Chronic Hepatitis: Grading and Staging

Need for Grading and Staging

In the past, the term chronic active hepatitis was used to label biopsies with interface hepatitis (formerly known as piecemeal necrosis), whereas the term chronic persistent/chronic lobular hepatitis referred to biopsies with portal/lobular inflammation without significant interface hepatitis. This distinction was based on the assumption that chronic persistent/lobular hepatitis were relatively benign processes without progression to cirrhosis. Identification of the hepatitis C virus (HCV) and elucidation of its natural history has made it clear that interface hepatitis does not represent the “conditio sine qua non” for the onset of cirrhosis, which can also evolve from morphologic chronic persistent/lobular hepatitis; therefore, the old nomenclature has been abandoned. However, in terms of histologic severity, necroinflammation and fibrosis remain powerful prognostic parameters, associated with the risk of progression to cirrhosis. In chronic viral hepatitis, the extent of fibrosis in the baseline biopsy is a strong predictor of further fibrotic progression. Discovering of HCV along with the progress in therapeutic options gave rise to the need for assessing the severity of chronic hepatitis in a more objective and reproducible way, possibly amenable to statistical analysis, to facilitate testing of drug efficacy in clinical trials.

In the last two decades, staging, and at a lesser extent, grading, have been the main indications to perform a liver biopsy in subjects with chronic viral hepatitis. This information is useful in predicting short-term and long-term prognosis, deciding treatment options and their timing, and assessing changes occurring during or after any treatment. Nowadays, the need to perform a liver biopsy in subjects with chronic viral hepatitis, particularly chronic HCV infection has decreased because of the availability of direct acting antivirals that allow sustained viral response (SVR) in the majority of treated individuals. Nevertheless, including grade and stage in the final pathology report on cases of chronic viral hepatitis remains mandatory.

General Principles of Grading and Staging

Several schemes of varying complexity have been proposed for grading and staging chronic viral hepatitis. The simplest method, familiar to most pathologists, consists of classifying both grade and stage in descriptive terms such as mild, moderate, and severe. The overall severity of necroinflammation and fibrosis is considered, but there are no specific rules to guide this evaluation, which remains highly subjective. In the more complex methods, the final grade and stage emerge from combining numerical scores attributed to each histologic lesion; all methods are based on similar principles, regardless of the specific criteria used ( Tables 16.1 and 16.2 ).

Grading is performed semiquantitatively by assessing necroinflammatory lesions, both in the portal-periportal area (ie, portal inflammation and interface hepatitis) and in the lobular parenchyma (ie, lobular necrosis/apoptosis and inflammation). Each lesion is scored, with higher numbers coinciding with more severe lesions. The sum of the scores gives the grade of hepatitis. Bear in mind that these numbers represent ordered categories and not genuine mathematic measurements; therefore, general mathematic rules are not always applicable for statistical analysis.

Staging is an assessment of the extent and location of fibrosis and of accompanying changes in parenchymal architecture. All systems express stage on a linear numerical scale, with stage 0 (zero) corresponding to no fibrosis and the highest stage to a diagnosis of cirrhosis; definitions of the intermediate stages differ with the staging systems. Even more so than with grading, these numbers do not reflect measurements but rather progressive pathologic stages such as portal fibrosis or septal fibrosis , which are qualitative rather than quantitative parameters. Clinicopathologic studies have demonstrated that formation of fibrous bands linking adjacent portal tracts, or portal tracts to central veins, the so-called septal fibrosis or bridging fibrosis , carries the highest risk of further fibrotic progression and cirrhosis in chronic viral hepatitis. Septal or bridging fibrosis is therefore referred to as clinically significant fibrosis . The use of special stains for collagen is strongly recommended for proper staging of fibrosis; in the absence of universal guidelines, the choice of stain is a matter of personal preference.

Grading and Staging Systems

The initial attempt at a semiquantitative scoring system was made by Knodell and colleagues, who proposed the histologic activity index (HAI), which combined the scores for grade and stage. Subsequent methods scored the stage and grade separately. The four systems currently in use include the Scheuer system; the Batts and Ludwig system, which is a modification of the Scheuer system; the METAVIR system; and the Ishak system, which is a modification of the HAI.