Higher Histological Activity Index Research Articles

#3053 CORRELATION OF SYSTEMIC AND IN SITU BIOMARKERS OF COMPLEMENT ACTIVATION WITH HISTOPATHOLOGICAL FEATURES AND PROGNOSIS IN C3 GLOMERULOPATHY

Abstract Background and Aims C3 glomerulopathy is a rare complement mediated disease, resulting from complement alternative pathway (AP) activation. In addition to AP activation, there are emerging evidence for terminal pathway (TP) implication in kidney damage. A C3G histopathologic index has recently been proposed to evaluate both activity and chronicity parameters. Only a chronicity index > 4 has been independently validated as prognosis factor for end stage kidney disease. We aimed to determine the impact of local activation of the TP on disease phenotype. Method C3G histopathological index grading were evaluated via central review of 53 kidney biopsies from 43 patients carrying C3G. C5b-9 staining was performed on 53 FFPE kidney sections and quantified (scoring from grade 0 to 3 for C5b-9 deposits in glomeruli and from 0 to 2 in the tubulointerstitial compartment). Clinical data, C3 and sC5b-9 levels at the time of KB were retrospectively collected. Results KB were performed at diagnosis for n = 31. In 22 cases, KB was performed during follow up, under specific treatment (n = 10), without treatment (n = 7), or at disease relapse (n = 5). Twenty-five (47%) were children. Median[Q1-Q3] C3 level at KB was 623 mg/l [236-931]mg/l. Median[Q1-Q3] sC5b-9 level at KB, available in 16, was 374 ng/ml [203-1295]. Median [Q1-Q3] activity and chronicity index were respectively 9[6-12] and 1[0-6]. We confirmed the prognostic impact of chronicity index (p = 0.03) (Figure 1A) without impact of the activity index. Glomerular C5b-9 staining was positive in 47/53 (87%) (grade 1: n = 16 (30%); 2: n = 17 (32%); 3: n = 14 (26%)) and n = 40 (75%) had interstitial C5b-9 staining (grade 1: n = 28 (53%); 2: n = 12 (23%)). Soluble C5b-9 measurement correlated with intensity of C5b-9 glomerular deposit (coef corr = 0.69). As compared to patients with normal C3 level, patients with AP activation had higher proteinuria but kidney function at KB was similar. We found distinct histological features according to C3 plasmatic level (Table 1): patients with low C3 level had higher histological activity index (p = 0.03) and higher glomerular and tubulointerstitial C5b-9 staining (p = 0.001 and p = 0.002 respectively). C5b-9 glomeruli staining allows the identification of 3 groups of KB (1: no or low, 2: medium and 3: high C5b-9 staining) with distinct histological and clinical features. Activity index were higher in groups 2 & 3 (p = 0.05) and chronicity index in groups 1 & 3 (p = 0.003) (Table 2). Renal prognosis was poorer in patients with higher glomerular C5b-9 deposits (Figure 1B). Patients with chronicity index >4 and high C5b-9 staining had the poorest renal survival (Figure 1C). Conclusion Our results suggest that TP activation in glomeruli may have an impact on histological features, contributing therefore to renal prognosis. Deeper exploration of correlation between systemic and in situ complement activation and histological features could allow to better identify patients with worst prognosis or who could benefit from emerging complement inhibition therapeutics.

Clinical characteristics and long-term outcomes in patients with mixed Class III/IV + V and pure proliferative lupus nephritis: A single-center experience

Proliferative lupus nephritis (LN) is a crucial complication in systemic lupus erythematosus (SLE). This study evaluated the clinical implications of coexistence of membranous LN in proliferative LN in terms of clinical characteristics and long-term outcome. We retrospectively reviewed the medical records of patients with SLE who underwent renal biopsy between 2005 and 2018. Patients with proliferative LN based on the 2003 International Society of Nephrology/Renal Pathology Society classification were subclassified into pure (Class III or IV only) and mixed (Class III or IV + Class V) proliferative LN. The clinical features at the time of renal biopsy, incidence of end-stage renal disease (ESRD), and all-cause mortality were compared between patients with mixed or pure proliferative LN. Of the 171 patients, 30 and 141 were classified into mixed and pure proliferative LN groups, respectively. Patients with pure proliferative LN showed higher anti-dsDNA antibody and lower hemoglobin, platelet, and complement 3 levels than patients with mixed proliferative LN. The SLE disease activity index was also higher in patients with pure proliferative LN (p = 0.047). The pure proliferative LN group showed a higher proportion of Class IV and higher histologic activity index scores (p < 0.001 and p = 0.004, respectively). During the follow-up period of 58.3months, 18 patients developed ESRD and 15 patients died. ESRD was exclusively observed in patients with pure proliferative LN, although the incidence of ESRD was not statistically different (p = 0.055). All-cause mortality was comparable between the two groups. Pure proliferative LN was associated with higher clinical and histological activities and modestly increased risk of ESRD. Active immunosuppressive treatment would be required to control the renal inflammation in patients with proliferative LN, regardless of the coexistence of membranous LN.

Adipokines, insulin resistance, hepatic steatosis, and necroinflammation in patients with chronic viral hepatitis

Abstract Background: Hypoadiponectinemia and hyperleptinemia, and reductions in the ratio of adiponectin to leptin (A/L ratio) are associated with the development of hepatic necroinflammation in nonalcoholic fatty liver, but the association of the adipokines with hepatic steatosis in chronic viral hepatitis is unclear. Objective: To investigate the relationship between serum A/L ratio, insulin resistance, degree of hepatic steatosis, and necroinflammation in patients with chronic viral hepatitis. Methods: We measured serum adiponectin, leptin, and resistin levels, insulin resistance, and analyzed the association between liver histopathology and the level of the adipokines in 44 patients with chronic viral hepatitis before they started treatment. Results: We found that insulin resistance, leptin, and resistin levels tended to increase in the group with a greater degree of hepatic steatosis and necroinflammation, but that the increase was not significant. The adiponectin/leptin ratio (A/L ratio) in a group with a low degree of hepatic steatosis was significantly higher than it was in the group with a high degree of hepatic steatosis (3.1 ± 3.1 vs 1.2 ± 0.8; P = 0.008). The A/L ratio in a group with low histological activity index (HAI) scores was significantly higher than in the group with high HAI scores (3.7 ± 3.4 vs 1.1 ± 1.1; P = 0.006). Abdominal obesity was the only variable that showed a significant association with the HAI score (P = 0.03). Conclusion: The serum A/L ratio in patients with chronic viral hepatitis showed a significant inverse association with their degree of hepatic steatosis and necroinflammation.

Lamivudine therapy in HBeAg negative chronic hepatitis B patients

Background: Lamivudine therapy in chronic hepatitis B (CHB) treatment is not encouraged because of its lower resistance barrier. In this study, we aimed to investigate the long-term efficacy of lamivudine treatment in HBeAg negative CHB patients. Methods & Materials: This retrospective study is conducted in three different tertiary care hospitals. Virological response (VR) is defined as undetectable HBV DNA by a sensitive PCR assay during therapy. Partial virological response (PVR) is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients. Virological breakthrough also called as relapse is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the lowest value of HBV DNA level on therapy. Results: A total of 145 patients (57,9% male) were evaluated. Theirmean agewas 44,6 years and 23 (15,9%) of themwere treated with interferons previously. The median value of the ISHAK histological activity index (HAI) and fibrosis were 6 (range: 2-16) and 1 (range: 1-5). Themeanvalue of ALT, AST, andHBVDNAwere57U/L, 42 U/L and 1.189.806 IU/mL, respectively. Treatment of fifty-three (36,6%) patientswas switched tomore potent drugs due to PVR (29; 20%) or relapse (24; 16,6%). Relapse was observed between 13 and 36 months in majority of relapsers (12 cases in 13 to 24 months and 8 cases in 25 to 36months). VRwas observed in 92 (63,4%) and their median time on lamivudine therapy was 34,5 months (range: 6-78 months). Baseline characteristics of virologic responders and switched group were shown in Table 1. Conclusion: Our results showed that more than 60% patients maintain viral suppression more than thirty months. Lamivudine can still be a reliable drug especially in low-income countries because of its low cost. However, lamivudine should be used with more caution in patients who have low thrombocyte and high HAI, fibrosis, ALT, and AST levels.

Impact of Intrahepatic Hepatitis B DNA and Covalently Closed Circular DNA on Survival After Hepatectomy in HBV-Associated Hepatocellular Carcinoma Patients

Chronic hepatitis B virus (HBV) infection induces persistent but ineffective immune activation that contributes to necroinflammation, fibrosis, and risk of hepatocellular carcinoma (HCC). This study aims to determine the relationship of intrahepatic total HBV (ih HBV) DNA and covalently closed circular DNA (cccDNA) with necroinflammation and fibrosis, and their impact on prognosis after resection in HBV HCC patients. Data are from 111 patients treated with primary liver resection for HBV HCC at Mount Sinai, New York (1991-2008). ih HBV DNA and cccDNA were quantitated by real-time PCR. Necroinflammation was graded according to histologic activity index (HAI), and liver fibrosis was staged by the modified Ishak method. A total of 106 (95%) and 89 patients (80%) had detectable ih HBV DNA and cccDNA, respectively, while 43% had detectable serum HBV DNA. cccDNA made up a small proportion of ih HBV DNA (median cccDNA/ih HBV DNA ratio = 0.022). Higher levels of ih HBV DNA were associated with higher HAI and serum alanine aminotransferase (ALT), while a lower ratio of cccDNA/ih HBV DNA was associated with higher HAI, ALT, and Ishak fibrosis stage. ih HBV and cccDNA were not associated with survival, but the lowest quintile of cccDNA/ih HBV DNA ratio (<0.0024) was independently associated with poor overall survival. A lower cccDNA/ih HBV DNA ratio was associated with greater necroinflammation and liver fibrosis, and was independently associated with poor overall survival. Thus, intracellular virus loads and relative proportions of virus DNA reflect histologic damage in the liver and influence the clinical outcome of HBV HCC patients.

Association Between a Polymorphism in Cannabinoid Receptor 2 and Severe Necroinflammation in Patients With Chronic Hepatitis C

The cannabinoid receptor 2 (CB2) has been implicated in liver disease. The single-nucleotide polymorphism rs35761398 in cannabinoid receptor 2 gene (CNR2), which encodes the CB2, substitutes glutamine (Q) 63 with arginine (R), and reduces the function of the gene product. We investigated the effects of CNR2 rs35761398 in patients with hepatitis C virus (HCV) infection. We studied 169 consecutive patients with asymptomatic chronic hepatitis (tested positive for anti-HCV and HCV RNA) at 2 liver units in southern Italy. First, liver biopsy samples were collected from July 2009 through December 2011. All patients were naive to antiviral therapy; CNR2 genotype was determined by polymerase chain reaction analysis. Patients with the CB2-63 QQ variant had higher serum levels of aminotransferase than those with the CB2-63 QR or RR variants; they also had higher histologic activity index (HAI) scores (8.6 ± 3.8) than patients without the CB2-63 RR variant (5.3 ± 3.6; P < .005) or those with the CB2-63 QR variant (5.8 ± 3.3; P < .001). Patients with the different variants of CNR2 did not differ in fibrosis stage or steatosis score. Moderate or severe chronic hepatitis (HAI score, >8) was identified more frequently (55.5%) in patients with the CB2-63 QQ variant than in those with the 63 QR (20%; P < .005) or RR variants (17.4%; P < .005). In logistic regression analysis, the CB2-63 QQ variant and fibrosis score were independent predictors of moderate or severe chronic hepatitis (HAI score, >8; P < .0001). The CB2-63 QQ variant of CNR2 is associated with more severe inflammation and hepatocellular necrosis in patients with HCV infection.

Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: A pilot study

The aim of the study was to evaluate early metabolic perfusion, and microstructural cerebral changes in patients with the hepatitis C virus (HCV) infection and normal appearing brain on plain MR using advanced MR techniques, as well as to assess correlations of MR measurements with the liver histology activity index (HAI). Fifteen HCV-positive patients and 18 control subjects underwent single voxel MR spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI), using a 1.5T MR unit. MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr) were calculated. PWI values of relative cerebral blood volume (rCBV) were assessed from 8 areas including several cortical locations, basal ganglia, and fronto-parietal white matter. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. Compared to controls, HCV-positive patients showed significantly (p < 0.05) lower NAA/Cr ratios within frontal and parietal white matters, lower rCBV values within frontal and temporo-parietal cortices, decreased FA values, as well as increased ADC values in several white matter tracts. We also found elevated rCBV values in basal ganglia regions. The increase in mI/Cr and Cho/Cr ratio was correlated with a higher HAI score. The results of advanced MR techniques indicate neurotoxicity of HCV reflected by neuronal impairment within white matter, cortical hypoperfusion, and disintegrity within several white matter tracts. Hyperperfusion in basal ganglia may be an indicator of brain inflammation in HCV patients. Our findings may suggest a biologic link between HCV-related liver disease and cerebral dysfunction.

Genetic polymorphisms of CYP2E1 and DNA repair genes HOGG1 and XRCC1: Association with hepatitis B related advanced liver disease and cancer

A population based case–control study was designed to explore the genetic risk factors for hepatitis B virus (HBV) related liver disease susceptibility. A total of 424 subjects comprising 210 controls, 50 acute HBV (AVH), 84 chronic HBV (CHBV), 25 HBV related cirrhosis and 55 HBV related hepatocellular carcinoma (HCC) cases were included in the study. PCR-RFLP was used for the genotyping of Cyp2E1*5B, hOGG1 codon 326 and XRCC1 codon 399. Compared to controls, Cyp2E1 rsaI variant c2 genotype increased the risk of HBV related liver disease severity by 2.68 fold, the highest for HCC cases (3.981 folds, p=0.106); and was associated with higher histology activity index (HAI) (p<0.001) in CHBV patients. Cyp2E1 and hOGG1 variants were independently associated with a significantly higher fibrosis score in CHBV group. Analysis of gene–gene interaction studies showed an increased risk of HCC, cirrhosis and CHBV in a Cyp2E1 variant+XRCC1 variant combination (p<0.001); and hOGG1 variants+XRCC1 variants. A mutually independent heterozygous hOGG1 and XRCC1 combination resulted in a decreased risk of HBV related liver disease. On the other hand, a wild-type hOGG1 and XRCC1 combination was associated with a significantly higher risk of AVH (p=0.010) but a lower risk of CHBV (p=0.032) and HCC (p=0.006). The gene–gene interactions were also associated with a significant increase in HAI and fibrosis score in CHBV patients. Cyp2E1, hOGG1 and XRCC1 genotypes significantly alter the risk of HBV related liver disease susceptibility and severity, independently or through gene–gene interaction.

The correlation between T helper type 17 cells and clinical characters in Chinese paediatric patients with chronic hepatitis B

Interleukin (IL)-17-mediated immune response has been shown to play a critical role in inflammation-associated disease. However, its role in the pathogenesis of chronic hepatitis B virus (HBV) in paediatric patients remains unknown. We investigated the frequency of T helper type 17 (Th17) cells and evaluated the association between the Th17 and clinical characters in paediatric patients with chronic hepatitis B (CHB). The frequency of Th17 cells was detected by flow cytometry analyses from 65 paediatric patients with CHB and nine healthy controls. The degree of hepatic inflammation was graded using the histological activity index (HAI). Compared with healthy controls, the frequency of Th17 cells in peripheral blood was significantly higher in paediatric patients with CHB. The proportion of Th17 cells was higher in the patients with higher HAI score (G2-G3) compared to those subjects with lower HAI score (G0-G1), but the frequency of Th17 cells had no correlation with serum HBV DNA loads or alanine aminotransferase levels. Compared with the younger age group (age 1-6 years), Th17 cell frequency was higher in the older age group (age 7-18 years). Peripheral Th17 cell frequency is associated closely with inflammation activity of liver tissues in paediatric patients with CHB.

Serum microRNA-125a-5p, a useful biomarker in liver diseases, correlates with disease progression.

It has been demonstrated that liver microRNA-125a-5p (miR-125a-5p) is correlated with disease progression in different liver diseases, including liver fibrosis and hepatocellular carcinoma (HCC). The present study investigated whether serum miR-125a-5p correlated with the progression of different liver diseases. Serum samples were obtained from healthy individuals, patients with chronic hepatitis B who had undergone a liver biopsy, and patients with HCC and were analyzed for the levels of miR-125a-5p. Compared with the healthy controls, the serum levels of miR-125a-5p were significantly higher in the liver fibrosis serum, and were reduced in HCC. With the development of liver fibrosis, there was a significant increase in the expression of miR-125a-5p (P<0.05). In comparing histological activity index (HAI) scores, higher expression levels of miR125a-5p were observed in the high HAI score group (P<0.05). Furthermore, correlation between serum miR-125a-5p and viral replication (P<0.001) was observed. Notably, miR-125a-5p demonstrated significant correlation with other markers in the liver fibrosis group (P<0.001). In the patients with HCC, lower serum levels of miR-125a-5p were correlated with a poor prognosis, determined by Kaplan-Meier curve analysis (P=0.009). In the liver fibrosis and HCC groups, different expression levels of serum miR-125a-5p were observed, and were correlated with disease progression. The results of the present study suggested that serum miR-125a-5p may be used as a non-invasive biomarker for monitoring disease progression in liver diseases.

Plasma osteopontin concentration correlates with the severity of hepatic fibrosis and inflammation in HCV-infected subjects

The association between OPN level and the histological severity of hepatic fibrosis and inflammation in hepatitis C virus (HCV) induced liver fibrosis remains unknown. 120 chronic HCV-infected subjects and 75 controls were enrolled in this study. Assessment of liver histology was performed based on liver biopsy. Plasma OPN levels were determined. Significant differences were noted in the mean plasma OPN levels between subjects with extensive fibrosis and those with mild fibrosis (4.29+/-1.01 ng/ml vs. 2.15+/-0.63 ng/ml, respectively; p<0.001). Similarly, the subjects with higher histological activity index (HAI) score had elevated OPN levels than those with mild HAI score (4.41+/-1.11 ng/ml vs. 2.25+/-0.94 ng/ml, respectively; p<0.001). The correlation between the plasma OPN levels and the severity of liver fibrosis degree and HAI score were noted (r=0.945, and r=0.788, respectively both p<0.001). Logistic regression analysis showed that serum OPN was an independent risk factor contributing to extensive liver fibrosis and inflammation (p=0.0018 and p<0.001, respectively) in patients with HCV subjects. The plasma OPN level is correlated with the severity of liver fibrosis and inflammation, suggesting OPN could be used as a biomarker to evaluate the severity of liver damages in HCV subjects.

Natural history of hepatic fibrosis progression in chronic hepatitis C virus infection in India

The rate of fibrosis progression per year can predict the time for the development of cirrhosis in chronic hepatitis C (CHC). We assessed the rate of fibrosis progression and the predictors of disease severity in Indian CHC patients. Of the 355 treatment-naïve, histologically-proven CHC patients, the precise duration of infection (from the time of exposure to HCV until liver biopsy) could be determined in 213 patients (age = 41.6 +/- 14.7 years, male : female = 139 : 74, genotype 3 = 75%). The rate of fibrosis progression per year was calculated. The correlation of the advanced degree of fibrosis and age, duration of infection, age at the onset of infection, sex, mode of infection, hepatitis C virus (HCV) genotype, histological activity index (HAI), and the presence of diabetes mellitus were studied. The median rate of fibrosis progression per year was 0.25 (0.0-1.5) fibrosis units. The fibrosis progression rate was higher in patients who acquired infection at > 30 years of age, those < 30 years (0.33 vs 0.15; P < 0.001), and those who acquired HCV infection with a history of blood transfusion than with other modes of transmission (0.25 vs 0.19; P = 0.04). The median time to progress to cirrhosis was 16 years. The multivariate analysis found that the HAI score (odds ratio [OR]= 14.03; P < 0.001) and the duration of infection > 10 years (OR = 4.83; P < 0.001) correlated with severe liver disease (fibrosis > or = 3). The median rate of fibrosis progression per year in Indian CHC patients is 0.25 fibrosis units. A higher HAI and longer duration of infection are associated with a significant risk of advanced liver disease, and merit early therapeutic interventions.

Treatment of Chronic Hepatitis B in Children

Chronic hepatitis B in children is mainly asymptomatic, but they are at life long risk for severe complications. Treatment is considered to suppress the virus and to prolong the survival by preventing the progression to cirrhosis and HCC. Therapeutic options for children are interferon-alpha (IFN-alpha) with antiviral, antiproliferative and immuno-modulatory effects and lamivudine (LAM) which inhibits HBV replication and increases cellular immune response. IFN-alpha, 5 MU/m(2), thrice weekly for 6 months is used in patients with high ALT levels which is associated with virologic response rate of 30-40%. Predictors of response are high ALT levels, low HBVDNA levels and high histological activity index. The response is sustained in 85%-90% of responders. Adverse events include flu-like syndrome, bone marrow suppression, hair loss, and psychiatric side effects, induction of autoimmunity and temporarily suppression of weight gain and growth velocity. LAM, a nucleoside anolog, leads to a virologic response rate of 20-30% when used for 12 months. High ALT levels, low HBVDNA levels and high histological activity index predict better response. Maintenance of HBeAg seroconversion is 56-80%. Longer courses of treatment with LAM increases the seroconversion rate but with high mutation rate and viral resistance. Except for causing mutations, LAM doesn't have serious adverse events. Different timing and durations of combination treatment with IFN and LAM were also evaluated without any significant superiority over monotherapy. In conclusion, the best approach for treatment of chronic HBV infection in children haven't been determined yet. Future developments concerning new drugs and different treatment strategies are needed.

Treatment of Chronic Hepatitis B with Lamivudine in Renal Transplant Recipients

Treatment of chronic hepatitis B in renal transplant recipients remains one of the major problems in clinical nephrology. Lamivudine is considered to be a drug of choice for these patients, however, its efficacy in patients with hepatitis B after renal transplantation (RT) has not been completely proven. Twenty-two RT recipients treated with lamivudine were evaluated. The duration of treatment was 15.6+/-1.9 months. Fourteen patients (64%) had normalization of aminotransferase (ALT); in 9 of them (41% of the whole group), serum HBV DNA was eliminated. Serum HBeAg was undetectable in 4 out of 15 (27%) previously positive patients. It has been statistically proven that the efficacy of lamivudine therapy correlates with degree of fibrosis and higher histological activity index values. We could not establish any correlation between the outcome of antiviral therapy and patients' age, sex, conditions of contagion (while on dialysis or after RT), time lapsed after the infection had been detected, duration of post-transplant period, type of immunosuppression, HBeAg positivity or negativity, ALT levels, concomitant HCV infection. The efficacy of antiviral HBV therapy is limited by the duration of lamivudine treatment: in 4 out of 5 patients with virologic response, the viremia condition relapsed several weeks after the medication had been stopped. Two patients continued to sustain their biochemical response and 1 patient had ALT levels elevated to above normal, but the value was almost twice as low as initially reported. Liver biopsy was repeated in 4 RT recipients after the end of antiviral therapy; in 3 of them positive morphologic changes were observed.

Cytokine—chemokine and apoptotic signatures in patients with hepatitis C

Cytokines and chemokines are proteins that play a critical role in the regulation of immunity and inflammation in patients with chronic Hepatitis C. The aim of our study was to correlate serum cytokines, chemokines and apoptosis in non-treated chronic hepatitis C patients with various degrees of inflammation and fibrosis. We studied 778 patients: 59 had low Knodell fibrosis score and low Knodell histological activity index; 372 had mild fibrosis and low histological activity index; 270 had moderate fibrosis and moderate histological activity index; and, 77 had high fibrosis and high histological activity index on their biopsy. Serum cytokines, chemokines and apoptosis were measured by enzyme-linked-immunosorbent-assay. Multivariate analysis was employed for statistical purposes. A positive correlation was seen between the degree of inflammation and tumor necrosis factor-alpha (TNF-alpha) levels (r = 0.92) in non-cirrhotic patients and between interleukin 2 in all patients (r = 0.85). Interleukin-8 increased significantly at higher histological activity indices and continued to increase in patients with cirrhosis. Transforming growth factor-beta (TGF-beta) levels increased significantly with the severity of fibrosis, but decreased in cirrhotics. In conclusion, cytokines, chemokines and apoptosis levels reflect the progression of inflammation and fibrosis in hepatitis C infected patients, but their signatures differ.

Profile of chronic hepatitis B virus in children in India: Experience with 116 children

Hepatitis B virus (HBV) infection in children is mostly asymptomatic and therefore the disease burden is likely to be under appreciated. There is limited information on the profile of chronic HBV infection in children from the Indian subcontinent. In 116 (male:female 89:27) children, aged <15 years, with persistent HBsAg positivity for more than 6 months, a clinical, biochemical, virological and histological assessment was carried out. At presentation, 21.6% of children were symptomatic, with icterus in 12%. Features of decompensation such as ascites (7%) and gastrointestinal (GI) bleed (5%) were noted uncommonly. Five (4.3%) children had hepatocellular carcinoma (HCC) at presentation. Elevated alanine aminotransferase (ALT) was observed in 76% of subjects (median 61; range 14-815). A significantly higher proportion of children with hepatitis B early antigen (HbeAg) positive status had higher histological activity index (HAI) (84% vs 16%, P < 0.001) and fibrosis score (80% vs 20%, P = 0.007). A strong positive correlation was noted between aspartate aminotransferase (AST), ALT, HBV-DNA and histological severity of the disease (HAI > or =4, fibrosis > or =2). Median HBV-DNA levels were significantly higher in the HBeAg positive compared to the HBeAg negative group (25.6 vs 0.7 pg/mL, P = 0.004). Seventy-four percent of the mothers had evidence of past or present HBV infection. Majority of the children with chronic HBV infection are asymptomatic at presentation. HBeAg positive status reflects histologically more severe disease, and a higher level of HBV-DNA. Almost two-thirds of the children may have acquired their HBV infection perinataly.

Comparison of Two Different Regimens of Combined Interferon-α2A and Lamivudine Therapy in Children with Chronic Hepatitis B Infection

Aim To evaluate the efficacy of two regimens of combined interferon-α2a (IFN-α2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. Methods A total of 177 patients received IFN-α2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7±3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-α2a, in group II (65 patients, 9.6±3.8 years) 3TC was started 2 months prior to IFN-α2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in non-responders. Results Baseline alanine aminotransferase (ALT) was 134.2 ±34.1 and 147.0 ±45.3; histological activity index (HAI) was 7.4 ±2.7 and 7.1 ±2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively ( P&gt;0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively ( P&lt;0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I ( P&lt;0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively ( P&gt;0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 ±4.6 and 14.1 ±5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively ( P&gt;0.05, P&gt;0.05, P&gt;0.05). Responders had higher HAI (HAI&gt;6) and higher pre-treatment ALT than non-responders. Conclusion Simultaneous 3TC+IFN-α2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies.

Co-infection of SENV-D among chronic hepatitis C patients treated with combination therapy with high-dose interferon-alfa and ribavirin

The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C (CHC) and response of both viruses to combination therapy with high-dose interferon-alfa (IFN) plus ribavirin remain uncertain and are being investigated. Total 164 (97 males and 67 females, the mean age 48.1+/-11.4 years, range: 20-73 years, 128 histologically proved) naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method. Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay (COBAS AMPLICOR HCV Test, version 2.0). HCV genotypes 1a, 1b, 2a, 2b, and 3a were determined by using genotype-specific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay (Quantiplex HCV RNA 3.0). There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined. Sixty-one (37.2%) patients were positive for SENV-D DNA and had higher mean age than those who were negative (50.7+/-10.6 years vs 46.6+/-11.6 years, P = 0.026). The rate of sustained viral response (SVR) for HCV and SENV-D were 67.3% (105/156) and 56.3% (27/48), respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b (P<0.001), younger ages (P = 0.014), lower pretreatment levels of HCV RNA (P = 0.019) and higher histological activity index (HAI) score for intralobular regeneration and focal necrosis (P = 0.037). By multivariate analyses, HCV genotype non-1b, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR (odds ratio (OR)/95% confidence interval (CI): 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively). The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy (P = 0.04). Coexistent SENV-D infection, apparently associated with higher ages, is found in more than one-third Taiwanese CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.

Influence of chronic coinfection with hepatitis B and C virus on liver histology.

Few data are available on histological features of chronic hepatitis B (HBV) and C (HCV) virus coinfection. We enrolled 142 consecutive patients with viral chronic hepatitis on their first liver biopsy: 27 HBsAg and anti-HCV positive (case BC group), 57 HBsAg positive and anti-HCV negative (control B group) and 58 anti-HCV positive, HBsAg/anti-HBs/anti-HBc negative (control C group). Patients in the case BC group showed serum HBVDNA (37% vs 71.9%, p < 0.005) and ground-glass hepatocytes (37% vs 66.7%, p < 0.01) less frequently than those in the control B group. The case BC group showed a lower prevalence of patients with detectable HCV-RNA than the control C group (60% vs 92.3%, p < 0.001) and a significantly higher fibrosis score (2.1 +/- 1.2 vs 1.5 +/- 1.1, p < 0.05). Of the 27 patients in the case BC group, 10 lacked serum HCV-RNA and showed significantly higher histological activity index (HAI) and fibrosis scores than those found in the 17 HCV-RNA positive (8.5 +/- 4.4 vs 5.4 +/- 2.4 for HAI, p < 0.05; 3.0 +/- 1.3 vs 1.69 +/- 1.0, p < 0.05 for fibrosis). Liver histology seems to be more severe in chronic coinfection with HBV and HCV than in single infection, particularly when HCV replication is impaired.

Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States

Background: Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined. Aims: The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients. Methods: This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center. Results: The frequency of hepatic steatosis was 66.0%. We demonstrated that not only being obese, but also overweight (i.e. body mass index ≥25 kg/m 2) was independently associated with hepatic steatosis. In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis. Grade II/III steatosis, was significantly associated with a higher histology activity index as well. Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. Conclusions: Being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.