Early periportal sinusoidal fibrosis is an accurate marker of accelerated HCV recurrence after liver transplantation Zoe Mariño 1 , Laura Mensa 1 , Gonzalo Crespo 1 , Rosa Miquel 2 , Miquel Bruguera 1 , Sofía Pérez-del-Pulgar 1 , Jaume Bosch 1 , Xavier Forns 1 , Miquel Navasa 1,⇑ 1 Liver Unit, Institut de Malalties Digestives, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain; 2 Pathology Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain Background & Aims: Significant liver fibrosis (F P2) and portal hypertension (hepatic venous pressure gradient [HVPG] P6 mmHg) 1 year after liver transplantation (LT) are predictors of severe hepatitis C recurrence. Periportal sinusoidal fibrosis (SF) is an early expression of the fibrogenic process in response to liver injury. We aimed to evaluate whether SF in early liver biopsies represents an early and accurate marker for identifying patients with severe HCV recurrence after LT. Methods: A total of 101 HCV LT patients with early biopsy (<6 months), and HVPG measurement and/or liver biopsy one year after LT were included. Early biopsies were stained with Sir- ius Red and SF was graded semi-quantitatively. Results were compared between groups (significant SF vs. non-significant SF) and correlated with the development of severe HCV recurrence one year after LT. Results: Patients with early significant SF had older donor age and higher necroinflammatory activity (NIA). The presence of early significant SF enabled identification of 78.9% and 90.6% of patients with F P2 and HVPG P6 mmHg, respectively, one year after LT. Donor age and NIA were independent predictors of sig- nificant fibrosis (F P2) one year after LT, whereas donor age, ALT (3 months), NIA, and SF grade were independent predictors of portal hypertension (HVPG P6). Conclusions: Significant SF in early biopsies is a good predictor of severe hepatitis C recurrence. This histological finding, when combined with simple variables, may be useful to select the best candidates for early antiviral therapy after LT. Ó 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Introduction HCV infection is universal after LT [1] and negatively impacts long-term survival [2,3]. A faster fibrotic rate has been exten- sively documented compared to immunocompetent HCV patients [3–6]. Up to one-third of HCV transplanted patients will develop an accelerated course to cirrhosis within 5 years following LT [7]. Assessment of fibrosis progression in the graft after LT can be made with different semiquantitative histological scores (i.e., METAVIR [8]) that measure specific architectural changes in the liver. The presence of significant fibrosis (F P2) in liver biopsies one year after LT identifies patients likely to have an aggressive course (‘‘rapid fibrosers’’) [9–11]. Such patients have a higher risk of graft loss than those with lower stages of fibrosis and normal portal pressure at the same time point (‘‘slow fibrosers’’). An alternative to classic morphometric scores is collagen pro- portionate area (CPA) measured 1 year after LT by digital image analysis, which has been shown to correlate with HVPG and to be a good predictor for clinical decompensation following LT [5,12,13]. HVPG is an excellent indicator of fibrosis progression, and a HVPG P6 mmHg one year after LT clearly identifies patients with an accelerated course [10]. More recently, non-invasive methods have been developed to assess fibrosis progression, such as liver stiffness measurement (LSM) [9,14–17] or indirect [18,19] and direct (i.e., ELF) serum mark- ers of fibrosis [20–23]. Although these methods have shown high accuracy in the fibrosis evaluation at one year, their usefulness dur- ing the very early stages after LT (3 months) seem to be poor [9,20]. The initial histological features associated with early HCV recurrence include sinusoidal dilatation, lobular inflammation, apoptotic bodies, and mild portal inflammatory infiltrate forming lymphoid aggregates. To date, however, only lobular necroin- flammatory activity (NIA) has been associated with severe HCV recurrence [24–26]. Fibrosis is the main consequence of chronic liver injury and is the result of an imbalance in the dynamic remodeling process of the extracellular matrix (ECM), which leads to an excessive accu- mulation of extracellular proteins, especially fibrillar collagen. Hepatic stellate cells (HSCs) of the perisinusoidal Disse’s space are essential in hepatic fibrogenesis [27]. When activated in response to liver injury, HSCs produce most of the matrix Journal of Hepatology 2014 vol. xxx j xxx–xxx Received 11 November 2013; received in revised form 18 March 2014; accepted 26 March 2014 ⇑ Corresponding author. Address: Liver Unit, Institut de Malaties Digestives, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 93 227 54 00x4406. E-mail address: mnavasa@clinic.ub.es (M. Navasa). Abbreviations: HCV, hepatitis C virus; LT, liver transplantation; F, fibrosis stage; CPA, collagen proportionate area; HVPG, hepatic venous pressure gradient; LSM, liver stiffness measurement; ELF, enhanced liver fibrosis; NIA, necroinflammatory activity; ECM, extracellular matrix; HSCs, hepatic stellate cells; SF, sinusoidal fibrosis; SR, Sirius Red; AUROC, area under the receiver operator characteristic curve; S, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value. Research Article Please cite this article in press as: Mariño Z et al. Early periportal sinusoidal fibrosis is an accurate marker of accelerated HCV recurrence after liver transplantation. J Hepatol (2014), http://dx.doi.org/10.1016/j.jhep.2014.03.029