Giovanni Casazza

Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease

Objective: Transient elastography (TE) is gaining popularity as a non-invasive method for predicting liver fibrosis, but intraobserver and interobserver agreement and factors influencing TE reproducibility have not been adequately assessed. This study investigated these aspects. Setting: Tertiary referral liver unit. Patients: Over a 4-month period, 200 patients with chronic liver disease (CLD) with varying aetiology consecutively underwent TE and liver biopsy. Interventions: TE was performed twice by two different operators either concomitantly or within 3 days of the bioptic procedure (METAVIR classification). Main outcome measures: Intraobserver and interobserver agreement were analysed using the intraclass correlation coefficient (ICC) and correlated with different patient-related and liver disease-related covariates. Results: 800 TE examinations were performed, with an indeterminate result rate of 2.4%. The overall interobserver agreement ICC was 0.98 (95% CI 0.977 to 0.987). Increased body mass index (>25 kg/m2), steatosis, and low staging grades (fibrosis (F) stage <2) were significantly associated with reduced ICC (p<0.05). Intraobserver agreement ICC was 0.98 for both raters. Using receiver operating characteristic curves, three diagnostic TE thresholds were identified: >7.9 kPa for F⩾2, >10.3 for F⩾3 and >11.9 for F = 4. TE values assessed by the two raters fell within the same cut-off of fibrosis in 88% of the cases for F⩾2, in 92% for F⩾3 and 91% for F = 4. Conclusions: TE is a highly reproducible and user-friendly technique for assessing liver fibrosis in patients with CLD. However, because TE reproducibility is significantly reduced (p<0.05) in patients with steatosis, increased BMI and lower degrees of hepatic fibrosis, caution is warranted in the clinical use of TE as a surrogate for liver biopsy.

Accuracy of Ultrasonography, Spiral CT, Magnetic Resonance, and Alpha-Fetoprotein in Diagnosing Hepatocellular Carcinoma: A Systematic Review

BACKGROUND AND AIM:In patients with chronic liver disease, the accuracy of ultrasound scan (US), spiral computed tomography (CT), magnetic resonance imaging (MRI), and alpha-fetoprotein (AFP) in diagnosing hepatocellular carcinoma (HCC) has never been systematically assessed, and present systematic review was aimed at this issue.METHODS:Pertinent cross-sectional studies having as a reference standard pathological examinations of the explanted liver or resected segment(s), biopsies of focal lesion(s), and/or a period of follow-up, were identified using MEDLINE, EMBASE, Cochrane Library, and CancerLit. Pooled sensitivity, specificity, and likelihood ratios (LR) were calculated using the random effect model. Summary receiver operating characteristic (SROC) curve and predefined subgroup analyses were made when indicated.RESULTS:The pooled estimates of the 14 US studies were 60% (95% CI 44–76) for sensitivity, 97% (95% CI 95–98) for specificity, 18 (95% CI 8–37) for LR+, and 0.5 (95% CI 0.4–0.6) for LR−; for the 10 CT studies sensitivity was 68% (95% CI 55–80), specificity 93% (95% CI 89–96), LR+ 6 (95% CI 3–12),and LR− 0.4 (95% CI 0.3–0.6); for the nine MRI studies sensitivity was 81% (95% CI 70–91), specificity 85% (95%CI 77–93), LR+ 3.9 (95%CI 2–7), and LR− 0.3 (95% CI 0.2–0.5). The sensitivity and specificity of AFP varied widely, and this could not be entirely attributed to the threshold effect of the different cutoff levels used.CONCLUSIONS:US is highly specific but insufficiently sensitive to detect HCC in many cirrhotics or to support an effective surveillance program. The operative characteristics of CT are comparable, whereas MRI is more sensitive. High-quality prospective studies are needed to define the actual diagnostic role of AFP.

Measurement of Spleen Stiffness to Evaluate Portal Hypertension and the Presence of Esophageal Varices in Patients With HCV-Related Cirrhosis

BACKGROUND & AIMS The hepatic vein pressure gradient (HVPG) is the standard used to determine the degree of portal hypertension (PH) and an important prognostic factor for patients with cirrhosis; HVPG values correlate with the presence of esophageal varices (EV). However, HVPG can only be accurately determined at specialized centers; noninvasive methods are needed to predict HVPG values and the presence of EV. We compared the diagnostic performance of spleen stiffness (SS) measurement by transient elastography with that of liver stiffness (LS) and of other recently proposed noninvasive tests. METHODS We measured SS and LS in 100 consecutive patients with hepatitis C virus-induced cirrhosis. Patients were also assessed by FibroScan, HVPG, esophagogastroduodenoscopy, and liver biopsy. We also analyzed LS-spleen diameter to platelet ratio score and platelet count to spleen diameter. RESULTS SS and LS were more accurate than other noninvasive parameters in identifying patients with EV and different degrees of PH. A linear model that included SS and LS accurately predicted HVPG values (R(2) = 0.85). The results were internally validated using bootstrap analysis. CONCLUSIONS Measurement of SS can be used for noninvasive assessment and monitoring of PH and to detect EV in patients with hepatitis C virus-induced cirrhosis.

Transient elastography predicts fibrosis progression in patients with recurrent hepatitis c after liver transplantation

Objective: Transient elastography (TE) allows non-invasive evaluation of the severity of liver disease in patients with chronic hepatitis C. This procedure, however, warrants further validation in the setting of liver transplantation (LT), including patients under follow-up for recurrent hepatitis C. Setting: Tertiary referral hospital. Patients: 95 patients (75 males) transplanted for end-stage liver disease due to hepatitis C virus. Interventions: Paired liver biopsy (LB) and TE were carried out 6–156 (median, 35) months after LT. 40 patients with recurrent hepatitis C sequentially evaluated 6–21 months apart. Main outcome measures: Clinical, laboratory and graft histological features influencing TE results. Results: Median TE values were 7.6 kPa in the 90 patients with a successful TE examination, being 5.6 kPa in the 30 patients with Ishak fibrosis score (S) of 0–1, 7.6 kPa in the 38 with S2–3; 16.7 kPa in the 22 with S4–6, (p<0.0001). Areas under the ROC curves were 0.85 (95% CI, 0.76 to 0.92) for S⩾3, 0.90 (95% CI, 0.82 to 0.95) for S⩾4 with 7.9 and 11.9 kPa optimal TE cut-off (81% and 82% sensitivity, 88% and 94% negative predictive value, respectively). Fibrosis, necroinflammatory activity and higher than 200 IU/l gamma-glutamyl transpeptidase levels independently influenced TE results. During post-LT follow-up, TE results changed in parallel with grading (r = 0.63) and staging (r = 0.71), showing 86% sensitivity and 92% specificity in predicting staging increases. Conclusions: TE accurately predicts fibrosis progression in LT patients with recurrent hepatitis C, suggesting that protocol LB might be avoided in patients with improved or stable TE values during follow-up.

Effect of periodontal disease treatment during pregnancy on preterm birth incidence: a metaanalysis of randomized trials

We conducted a metaanalysis of randomized controlled trials to determine whether periodontal disease treatment with scaling and/or root planing during pregnancy may reduce preterm birth (PTB) or low birthweight (LBW) infant incidence. Treatment resulted in significantly lower PTB (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.35-0.86; P = .008) and borderline significantly lower LBW (OR, 0.48; 95% CI, 0.23-1.00; P = .049), whereas no difference was found for spontaneous abortion/stillbirth (OR, 0.73; 95% CI, 0.41-1.31; P = .292). Subgroup analysis suggested significant effect of treatment in the absence of history of PTB or LBW (OR, 0.48; 95% CI, 0.29-0.77; P = .003) and less severe periodontal disease as defined by probing depth (OR, 0.49; 95% CI, 0.28-0.87; P = .014) or bleeding on probing site (OR, 0.37; 95% CI, 0.14-0.95; P = .04). If ongoing large and well-designed randomized trials support our results, we might need to reassess current practice or at least be cautious prior to rejecting treatment of periodontal disease with scaling and/or root planing during pregnancy.

Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C

BACKGROUND & AIMS Transient elastography (TE) has gained popularity for the non-invasive assessment of severity of chronic viral hepatitis, but a comprehensive evaluation of the factors that might account for discrepancy in diagnostic accuracy between TE and the standard of care liver biopsy (LB) is still needed. METHODS Patients with chronic hepatitis-B (HBV, n=104) or -C (HCV, n=453) underwent percutaneous LB concomitantly with TE (FibroScan®; Echosens, Paris, France). Liver cell necroinflammatory activity (A) and fibrosis (F) were assessed by METAVIR. Perisinusoidal fibrosis was rated with a 0-3 score. Determinants of TE results were investigated by a linear regression model whereas discordance between TE and LB results was assessed by logistic regression. RESULTS Fibrosis (p<0.0001) and liver cell necroinflammatory activity (p<0.0001) were independently associated with TE results in both HBV and HCV patients, whereas steatosis (p<0.0001) was independently associated with TE in HCV only. Fibrosis overestimation was predicted by severe/moderate necroinflammatory activity in HBV and by older age (41-60 or>60years vs.<40), >2 UNL AST and>2 UNL GGT, as well as severe/moderate necroinflammatory activity and severe/moderate steatosis in HCV. In the latter patients, however, moderate/severe necroinflammatory activity and steatosis were the only independent predictors of fibrosis overestimation. CONCLUSIONS Fibrosis and necroinflammatory activity are the main determinants of TE in chronic viral hepatitis. Since TE staging of fibrosis is influenced by necroinflammatory activity and steatosis, a diagnostic LB is deemed necessary for a reliable intra-patient TE monitoring of the course of viral hepatitis.

Combined vitamin C and E supplementation during pregnancy for preeclampsia prevention: a systematic review.

The effect of combined vitamin C and E supplementation during pregnancy on the prevention of preeclampsia and major adverse infant outcomes has been reviewed. We searched MEDLINE and the Central Library of Controlled Trials of the Cochrane Library through August 2006 for relevant clinical trials. Interstudy heterogeneity was evaluated using the &khgr;2 statistic (Q statistic) test. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with a fixed or random-effects model as appropriate. Four trials that collectively randomized 4680 pregnant women to either the combination of vitamin C and vitamin E or placebo were included in the analysis. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia, 11% versus 11.4%, RR 0.97 (95% CI 0.82–1.13), fetal or neonatal loss, 2.6% versus 2.3%, RR 1.10 (95% CI 0.78–1.57), or small for gestational age (SGA) infant, 20.6% versus 20%, RR 0.94 (95% CI 0.74–1.19). Although there was a higher risk for preterm birth in the vitamin group, 19.5% versus 18%, RR 1.07 (95% CI 0.96–1.20), this finding was not significant. Combined vitamin C and E supplementation during pregnancy does not reduce the risk of preeclampsia, fetal or neonatal loss, small for gestational age infant, or preterm birth. Such supplementation should be discouraged unless solid supporting data from randomized trials become available. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall that many methods have been used to prevent preeclampsia, state that increased oxidative stress has been postulated and many trials have used antioxidants to prevent the disease, and explain that MEDLINE analysis of the literature questions the use of vitamin C and E supplements.

Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial.

OBJECTIVES:Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Probiotics were effective in preventing AAD and CDAD in several randomized controlled trials. This study was aimed at testing the effect of Saccharomyces boulardii on the occurrence of AAD and CDAD in hospitalized patients.METHODS:A single-center, randomized, double-blind, placebo-controlled, parallel-group trial was performed. Patients being prescribed antibiotics or on antibiotic therapy for <48 h were eligible. Exclusion criteria were ongoing diarrhea, recent assumption of probiotics, lack of informed consent, inability to ingest capsules, and severe pancreatitis. Patients received a capsule containing S. boulardii or an indistinguishable placebo twice daily within 48 h of beginning antibiotic therapy, continued treatment for 7 days after antibiotic withdrawal, and were followed for 12 weeks after ending antibiotic treatment.RESULTS:Of 562 consecutive eligible patients, 275 patients aged 79.2±9.8 years (134 on placebo) were randomized and 204 aged 78.4±10.0 years (98 on placebo) completed the follow-up. AAD developed in 13.3% (13/98) of the patients receiving placebo and in 15.1% (16/106) of those receiving S. boulardii (odds ratio for S. boulardii vs. placebo, 1.16; 95% confidence interval (CI), 0.53–2.56). Five cases of CDAD occurred, 2 in the placebo group (2.0%) and 3 in the probiotic group (2.8%; odds ratio for S. boulardii vs. placebo, 1.40; 95% CI, 0.23–8.55). There was no difference in mortality rates (12.7% vs. 15.6%, P=0.60).CONCLUSIONS:In elderly hospitalized patients, S. boulardii was not effective in preventing the development of AAD.

Partial breast irradiation or whole breast radiotherapy for early breast cancer: a meta-analysis of randomized controlled trials.

Abstract:  The purpose of the study was to compare treatment outcomes in patients with breast cancer treated with partial breast irradiation (PBI) and of those treated with whole breast‐radiation therapy (WBRT). We conducted a systematic review and meta‐analysis of published randomized clinical trials comparing PBI versus WBRT. Primary outcome was overall survival and secondary outcomes were locally, axillary, supraclavicular, and distant recurrences. A search of the literature identified three trials with pooled total of 1,140 patients. We found no statistically significant difference between partial and whole breast radiation arms associated with death (OR 0.912, 95% CI 0.674–1.234, p = 0.550), distant metastasis (OR 0.740, 95% CI, 0.506–1.082, p = 0.120), or supraclavicular recurrences (pooled OR 1.415, 95% CI 0.278–7.202, p = 0.560). However, PBI was statistically significantly associated with an increased risk of both local (pooled OR 2.150, 95% CI, 1.396–3.312; p = 0.001) and axillary recurrences (pooled OR 3.430, 95% CI, 2.058–5.715; p < 0.0001) compared with whole breast‐radiation. Partial breast irradiation does not seem to jeopardize survival and may be used as an alternative to whole breast‐radiation. Nevertheless the issue of loco‐regional recurrence needs to be further addressed.

Syncope risk stratification tools vs clinical judgment: An individual patient data meta-analysis

BACKGROUND There have been several attempts to derive syncope prediction tools to guide clinician decision-making. However, they have not been largely adopted, possibly because of their lack of sensitivity and specificity. We sought to externally validate the existing tools and to compare them with clinical judgment, using an individual patient data meta-analysis approach. METHODS Electronic databases, bibliographies, and experts in the field were screened to find all prospective studies enrolling consecutive subjects presenting with syncope to the emergency department. Prediction tools and clinical judgment were applied to all patients in each dataset. Serious outcomes and death were considered separately during emergency department stay and at 10 and 30 days after presenting syncope. Pooled sensitivities, specificities, likelihood ratios, and diagnostic odds ratios, with 95% confidence intervals, were calculated. RESULTS Thirteen potentially relevant papers were retrieved (11 authors). Six authors agreed to share individual patient data. In total, 3681 patients were included. Three prediction tools (Osservatorio Epidemiologico sulla Sincope del Lazio [OESIL], San Francisco Syncope Rule [SFSR], Evaluation of Guidelines in Syncope Study [EGSYS]) could be assessed by the available datasets. None of the evaluated prediction tools performed better than clinical judgment in identifying serious outcomes during emergency department stay, and at 10 and 30 days after syncope. CONCLUSIONS Despite the use of an individual patient data approach to reduce heterogeneity among studies, a large variability was still present. Current prediction tools did not show better sensitivity, specificity, or prognostic yield compared with clinical judgment in predicting short-term serious outcome after syncope. Our systematic review strengthens the evidence that current prediction tools should not be strictly used in clinical practice.