Contribution of the ELFG Test in Algorithms of Non-Invasive Markers towards the Diagnosis of Significant Fibrosis in Chronic Hepatitis C

Background and Aims

We aimed to determine the best algorithms for the diagnosis of significant fibrosis in chronic hepatitis C (CHC) patients using all available parameters and tests.

Patients and Methods

We used the database from our study of 507 patients with histologically proven CHC in which fibrosis was evaluated by liver biopsy (Metavir) and tests: Fibrometer®, Fibrotest®, Hepascore®, Apri, ELFG, MP3, Forn''s, hyaluronic acid, tissue inhibitor of metalloproteinase-1 (TIMP1), MMP1, collagen IV and when possible Fibroscan™. For the first test we used 90% negative predictive value to exclude patients with F≤1, next an induction algorithm was applied giving the best tests with at least 80% positive predictive value for the diagnosis of F≥2. The algorithms were computed using the R Software C4.5 program to select the best tests and cut-offs. The algorithm was automatically induced without premises on the part of the investigators. We also examined the inter-observer variations after independent review of liver biopsies by two pathologists. A medico-economic analysis compared the screening strategies with liver biopsy.

Results

In “intention to diagnose” the best algorithms for F≥2 were Fibrometer ®, Fibrotest®, or Hepascore® in first intention with the ELFG score in second intention for indeterminate cases. The percentage of avoided biopsies varied between 50% (Fibrotest® or Fibrometer®+ELFG) and 51% (Hepascore®+ELFG). In “per-analysis” Fibroscan™+ELFG avoided liver biopsy in 55% of cases. The diagnostic performance of these screening strategies was statistically superior to the usual combinations (Fibrometer® or Fibrotest®+Fibroscan™) and was cost effective. We note that the consensual review of liver biopsies between the two pathologists was mainly in favor of F1 (64–69%).

Conclusion

The ELFG test could replace Fibroscan in most currently used algorithms for the diagnosis of significant fibrosis including for those patients for whom Fibroscan™ is unusable.     

Significant Fibrosis Is Not Rare in Chinese Chronic Hepatitis B Patients with Persistent Normal ALT

Background

Limited studies have been done on chronic hepatitis B (CHB) patients defined according to the latest Asian-Pacific Association for the Study of the Liver guideline with liver histology by a large sample size.

Methods

We retrospectively evaluated liver histological characteristics on a cohort of consecutive treatment-naive CHB patients with persistent normal alanine aminotransferase (PNALT) or elevated ALT from May 2005 to October 2011. Histological assessment was based on the Metavir scoring system, significant abnormality was defined as necroinflammation grade ≥A2 and/or fibrosis stage ≥F2.

Results

A total of 675 CHB patients were recruited, including 516 HBeAg-positive and 159 HBeAg-negative patients. In HBeAg-positive patients, significant fibrosis was found 49.4% (42/85) in PNALT, 69.8% (88/126) in ALT 1-2×upper limit normal (ULN) and 81.6% (249/305) in ALT>2×ULN group, respectively. In HBeAg-negative patients, significant fibrosis was found 30.9% (17/55) in PNALT, 73.3% (33/45) in ALT 1-2×ULN and 94.9% (56/59) in ALT>2×ULN group, respectively. HBeAg-positive patients with PNALT over 30 years old had a higher frequency of significant fibrosis than those under 30 years old (87.5% vs. 45.5%, P = 0.058). Multivariate logistic regression analysis indicated increasing age (P = 0.012), higher aspartate aminotransferase (AST) (P < 0.001) and lower HBV DNA (P < 0.001) were associated with significant necroinflammation, while higher AST (P < 0.001), lower albumin (P = 0.027) and HBV DNA (P = 0.004) were associated with significant fibrosis in HBeAg-positive patients with elevated ALT. Higher AST was associated with significant necroinflammation in HBeAg-negative patients with elevated ALT (P = 0.009).

Conclusions

Significant fibrosis is not rare in Chinese CHB patients with PNALT, especially HBeAg-positive patients over 30 years old.     

Head-to-Head Comparison between Collagen Proportionate Area and Acoustic Radiation Force Impulse Elastography in Liver Fibrosis Quantification in Chronic Hepatitis C

BackgroundThe aim of this study was to compare the diagnostic performances of the collagen proportionate area (CPA) and liver stiffness measurement (LSM) for liver fibrosis quantification in chronic hepatitis C (CHC).MethodsA total of 137 eligible consecutive Taiwanese patients (74 women and 63 men; age 21–80 years; median age 54 years), with CHC underwent LSM by using acoustic radiation force impulse (ARFI) elastography and an immediate percutaneous liver biopsy for METAVIR scoring. Liver tissue sections were stained using picrosirius red. Areas of the stained collagen and the tissue parenchyma were calculated in pixels. The ratio between the two areas was expressed as a CPA percentage. The result of LSM was presented as shear wave velocity (SWV).ResultsMETAVIR fibrosis (F) stages were dichotomized using the CPA (%) and SWV (m/s), and the optimal cut-off values were 7.47 and 1.59 for F1 versus F2–4; 12.56 and 1.73 for F1, 2 versus F3, 4; 15.32 and 1.96 for F1–3 versus F4. To dichotomize F1 versus F2–4, the areas under receiver operating characteristic curves for the CPA was 0.9349 (95% confidence interval: 0.8943–0.9755) and for SWV was 0.8434 (0.7762–0.9105) (CPA versus SWV, P = 0.0063). For F1, 2 versus F3, 4, the CPA was 0.9436 (0.9091–0.9781); SWV was 0.8997 (0.8444–0.9551) (P = 0.1587). For F1–3 versus F4, the CPA was 0.8647 (0.7944–0.9349); SWV was 0.9036 (0.8499–0.9573) (P = 0.2585). The CPA could be predicted in a linear regression formula by using SWV and platelet count (R² = 0.524).ConclusionsThe CPA and ARFI elastography are promising tools for liver fibrosis evaluation. The CPA was superior to ARFI elastography in the diagnosis of significant fibrosis (≥ F2). The CPA may be independent of severe necroinflammation, which may augment liver stiffness.     

慢性丙型肝炎患者中丙型肝炎病毒准种变异研究进展

丙型肝炎病毒（HCV）具有较高的变异性,通常以准种的形式分布在感染者的体内,病毒容易逃离机体的免疫监控,因而无法被有效地清除,导致机体很难控制其感染的发展,故易转变成慢性肝炎。HCV准种变异在宿主体内的持续存在对病毒感染的控制、抗病毒药物和疫苗的发展都是一个巨大的挑战。,我们重点阐述近年来关于HCV准种变异及其与慢性丙型肝炎患者的机体免疫、疾病进展、治疗效果之间关系的研究进展。     

MicroRNAs as Predictor Markers for Response to Interferon Treatment of Chronic Hepatitis C Genotype-4 in Egyptian Patients

Background

Hepatitis C virus genotype 4 (HCV-4) infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection. The aim of the present study was to assess serum miR-122, miR-221 and miR-21 expression profiles in HCV-4 patients prior to treatment with HCV-4 combination therapy (pegylated alpha interferon and ribavirin) and to determine whether the miRNAs were associated with the drug response.

Methods

RNA was extracted from pretreatment serum samples, and miR-122, miR-221 and miR-21 levels were measured by quantitative PCR. The results were compared among patients with sustained virological responses (SVR) and non-responders (NR).

Results

The expression levels of miR-21 and miR-122 were significantly different between the SVR and NR groups. Receiver operator characteristic (ROC) analysis revealed that the sensitivity, specificity and positive predictive values of miR-21 were 82.2%, 77.3% and 88.1%, respectively, with a cut-off value of 1.7. The sensitivity, specificity and positive predictive values of miR-122 were 68.9%, 59.1% and 77.5%, respectively, with a cut-off value of 3.5.

Conclusion and Significance

miR-21 and miR-122 might be useful predictors for SVR in HCV-4 patients prior to the administration of combination therapy. A higher predictive response power was obtained for miR-21 than for miR-122. These results should reduce ineffective treatments.     

瞬时弹性成像对慢性乙肝肝纤维化诊断的研究

目的:探讨瞬时弹性成像(FibroScan)诊断慢性乙型肝炎肝纤维化的准确性。方法:选取慢性乙型肝炎患者289例,其中未做病理组198例,病理组91例,正常对照50例,病理组患者行病理肝纤维化检测,未做病理组患者检查B超,全部患者及正常对照应用FibroScan进行肝脏硬度检测(liver stiffness measurement,LSM)值测量。分析未做病理组慢乙肝组与正常对照组间及未做病理组慢乙肝组B超肝纤维化各级间LSM值的差异;病理慢乙肝组采用受试者工作特征(Receiver Operating haracteristic,ROC)曲线分析FibroScan诊断肝纤维化的准确性,并得出各期诊断界值;根据该诊断界值对未做病理慢乙肝组进行FibroScan肝纤维化分期,分析其与B超肝纤维化分级的一致性。结果:LSM值在未做病理慢乙肝组和正常对照组间及B超肝纤维化各级间差别显著(P0.05);其中病理组统计结果显示F1、F2、F3、F4期肝纤维化的ROC曲线下面积(Area under Receiver Operating Characteristic,AUROC)分别为0.726、0.847、0.806、0.864,诊断界值分别为6.5、7.4、10.1、17.0 kPa,敏感性分别为69.62%、68.33%、66.67%、72.22%,特异性分别为66.67%、87.10%、85.71%、91.78%;肝纤维化的FibroScan分期和B超分级具有一致性(Kappa值=0.366,P0.05)。结论:FibroScan对慢性乙型肝炎肝纤维化尤其是严重肝纤维化及肝硬化诊断准确性高,具有良好的临床应用价值。     

Enhanced HBsAg Synthesis Correlates with Increased Severity of Fibrosis in Chronic Hepatitis B Patients

Background and Aims

Little is known about whether low serum HBsAg levels result from impaired HBsAg synthesis or a reduced number of hepatocytes caused by advanced liver fibrosis. Therefore, we investigated the capacity for HBsAg synthesis in a cross-sectional cohort of treatment-naïve chronic hepatitis B patients.

Methods

Chronic hepatitis B patients (n = 362) were enrolled; liver biopsies were performed and liver histology was scored, and serum HBsAg and HBV DNA levels were investigated. In the enrolled patients, 183 out of 362 have quantitative serum HBsAg levels. Tissue HBsAg was determined by immunohistochemistry.

Results

A positive correlation between serum HBsAg and HBV DNA levels was revealed in HBeAg(+) patients (r = 0.2613, p = 0.0050). In HBeAg(+) patients, serum HBsAg and severity of fibrosis were inversely correlated (p = 0.0094), whereas tissue HBsAg levels correlated positively with the stage of fibrosis (p = 0.0280). After applying the mean aminopyrine breath test as a correction factor, adjusted serum HBsAg showed a strong positive correlation with fibrosis severity in HBeAg(+) patients (r = 0.5655, p<0.0001). The adjusted serum HBsAg values predicted ‘moderate to severe’ fibrosis with nearly perfect performance in both HBeAg(+) patients (area under the curve: 0.994, 95% CI: 0.983–1.000) and HBeAg(−) patients (area under the curve: 1.000, 95% CI: 1.000–1.000).

Conclusions

Although serum HBsAg levels were negatively correlated with fibrosis severity in HBeAg(+) patients, aminopyrine breath test-adjusted serum HBsAg and tissue HBsAg, two indices that are unaffected by the number of residual hepatocytes, were positively correlated with fibrosis severity. Furthermore, adjusted serum HBsAg has an accurate prediction capability.     

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease

In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.     

Duodenal Ferroportin Is Up-Regulated in Patients with Chronic Hepatitis C

Hepatitis C virus (HCV) infection is a leading cause of liver-related mortality. Chronic hepatitis C (CHC) is frequently associated with disturbances in iron homeostasis, with serum iron and hepatic iron stores being elevated. Accumulating evidence indicates that chronic HCV infection suppresses expression of hepatic hepcidin, a key mediator of iron homeostasis, leading to iron overload conditions. Since hepcidin mediates degradation of ferroportin, a basolateral transporter involved in the release of iron from cells, diminished hepcidin expression probably leads to up-regulation of ferroportin-1 (Fpn1) in patients with CHC. In this study, we determined the protein levels of duodenal Fpn1, and found that its expression was significantly up-regulated in patients with CHC. The expression of duodenal Fpn1 is negatively correlated with mRNA levels of hepcidin, and positively correlated with serum iron parameters. Although iron is a critical factor for growth of a variety of pathogenic bacteria, our results suggest that iron overload in blood does not increase the infection rate of bacteria in patients with CHC.     

超声导入疗法治疗慢性乙型肝炎肝纤维化临床研究

目的：探讨超声导入疗法对乙型肝炎肝纤维化患者进行治疗的临床效果。方法：选择符合诊断标准的慢性乙型肝炎肝纤维化患者52例,随机分为试验组和对照组,各26例。对照组患者给予基本保肝治疗,试验组在对照组的基础上加用黄芪注射液进行超声导入,3个月为1个疗程。观察两组患者治疗前后症状、体征、血清肝纤维化指标、肝功能变化及影像学指标。结果：两组患者症状、体征均有不同程度的改善,差异无统计学意义（P〉0．05）;试验组血清肝纤维化指标明显改善,与对照组比较,差异有统计学意义（P〈0．05）;肝功能及影像学指标的改善更明显（P〈0．01）。结论：超声导入疗法对慢性乙型肝炎肝纤维化具有改善肝功能,减少肝细胞外基质的增生与沉积的效用,能够减轻或延缓肝纤维化的进展。     

Age as a Predictor of Significant Fibrosis Features in HBeAg-Negative Chronic Hepatitis B Virus Infection with Persistently Normal Alanine Aminotransferase

Background

Although alanine aminotransferase (ALT) levels reflect the degree of liver damage, not all patients with chronic hepatitis B virus (HBV) infection exhibit persistently elevated ALT levels. In the present study, we aimed to comprehensively evaluate the characteristics of histological abnormalities in a large population of Chinese patients with chronic HBV and persistently normal ALT levels.

Methods

In total, 2303 consecutive patients who underwent liver biopsy were screened. Of these patients, 273 were categorized as having persistently normal ALT levels (PNALT), whereas 618 were categorized as having persistently or intermittently elevated ALT levels (PIALT). All these patients had at least three ALT values recorded in the year prior to the baseline liver biopsy.

Results

Significant necroinflammation was observed in 9.7% (11/113) patients with PNALT, 23.3% (42/180) patients with PIALT (ALT 1–2× upper limit of normal [ULN]), and 27.8% (42/151) patients with PIALT (ALT > 2× ULN), whereas significant fibrosis was observed in 8.8% (10/113) patients with PNALT, 27.8% (42/151) patients with PIALT (ALT 1–2× ULN), and 21.2% (32/151) patients with PIALT (ALT > 2× ULN). Multiple logistic regression analysis indicated that age parameters were associated with significant histological abnormalities in patients with PNALT. The area under the curve showed that age was associated with significant fibrosis characteristics in patients with hepatitis B extracellular antigen (HBeAg)-negative PNALT.

Conclusion

Significant histological abnormalities are not often observed in Chinese patients with PNALT. Interestingly, age appears to be a predictor of significant fibrosis in patients with HBeAg-negative PNALT.     

Evaluation of Fucosylated Haptoglobin and Mac-2 Binding Protein as Serum Biomarkers to Estimate Liver Fibrosis in Patients with Chronic Hepatitis C

Fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac-2 bp) are identified as cancer biomarkers, based on the results from a glyco-proteomic analysis. Recently, we reported that these glyco-biomarkers were associated with liver fibrosis and/or ballooning hepatocytes in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the ability of these glycoproteins to estimate liver fibrosis in 317 patients with chronic hepatitis C. We measured the serum Fuc-Hpt and Mac-2 bp levels using a lectin-antibody ELISA and ELISA, respectively. The serum levels of both Fuc-Hpt and Mac-2 bp increased with the progression of liver fibrosis. The multivariate analysis revealed that Mac-2 bp was an independent factor associated with moderate liver fibrosis (F ≥ 2). In contrast, Fuc-Hpt was an independent factor associated with advanced liver fibrosis (F ≥ 3). In terms of evaluating liver fibrosis, the serum levels of these glycomarkers were correlated with well-known liver fibrosis indexes, such as the aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB4) index. An assay that combined the APRI or FIB4 index and the Fuc-Hpt or Mac-2 bp levels increased the AUC value for diagnosing hepatic fibrosis. Interestingly, the cumulative incidence of hepatocellular carcinoma (HCC) was significantly higher in the patients with elevated serum levels of Fuc-Hpt and Mac-2 bp. In conclusion, both Fuc-Hpt and Mac-2 bp could be useful glyco-biomarkers of liver fibrosis and predictors of HCC in patients with chronic hepatitis C.     

Longitudinal Evaluation of the Structure of Replicating and Circulating Hepatitis C Virus Quasispecies in Nonprogressive Chronic Hepatitis C Patients

In previous cross-sectional studies, we demonstrated that, in most patients with chronic hepatitis C, the composition and complexity of the circulating hepatitis C virus (HCV) population do not coincide with those of the virus replicating in the liver. In the subgroup of patients with similar complexities in both compartments, the ratio of quasispecies complexity in the liver to that in serum (liver/serum complexity ratio) of paired samples correlated with disease stage. In the present study we investigated the dynamic behavior of viral population parameters in consecutive paired liver and serum samples, obtained 3 to 6 years apart, from four chronic hepatitis C patients with persistently normal transaminases and stable liver histology. We sequenced 359 clones of a genomic fragment encompassing the E2(p7)-NS2 junction, in two consecutive liver-serum sample pairs from the four patients and in four intermediate serum samples from one of the patients. The results show that the liver/serum complexity ratio is not stable but rather fluctuates widely over time. Hence, the liver/serum complexity ratio does not identify a particular group of patients but a particular state of the infecting quasispecies. Phylogenetic analysis and signature mutation patterns showed that virtually all circulating sequences originated from sequences present in the liver specimens. The overall behavior of the circulating viral quasispecies appears to originate from changes in the relative replication kinetics of the large mutant spectrum present in the infected liver.     

Validation of Ten Noninvasive Diagnostic Models for Prediction of Liver Fibrosis in Patients with Chronic Hepatitis B

Background and Aims

Noninvasive models have been developed for fibrosis assessment in patients with chronic hepatitis B. However, the sensitivity, specificity and diagnostic accuracy in evaluating liver fibrosis of these methods have not been validated and compared in the same group of patients. The aim of this study was to verify the diagnostic performance and reproducibility of ten reported noninvasive models in a large cohort of Asian CHB patients.

Methods

The diagnostic performance of ten noninvasive models (HALF index, FibroScan, S index, Zeng model, Youyi model, Hui model, APAG, APRI, FIB-4 and FibroTest) was assessed against the liver histology by ROC curve analysis in CHB patients. The reproducibility of the ten models were evaluated by recalculating the diagnostic values at the given cut-off values defined by the original studies.

Results

Six models (HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest) had AUROCs higher than 0.70 in predicting any fibrosis stage and 2 of them had best diagnostic performance with AUROCs to predict F≥2, F≥3 and F4 being 0.83, 0.89 and 0.89 for HALF index, 0.82, 0.87 and 0.87 for FibroScan, respectively. Four models (HALF index, FibroScan, Zeng model and Youyi model) showed good diagnostic values at given cut-offs.

Conclusions

HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest show a good diagnostic performance and all of them, except S index and FibroTest, have good reproducibility for evaluating liver fibrosis in CHB patients.

Registration Number

ChiCTR-DCS-07000039.     

Angiopoietin-2 Serum Levels Improve Noninvasive Fibrosis Staging in Chronic Hepatitis C: A Fibrogenic-Angiogenic Link

Aims

Accurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis.

Methods

Serum levels of angiopoietin-1 and -2 were measured by ELISA in 108 CHC patients who underwent pretreatment liver biopsy. The correlation between angiopoietins and clinical and demographic variables with liver fibrosis was analyzed by univariate regression. Significant factors were then subjected to multivariate analysis, from which we constructed a novel noninvasive liver fibrosis index (AngioScore), whose performance was validated in an independent series of 71 CHC patients. The accuracy of this model was compared with other documented fibrosis algorithms by De Long test.

Results

Angiopoietins correlated significantly with hepatic fibrosis; however, only angiopoietin-2 was retained in the final model, which also included age, platelets, AST, INR, and GGT. The model was validated and behaved considerably better than other fibrosis indices in discriminating all, significant, moderate and severe liver fibrosis (0.886, 0.920, 0.923). Using clinically relevant cutoffs, we classified CHC patients by discarding significant fibrosis and diagnosing moderate and severe fibrosis with greater accuracy, sensitivity, and specificity.

Conclusions

Our novel noninvasive liver fibrosis model, based on serum angiopoietin-2 levels, outperforms other indices and should help substantially in managing CHC and monitoring long-term follow-up prognosis.     

Identifying Adult Dengue Patients at Low Risk for Clinically Significant Bleeding

Background

Clinically significant bleeding is important for subsequent optimal case management in dengue patients, but most studies have focused on dengue severity as an outcome. Our study objective was to identify differences in admission parameters between patients who developed clinically significant bleeding and those that did not. We sought to develop a model for discriminating between these patients.

Methods

We conducted a retrospective study of 4,383 adults aged >18 years who were hospitalized with dengue infection at Tan Tock Seng Hospital, Singapore from 2005 to 2008. Patients were divided into those with clinically significant bleeding (n = 188), and those without (n = 4,195). Demographic, clinical, and laboratory variables on admission were compared between groups to determine factors associated with clinically significant bleeding during hospitalization.

Results

On admission, female gender (p<0.001); temperature >38°C (p<0.001); nausea/vomiting (p = 0.009) and abdominal pain/tenderness (p = 0.005); lower systolic blood pressure (p<0.001); higher pulse rate (p<0.001); increased absolute neutrophil count (ANC; p<0.001); reduced absolute lymphocyte count (ALC; p<0.001), haematocrit percentage (p<0.001) and platelet count (p = 0.04), and increased prothrombin time (p = 0.003) were significantly associated with clinically significant bleeding on univariate analysis. Multivariate analysis showed that independent variables in the final model were female gender (aOR 2.85; 95% CI: 1.9–4.33); temperature >38°C (aOR 1.81; 95% CI: 1.27–2.61), nausea/vomiting (aOR 1.39; 95% CI: 0.94–2.12), ANC (aOR 1.3; 95% CI: 1.15–1.46), ALC (aOR 0.4; 95% CI: 0.25–0.64), hematocrit percentage (aOR 0.96; 95% CI: 0.92–1.002) and platelet count (aOR 0.993; 95% CI: 0.988–0.998). At the cutoff of -3.919, the model achieved an AUC of 0.758 (sensitivity:0.87, specificity: 0.38, PPV: 0.06, NPV: 0.98).

Conclusion

Clinical risk factors associated with clinically significant bleeding were identified. This model may be useful to complement clinical judgement in triaging adult dengue patients given the dynamic nature of acute dengue, particularly in pre-identifying those less likely to develop clinically significant bleeding.     

Altered Functionality of Anti-Bacterial Antibodies in Patients with Chronic Hepatitis C Virus Infection

Background

Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease.

Methods

The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined.

Results

Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure.

Conclusions

Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.     

Longitudinal Liver Stiffness Assessment in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

Background/Aims

Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC).

Methods

TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC.

Results

323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS ≥ 7.1 kPa (P<0.0001 and P 0.03, for LS ≥9.5 and ≥7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change −16%, −10% and −2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement.

Conclusions

LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage.     

Immune Activation Response in Chronic HIV-Infected Patients: Influence of Hepatitis C Virus Coinfection

Objectives

We have analyzed the parameters (bacterial translocation, immune activation and regulation, presence of HCV coinfection) which could be implicated in an inappropriate immune response from individuals with chronic HIV infection. The influence of them on the evolution of CD4+ T cell count has been investigated.

Patients and methods

Seventy HIV-infected patients [monoinfected by HIV (n = 20), HCV-coinfected (with (n = 25) and without (n = 25) liver cirrhosis)] and 25 healthy controls were included. Median duration of HIV infection was 20 years. HIV- and HCV-related parameters, as well as markers relative to bacterial translocation, monocyte and lymphocyte activation and regulation were considered as independent variables. Dependent variables were the increase of CD4+ T cell count during the follow-up (12 months).

Results

Increased values of bacterial translocation, measured by lipopolysaccharide-binding protein, monocyte and lymphocyte activation markers and T regulatory lymphocytes were detected in HIV-monoinfected and HIV/HCV coinfected patients. Serum sCD14 and IL-6 were increased in HIV/HCV-coinfected patients with liver cirrhosis in comparison with those with chronic hepatitis or HIV-monoinfected individuals. Time with undetectable HIV load was not related with these parameters. The presence of cirrhosis was negatively associated with a CD4+ T cell count increase.

Conclusion

In patients with a chronic HIV infection, a persistent increase of lipopolysaccharide-binding protein and monocyte and lymphocyte modifications are present. HCV-related cirrhosis is associated with more elevated serum concentrations of monocyte-derived markers. Cirrhosis influences the continued immune reconstitution of these patients.