rates to hepatitis B vaccination than healthy adults, but also that these are frequently transient.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality of life in cirrhosis is related to potentially treatable factors.

Objective Improvement of prognosis and availability of diverse therapeutic options for complications of advanced liver disease highlight the importance of health-related quality of life (HRQOL) in cirrhosis. The aim of this study was to identify factors that influence HRQOL and may be potentially treatable in patients with cirrhosis. Methods HRQOL was measured in 212 outpatients with cirrhosis using a generic questionnaire (Medical Outcomes Study Form, SF-36) and a liver-specific questionnaire (Chronic Liver Disease Questionnaire, CLDQ). All patients underwent a systematic clinical and neuropsychological assessment. Independent factors associated with poor HRQOL were identified by multiple linear regression. Results HRQOL scores exhibited by patients were: global CLDQ: 4.8±1.2; Physical Component Score of SF-36: 38.5±10.7; Mental Component Score of SF-36: 45.3±14.3. The independent variables for global CLDQ were female sex, nonalcoholic etiology, current ascites, and a decrease in albumin (R2 = 0.22). For Physical Component Score of SF-36, the independent variables were prior hepatic encephalopathy, current ascites, and a decrease in hemoglobin (R2 = 0.22). For Mental Component Score of SF-36, the independent variables were nonalcoholic etiology, the Grooved Pegboard test, and a decrease in hemoglobin (R2 = 0.14). Conclusion Several clinical variables, potentially treatable, may alter particular aspects of HRQOL. Correction of ascites, hypoalbuminemia, minimal hepatic encephalopathy, and anemia may cause a positive impact on HRQOL of patients with cirrhosis.

Predicting Early Mortality After Acute Variceal Hemorrhage Based on Classification and Regression Tree Analysis

BACKGROUND & AIMS Available prognostic models for mortality after an acute variceal hemorrhage have limitations that restrict their clinical value. We assessed the performance of a novel prognostic approach based on classification and regression tree (CART) analysis. METHODS Logistic regression (LR) and CART analyses were performed to identify prognostic models for mortality at 6 weeks in a single-center cohort of 267 consecutive patients with acute variceal bleeding. Receiver operating characteristic (ROC) curves were constructed to assess the performance of the models. Prognostic models were fitted and validated by split-sample technique (training set, 164 patients, 2001-2005; test set, 103 patients, 2006-2008). RESULTS After 6 weeks, 21% of patients experienced rebleeding and 24% died. The best LR model was based on Child-Pugh score, creatinine level, bacterial infection, and hepatocellular carcinoma. CART analysis provided a simple algorithm based on the combined use of just 3 variables (Child-Pugh score, creatinine level, and bacterial infection), allowing accurate early discrimination of 3 distinct prognostic subgroups with 8% (low risk), 17% (intermediate), and 50% to 73% (high) mortality. Its accuracy was similar to the LR model (area under the ROC curves, 0.81 vs 0.84; P = .17) and better than that of Child-Pugh (0.75; P = .05) and model for end-stage liver disease (0.74; P = .05). The prognostic accuracy of both LR and CART models was validated in the test set (area under the ROC curve values, 0.81 and 0.83, respectively). CONCLUSIONS A simple CART algorithm based on Child-Pugh score, creatinine level, and infection allowed an accurate predictive assessment of 6-week mortality after acute variceal bleeding.

Role of Doppler echocardiography in the assessment of portopulmonary hypertension in liver transplantation candidates.

Background. Portopulmonary hypertension is a severe complication of liver cirrhosis that carries a high risk for posttransplantation mortality. We aimed at evaluating the utility of Doppler echocardiography in screening for portopulmonary hypertension in liver transplantation candidates. Methods. One hundred seven cirrhotic patients candidates for liver transplantation were studied by Doppler echocardiography and subsequently, by cardiac catheterization at transplantation. Two parameters were estimated by Doppler: systolic pulmonary arterial pressure (SPAP) derived from tricuspid regurgitation and the pulmonary acceleration time. Portpulmonary hypertension was suspected when SPAP was ≥40 mm Hg and/or pulmonary acceleration time <100 ms. Results. Portpulmonary hypertension was suspected by Doppler study in 17 patients (15%). However, portopulmonary hypertension (mean pulmonary arterial pressure ≥25 mm Hg and pulmonary vascular resistance>120 dynes.s/cm5) was confirmed by the hemodynamic study in five patients (4.7%). Sensitivity and specificity of Doppler echocardiography for detecting portopulmonary hypertension was 100 and 88%, respectively, with a positive predictive value of 30%. The diagnostic accuracy of pulmonary acceleration time alone (96%) was better than pulmonary arterial pressure alone (90%). Conclusions. Doppler echocardiography, and especially the determination of pulmonary acceleration time, is a useful screening method for portopulmonary hypertension in patients with liver cirrhosis who are candidates for liver transplantation.

Nucleotide and Amino Acid Complexity of Hepatitis C Virus Quasispecies in Serum and Liver

ABSTRACT The quasispecies nature of the hepatitis C virus (HCV) is thought to play a central role in maintaining and modulating viral replication. Several studies have tried to unravel, through the parameters that characterize HCV circulating quasispecies, prognostic markers of the disease. In a previous work we demonstrated that the parameters of circulating viral quasispecies do not always reflect those of the intrahepatic virus. Here, we have analyzed paired serum and liver quasispecies from 39 genotype 1b-infected patients with different degrees of liver damage, ranging from minimal changes to cirrhosis. Viral level was quantified by real-time reverse transcription-PCR, and viral heterogeneity was characterized through the cloning and sequencing of 540 HCV variants of a genomic fragment encompassing the E2-NS2 junction. Although in 95% of patients, serum and liver consensus HCV amino acid sequences were identical, quasispecies complexity varied considerably between the viruses isolated from each compartment. Patients with HCV quasispecies in serum more complex (26%) than, less complex (28%) than, or similarly complex (41%) to those in liver were found. Among the last, a significant correlation between fibrosis and all the parameters that measure the viral amino acid complexity was found. Correlation between fibrosis and serum viral load was found as well (R = 0.7). With regard to the origin of the differences in quasispecies complexity between serum and liver populations, sequence analysis argued against extrahepatic replication as a quantitatively important contributing factor and supported the idea of a differential effect or different selective forces on the virus depending on whether it is circulating in serum or replicating in the liver.

Effectiveness of Combined Pharmacologic and Ligation Therapy in High-Risk Patients With Acute Esophageal Variceal Bleeding

OBJECTIVES:After an acute variceal bleeding, early decision for aggressive management of patients with worse prognosis may improve outcomes. The effectiveness of currently recommended standard therapy (drugs plus endoscopic ligation) for different risk subgroups and the validity of available risk criteria in clinical practice are unknown.METHODS:We analyzed data of 301 consecutive cirrhotic patients admitted with esophageal variceal bleeding. All patients received antibiotics, somatostatin, and in 263 early endoscopic therapy. A stratified 6-week mortality assessment according to risk (low-risk: Child-Pugh B without active bleeding or Child-Pugh A; high-risk: Child-Pugh B with active bleeding or Child-Pugh C) was performed. A multivariate analysis was conducted to elaborate a new risk classification rule.RESULTS:Among the 162 patients receiving emergency ligation, 14% rebled and 16% died. Standard therapy was very effective in all risk strata, even in high-risk patients, specially if eligible for therapeutic trials (child <14, age ≤75 years, creatinine ≤3.0 mg/dl, no hepatocellular carcinoma, or portal thrombosis), showing this stratum a 10% mortality. In patients receiving ligation, Child-Pugh C patients with baseline creatinine <1.0 mg/dl showed similar mortality to Child-Pugh A or B patients (8% vs. 7%, respectively). Only Child-Pugh C patients with creatinine ≥1.0 were at a significant higher risk (Child-Pugh C: 46% mortality if creatinine ≥1.0 vs. 8% if creatinine <1.0, P=0.006).CONCLUSIONS:The combination of somatostatin, antibiotics, and endoscopic ligation after an acute variceal bleeding in a real-life situation is associated with very low mortality. Child-Pugh C patients with baseline creatinine ≥1.0 mg/dl should be considered high-risk patients in this setting.