Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer-assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2-45), correlating with Ishak stage (stage 6 range, 13%-45%), and with HVPG (r ‫؍‬ 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094-1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026-1.191; P ‫؍‬ 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. Conclusion: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis.

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To evaluate whether hepatitis B virus (HBV) preS/S gene variability has any impact on serum hepatitis B surface antigen (HBsAg) levels and to analyze the replication capacity of naturally occurring preS/S variants, sera from 40 untreated patients with HBV-related chronic liver disease (hepatitis B e antigen [HBeAg]-positive, n 5 11; HBeAg-negative, n 5 29) were virologically characterized. Additionally, phenotypic analysis of three different preS/S variant isolates (carrying a 183-nucleotide deletion within the preS1 region, the deletion of preS2 start codon, and a stop signal at codon 182 within the S gene, respectively) was performed. HBV infecting 14 (35%) patients had single or multiple preS/S genomic mutations (i.e., preS1 and/or preS2 deletions, preS2 start codon mutations, C-terminally truncated and/or ''a'' determinant mutated S protein). Presence of preS/S variants negatively correlated with HBsAg titers (r 5 20.431; P 5 0.005) and its prevalence did not significantly differ between HBeAg-positive and HBeAg-negative patients. No correlation was found between HBsAg and HBV DNA levels in patients infected with preS/S mutants, whereas a significant correlation was found between HBsAg and viremia levels (r 5 0.607; P 5 0.001) in patients infected with wild-type HBV strains. HepG2 cells replicating the abovementioned three preS/S variants showed significant reduction of HBsAg secretion, retention of envelope proteins in the endoplasmic reticulum, less efficient virion secretion and nuclear accumulation of significantly higher amounts of covalently closed circular DNA compared with wild-type HBV replicating cells. Conclusion: In patients infected with preS/S variants, HBV DNA replication and HBsAg synthesis/secretion appear to be dissociated. Therefore, the use of HBsAg titer as diagnostic/prognostic tool has to take into account the frequent emergence of preS/S variants in chronic HBV infection. (HEPATOLOGY 2012;56:434-443) See Editorial on Page 411 H epatitis B virus (HBV) belongs to the Hepadnaviridae family, which comprises hepatotropic DNA viruses sharing with HBV most of the genetic structure and replicative characteristics. 1 HBV is one of the smallest viruses in nature and its genome presents a highly compact genetic organization. It consists of a partially double-stranded relaxed circular DNA of approximately 3,200 nucleotides in length and contains four partially overlapping open-reading frames: preS/S, pre-C-C, P, and X. The preS/S openreading frame encodes three different, structurally related envelope proteins termed the large (L), middle (M), and small (S) protein that are synthesized from alternative initiation codons. The three proteins share the same carboxy-terminus part but have different aminoterminal extensions. In particular, the S protein-corresponding to the HBV surface antigen (HBsAg)-consists of only 226 amino acids (aa), the M protein contains an extra N-terminal extension of 55 aa, and the L

SummaryBackground and objectives Renal function is an important predictor of survival in cirrhosis and liver transplantation. GFR estimates using serum cystatin C (CysC) are proposed as better predictors of renal function than ones on the basis of serum creatinine (Cr). Our aims were: (1) evaluate correlations between serum CysC and different methods of creatinine measurements; (2) compare CysC and Cr GFR formulas with 51 Cr-EDTA; and (3) evaluate liver-related parameters potentially influencing GFR.Design, setting, participants, & measurements 254 blood samples in 65 patients with cirrhosis correlating CysC with four Cr methods were used; another 74 patients comparing 51 Cr-EDTA GFR to Modification of Diet in Renal Disease and Larsson and Hoek formulas for CysC were also included. Agreement was assessed using Bland-Altman plots and concordance correlation coefficients. Multivariate linear regression analysis was used for GFR predictors.Results Serum CysC correlated modestly with O'Leary modified Jaffe, compensated kinetic Jaffe, enzymatic creatinine, and standard kinetic Jaffe 0.72/0.71/0.72/0.72 (all P Ͻ 0.001). Bland-Altman agreement with 51 Cr-EDTA GFR was poor; the best agreement was Modification of Diet in Renal Disease (concordance 0.61; 95% CI, 0.47 to 0.71); the worst agreement was the Hoek formula (concordance 0.46; 95% CI, 0.27 to 0.61). A new GFR formula including the Child-Pugh score improved the accuracy of Cr GFR formulas compared with 51 Cr-EDTA GFR.Conclusions Estimated GFR in cirrhosis is not better with CysC formulas compared with creatinine ones: specific formulas may be necessary.

Conflict of interest: The authors who have taken part in this study do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Ethics: This was a single-centre retrospective audit including consecutive patients with cirrhosis and variceal bleeding admitted at the Royal Free Hospital who underwent TIPS placement. As such, ethical approval and consent was not required.