THE BRIDGE – May 2001

THE BRIDGE – May 2001

Journal of Hepatology 34 (2001) 643 THE BRIDGE ± May 2001 Angiogenesis in portal hypertension and liver regeneration (see pages 644±650, 683±689, 690...

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Journal of Hepatology 34 (2001) 643

THE BRIDGE ± May 2001 Angiogenesis in portal hypertension and liver regeneration (see pages 644±650, 683±689, 690±698) The fact that three articles and an editorial in this issue deal with angiogenesis suggest that this is an important and hot topic. Initially, mostly tumor biologists and cardiologists were interested in angiogenesis but these three papers convince us that the topic is timely and important for hepatologists also. Sieber points out that angiogenesis is an important part of wound healing ± which interests hepatologists as cirrhogenesis. In an elegant model he demonstrates that NO is necessary for portalvein ligation induced angiogenesis and that basic ®broblast growth factor ± besides vascular endothelial growth factor (VEGF) a major initiator of the process ± is dependent upon NO in inducing angiogenesis. Sato et al. demonstrate sinusoidal endothelial cell (SEC) proliferation to lag behind hepatocyte proliferation; proliferation seems to be initiated by VEGF and its receptor, ¯t1. Lagging behind the peak is another vascular growth factor and its receptor, namely angiopoietin/Tie factor. This is thought to stabilize nascent sinusoids. Shimizu and colleagues con®rm that VEGF is produced in hepatocytes and demonstrate that this production is increased prior to SEC proliferation after hepatectomy. Amino acid challenge ± a new model of hepatic encephalopathy in humans and methods to assess subclinical encephalopathy (see pages 658±664, 768±773) Douglass and colleagues present an ingeniously simple clinical tool: they provide a load of amino acids mimicking the composition of hemoglobin to patients with cirrhosis. This induces a picture of hepatic encephalopathy and should be a wonderful tool to study novel therapeutic interventions. Weissenborn and collaborators evaluate a number of neuropsychological tests to assess low-grade (grade 0 and 1) hepatic encephalopathy. After sensitivity analysis they propose to combine the results of a battery of tests ± which can be accomplished in a reasonable amount of time and appears to be applicable to the bedside ± into a score with high sensitivity and speci®city. Validation of this score is promised and eagerly awaited. Cytokeratins and heat shock proteins in Mallory body formation (see pages 665±675) Denk and his group using transgenic mice lacking one or the other cytokeratin have recently demonstrated that the ratio of cytokeratin 8/18 determines development of Mallory bodies ± the hallmark of (non) alcoholic steatohepatitis (Am J Pathol 156:1263). In this issue, Stumptner et al. from the Graz group demonstrate that the ratio of cytokeratin 8/18 as well as a novel player, a heat-shock protein are among the earliest events in Mallory body formation. This adds

Juerg Reichen [email protected] evidence to their earlier paper that Mallory bodies are part of a defensive mechanism against cell damage. The crucial role of a heat-shock protein also points to a stress reaction, presumably oxidative stress which makes the link to (non) alcoholic steatohepatitis apparent. Progression of ®brosis in hepatitis C (see pages 730±739, 740± 747, 748±755) Three papers are concerned with the progression of ®brosis in hepatitis C, its assessment and the effects of interferon treatment. Poynard et al. con®rm their earlier observation ± now in a large number of patients extracted from different studies ± that male sex, age at infection and alcohol consumption are the major determinants of ®brosis progression while genotype or viral load do not affect it. Their Fig. 1 will be very helpful in aiding treatment decisions. Bruno and colleagues report the evolution of 47 patients from interferon trials with a sustained biochemical response. Among those who also had a sustained virologic response, liver biopsy further improved, 41% reaching a Knodell score # 2, corresponding to virtually normal histology. Unfortunately, the cirrhotic patients were not rebiopsied but, as shown before by others, there were less decompensations in sustained responders. Caballero et al. demonstrate superiority of a semiquantitative image analysis system (Fibroquant ± which can be run on a PC) over the Knodell and Scheuer scoring system. Apparently, some interactive corrections have still to be used in the assessment of the area of certain portal tracts. Unfortunately, the authors do not tell us in which percentage this was necessary and how much time this adds to the analysis of a biopsy. This criticism notwithstanding I believe that this system will allow for a more objective, re®ned and precise analysis of ®brosis in liver biopsies. Hepatocyte growth factor (HGF) and its receptor c-met in hepatogenesis (see pages 699±710) HGF and its receptor c-met play a crucial role in organogenesis in the endoderm. In a thorough study Spijkers and colleagues demonstrate this to be also true for the liver. C-met is expressed in hepatocytes during the proliferative phase of organogenesis while HGF is expressed in the surrounding parenchyma. During differentiation to adult hepatocytes ± assessed by the expression of liver-speci®c gene products ± expression of c-met diminishes. This transition from the embryonal phase to fetal maturation is followed by the expression of acinar zone-speci®c proteins such as glutamin synthase. Simultaneous use of sensitive and reproducible immunohistochemistry and in situ hybridization also permitted to detect post-translational modi®cation of c-met as an important determinant of spatial organization of the developing liver.

0168-8278/01/$20.00 q 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(01)00100-3