Section 1 -

Current Nomenclature of Chronic Hepatitis and Staging/grading Systems Helmut Denk Department of Pathology, Medical University of Graz, Graz, Austria

The liver biopsy is still the gold standard, particularly in the assessment of chronic liver disease following a subclinical course. It is a reliable procedure to confirm the clinical diagnosis, assess the severity of necroinflammation, type and extent of fibrosis and related architectural alterations, to uncover concomitant diseases and to evaluate the effect of therapy. The histologic classification of chronic hepatitis proposed in 1968 by an international group of liver pathologists [1] has proved to be a valuable basis for the clinic at a time when many aspects of etiology, natural history and pathogenesis were still unclear. However, the terminology proposed, i.e. chronic active or aggressive (CAH) and chronic persistent (CPH) hepatitis, although not intended by the authors, sometimes led to misinterpretation in the sense that clinical hepatologists regarded CPH and CAH as long-term diagnostically and prognostically relevant labels for individual patients and thus as distinct entities rather than only different grades of necroinflammatory activity [2]. Particularly in chronic hepatitis C, progression to cirrhosis occurs in a substantial proportion of patients, even despite relatively mild activity in the biopsy. Moreover, the term "piecemeal necrosis" indicating erosion of the limiting plate is now obsolete and replaced by "interface hepatitis" because the mechanism of this type of liver cell damage is predominantly apoptosis rather than necrosis. The traditional evaluation of liver biopsies is based on the identification of morphologic features of proven or suggested clinical (prognostic and therapeutic) relevance in correlation with clinical findings. Etiology is most important with respect to diagnosis, prognosis, natural history and therapeutic options, which may, in certain instances, be recognized on the basis of morphologic features of the biopsy. The descriptive approach of liver biopsy interpretation can be supplemented by semiquantitative scoring of morphologic features with major emphasis on necroinflammatory activity (grading) and fibrosis (staging). Grading and staging with resulting numerical scores seem to satisfy clinicians better than purely descriptive histologic reports and are more amenable to statistical evaluation. Therefore, semiquantitative grading and staging has its place in clinical trials, enabling comparison of different series of patients and therapy regimens, as well as in research. In the daily practice, however, semiquantitative scoring can be avoided. Several histological scoring systems for different types of chronic liver diseases have been proposed. Chronic Hepatitis. In the Knodell system [3] periportal and bridging necrosis, intralobular liver cell damage, portal inflammation and fibrosis are assessed and by adding up scores for the individual categories an overall histologic activity index (HAI) is calculated. However, despite other problems (e.g. combination of different types of necrosis in one category), the combination of scores representing grading (intensity of necroinflammation) and staging (measure of fibrosis and architectural alteration) can be misleading. In other scoring systems, fibrosis is considered separately and grading is either simplified or types of necrosis are more individualized [2, 4, 5, 6, 7, 8, 9]. For example, in the Ishak system [5] the modified HAI reflects the intensity of periportal and periseptal interface hepatitis, confluent and bridging necrosis, spotty lytic necrosis, apoptosis and focal inflammation in the lobule and portal inflammation. The modified staging is based on the degree of portal and septal fibrosis and related architectural alterations. Steatohepatitis. Histological scoring systems have also been proposed for non-alcoholic steatohepatitis (NASH) taking into account amount of steatosis, hepatocyte ballooning, lobular and portal inflammation and Mallory body formation (grading) as well as staging of fibrosis (zone 3 perivenular perisinusoidal/pericel­lular, periportal, bridging, cirrhosis) resulting in a numerical activity score (NAS) as the sum of the scores for steatosis, lobular inflammation and ballooning [10, 11, 12, 13]. Chronic Cholestatic Conditions. Staging of chronic biliary diseases, like primary biliary cirrhosis and primary sclerosing cholangitis, has been described based on portal and periportal inflammation with accompanying periportal fibrosis, bridging fibrosis (fibrous septa) and bridging fibrosis with nodular regeneration (cirrhosis) [14, 15]. Conclusions. Advances in our understanding of etiology and evolution of chronic hepatitis and other chronic liver diseases require a reassessment of our traditional morphologic classification with the goal to closer correlate morphology with clinical presentation, serologic and immunohistochemical data, etiology and possible therapeutic strategies. A semiquantitative scoring system including stage and grade of the disease is helpful for overall assessment. Several problems are inherent to all scoring systems; they include sampling and inter- and intra-observer variations. Moreover, it has to be kept in mind that, in contrast to biochemical measurements, the numbers generated by scoring represent only categories of severity and non-parametric tests are necessary for statistical analysis. It should always be borne in mind that scores are added-up numbers of variables with quite different biologic and clinical significance. Thus, in patients with different histologic changes the same total score may be obtained, but the total score may be differently composed and thus of different clinical significance. Therefore, particularly in clinical trials individual components of grading have to be separately studied. Finally, etiologically different types of liver diseases may show differences in evolution (natural history, behaviour) and response to therapy, without close correlation with morphology. References De Groote J, Desmet V, Gedigk P, Korb G, Popper H, Poulsen H, Schmid M, et al. A classification of chronic hepatitis. Lancet 1968; ii: 626-628. 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