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Histological grading and staging in chronic hepatitis: clinical applications and problems
Copyright C European Association for the Study of the Liver 1998
Journal of Hepatology 1998; 29: 1015–1022 Printed in Denmark ¡ All rights reserved Munksgaard ¡ Copenhagen
Journal of Hepatology ISSN 0168-8278
Special Article
Histological grading and staging in chronic hepatitis: clinical applications and problems Stefan G. Hu¨bscher Department of Pathology, University of Birmingham, Birmingham, UK
years there has been a marked change in the approach to the histological classification of chronic hepatitis. The terms ‘‘chronic active hepatitis’’ (CAH), ‘‘chronic persistent hepatitis’’ (CPH) and ‘‘chronic lobular hepatitis’’ (CLH), which have been in use for almost 30 years, were proposed at a time when little was known about the aetiology or pathogenesis of chronic hepatitis (1,2). With better understanding of the different causes and varying natural history of chronic hepatitis, several deficiencies in the old system of classifying chronic hepatitis were identified (3,4). A new approach to classifying chronic viral hepatitis was proposed by Scheuer in 1991 (4) and is now widely accepted for classifying other types of chronic hepatitis also (5–7). The new approach to classifying chronic hepatitis involves three separate considerations. The first is a comment on the aetiology. Frequently, this cannot be determined with certainty on the basis of histological appearances alone, and the diagnosis is made on the basis of other laboratory investigations. The second assessment relates to the severity and distribution of necroinflammatory activity (histological ‘‘grade’’). This component of the disease can be regarded as potentially treatable. Thirdly, an attempt should be made to assess the degree of fibrosis (histological ‘‘stage’’). Fibrosis is considered to be a marker of progressive damage, which is less likely to be reversible. As a consequence of these developments, the terms CAH, CPH and CLH can now be regarded as obsolete, and their use is no longer recommended. The reasons for the demise of the old system of classifying chronic hepatitis and the advantages of the new approach have been extensively discussed elsewhere (4–9) and will therefore not be considered in further detail here. The traditional method of reporting on liver biopsies
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Correspondence: Stefan G. Hu¨bscher, Department of Pathology, University of Birmingham, Birmingham, B15 2TT, UK. Tel: 44 (0) 121 414 4005. Fax: 44 (0) 121 414 4019. E-mail: s.g.hubscher/bham.ac.uk
from patients with chronic hepatitis (and other liver diseases) involves identifying histological features which are thought to be clinically relevant and then interpreting any abnormalities identified in the light of clinical findings and other laboratory investigations. This descriptive approach can be supplemented by semi-quantitative assessments of one or more histological features. Terms such as ‘‘minimal’’, ‘‘mild’’, ‘‘moderate’’ and ‘‘severe’’ may be used to describe the degree of necroinflammatory activity or the extent of fibrosis. Severity of necroinflammatory activity can be expressed as an overall grade or subdivided according to individual histological components (see below). A number of attempts have been made to convert these subjective semi-quantitative assessments into formal numerical scores (4,10–13). Histological scoring systems are now widely used as a supplement to conventional histopathological reporting of liver biopsies from patients with chronic hepatitis, particularly from patients involved in clinical trials assessing the efficacy of new therapeutic agents. In these circumstances, descriptive histological reports (on which it is difficult to make direct comparisons or carry out statistical analysis) are sometimes replaced by numerical scores, which are much more amenable to statistical manipulation. Whilst pressure from clinical colleagues and members of the pharmaceutical industry will no doubt ensure that scoring systems will continue to be used, there are several problems (both theoretical and practical) which will be considered in further detail here. The majority of activity relating to the histological scoring of chronic hepatitis is in the field of chronic viral hepatitis. However, similar approaches may also be applied to other forms of chronic hepatitis, such as autoimmune hepatitis, drug-induced chronic hepatitis and chronic hepatitis of undetermined cause.
Patterns of Necroinflammatory Activity Inflammatory activity in the liver can be divided into two main components. The first involves portal tracts
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simple ‘‘inflammatory spillover’’ in which destruction of periportal hepatocytes does not occur. For these reasons the term ‘‘interface hepatitis’’ is now used to describe any inflammatory lesions which breach the interface between portal areas (or fibrous septa) and the adjacent liver parenchyma. Fig. 1. Pathways of lymphocyte migration to the liver. Three main pathways whereby circulating lymphocytes can gain access to the liver are illustrated in this figure: (i) through portal vessels into portal tracts, (ii) across sinusoidal endothelium into liver parenchyma and (iii) via hepatic venules into perivenular regions (acinar zone 3).
(‘‘portal hepatitis’’) with variable extension into the adjacent periportal regions (‘‘periportal hepatitis’’). The second involves the liver parenchyma (‘‘lobular hepatitis’’). These different patterns of inflammation are probably related to the different pathways whereby circulating inflammatory cells can gain access to the liver (Fig. 1) (14). Portal/periportal hepatitis Inflammatory cells migrating across the endothelium of portal vessels pass into portal connective tissue which is rich in antigen presenting dendritic cells (15,16). A predominantly portal inflammatory infiltrate is one of the characteristic histological features of chronic hepatitis. However, it should be borne in mind that portal hepatitis by itself does not necessarily indicate a diagnosis of chronic hepatitis. Mild portal inflammatory changes, indistinguishable from low-grade chronic viral hepatitis, can be seen in a variety of conditions including systemic illness (7), nearby space-occupying lesions and even in some livers which otherwise would be considered as normal (17). Furthermore, a predominantly portal inflammatory infiltrate is sometimes present in cases of acute viral hepatitis (18), without any implications for chronicity. Considerable attention has focused on the extension of portal inflammatory cells into the adjacent liver parenchyma associated with destruction of the limiting plate and damage to periportal hepatocytes. The terms ‘‘piecemeal necrosis’’ (PMN) or ‘‘lymphocytic piecemeal necrosis’’ have traditionally been used to describe this process. There are two reasons why these terms may no longer be appropriate. Firstly, there is increasing evidence to suggest that death of periportal hepatocytes is mediated via apoptosis rather than necrosis (19–21). Secondly, there are often difficulties in distinguishing ‘‘true’’ piecemeal necrosis (in which there is presumed damage to periportal hepatocytes), from
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Lobular hepatitis Inflammatory cells migrating across the endothelium of hepatic sinusoids can gain direct access to the liver parenchyma causing lobular (or acinar) inflammation. Typically this is present as ‘‘spotty’’ inflammation dispersed randomly throughout the liver parenchyma. In some cases, inflammatory changes are more pronounced in perivenular (acinar zone 3) regions. One possible explanation for this zonal accentuation might be the migration of lymphoid cells across the endothelium of hepatic venules into perivenular areas which are rich in antigen-presenting dendritic cells (22) (Fig. 1). Other functional differences which exist between different acinar zones could also play a role in this respect. In some cases zone 3 damage may be more severe and is associated with areas of confluent necrosis. When areas of zone 3 necrosis link vascular structures (in particular portal tracts to hepatic venules), the term ‘‘bridging’’ necrosis is used. Rarely, in severe cases, there may be complete destruction of hepatocytes in one or more acini (panacinar necrosis or multiacinar necrosis). Functional significance of necroinflammatory activity The main purpose in identifying different patterns of necroinflammatory activity is that these may have differerent functional and prognostic significance in terms of progression to fibrosis and ultimately cirrhosis. Similar comments apply to the numerical scoring of necroinflammatory activity. Piecemeal necrosis (interface hepatitis) has long been considered as an important lesion in the evolution of chronic hepatitis to cirrhosis. In the original classification proposed by de Groote et al. (1), chronic persistent hepatitis (portal inflammation without PMN) was thought to have a favourable prognosis, whereas chronic active hepatitis (portal inflammation with PMN) was regarded as having a substantial risk of progression to cirrhosis. Whilst interface hepatitis (with associated periportal liver cell loss and collapse of the reticulin framework) can readily be visualised as a mechanism for the development of periportal fibrosis (23), there have been few attempts to validate this lesion as a prognostic feature in serial biopsies. One study by Mattsson et al. (24) showed that the presence of PMN in initial biopsies from patients with chronic
Histological grading and staging in chronic hepatitis
post-transfusion non A, non B hepatitis (presumably hepatitis C) correlated with the subsequent development of cirrhosis. Two more recent studies (again in cases of chronic hepatitis C) have demonstrated an association between the severity of necroinflammatory activity (including PMN as a major component) in an initial biopsy and the development of fibrosis or cirrhosis in follow-up biopsies (25,26). The possible role of lobular inflammatory lesions in the progression of chronic hepatitis to cirrhosis has been recognised more recently. Bridging necrosis was noted as a risk factor for the development of cirrhosis by Boyer & Klatskin (27) and this observation was confirmed in a subsequent study by Cooksley et al. (28). Bursts of lobular inflammatory activity are thought to be particularly important in the pathogenesis of chronic hepatitis C infection, where progression to cirrhosis is common despite the lack of interface activity (3,12,29–31). For these reasons it has been suggested that the pattern and severity of lobular inflammation should be taken into account in assessing the likely outcome in some cases of chronic hepatitis (3,23). It is clear that factors other than histological severity of inflammation must play a role in the development of fibrosis. Perhaps the best evidence for this comes from studies on patients with chronic hepatitis C infection. Chronic HCV infection is characterised by low-grade inflammatory changes, which would be classified as CPH or very mild CAH using the old system. Interface activity is seldom conspicuous and bridging necrosis is very rarely seen. Despite these ‘‘favourable’’ histological appearances, a substantial proportion of patients develop progressive fibrosis leading eventually to cirrhosis. As noted above, it is possible that transient bursts of lobular inflammatory activity (not necessarily seen in liver biopsies), are important in the pathogenesis of fibrosis in chronic HCV infection. However, other factors including direct cytopathic damage to hepatocytes or activation of hepatic stellate cells by non-inflammatory pathways may also have an important role in the development of liver damage in this situation.
liver transplantation), cirrhosis can develop much more quickly (within a few months). Parenchymal fibrosis can also occur in the wake of lobular inflammation, particularly in areas of bridging necrosis. This may be responsible for the formation of portal-central septa (28), which have been regarded as more significant in the development of cirrhosis than portal-portal linkages (5). Connective tissue stains are essential for the accurate assessment of liver architecture and hepatic fibrosis. A distinction should be drawn between areas of recent collapse (demonstrated by reticulin staining) and the development of mature fibrous septa (demonstrated by trichrome methods or Orcein staining for elastic fibres) (32). The former lesions are potentially recoverable by hepatocellular regeneration, whereas the latter are more likely to be associated with progressive architectural disturbance.
Other Histological Findings In addition to the basic patterns of necroinflammatory activity and fibrosis described above, there may be other histological abnormalities reflecting different aetiological factors. Some of these factors may have an additional role in the development of chronic liver damage. Hepatitis B virus (HBV) infection is characterised by features such as nuclear pleomorphism, cytoplasmic eosinophilia and acidophil bodies surrounded by inflammatory cells (satellitosis) (33). Immunohistochemical staining for HBV-associated antigens is useful in confirming the presence of viral infection in tissue sections and may provide additional information on the likely state of viral replication. Characteristic histological features of hepatitis C virus (HCV) infection include portal lymphoid aggregates, bile duct damage and fatty change (29,30). A variety of techniques have been used to identify HCV antigens in tissue sections. These include immunohistochemistry, in-situ hybridization and in-situ polymerase chain reaction. However, none of these approaches is sufficiently reliable to be used in routine diagnosis. Diagnostic features relating to other causes of chronic hepatitis will not be considered in further detail here.
Assessment of Hepatic Fibrosis In the majority of cases fibrosis begins as expansion of portal tracts occurring in association with interface hepatitis. As fibrosis progresses, there is formation of septa with the development of portal-portal linkages. Eventually hepatocyte nodules are completely surrounded by fibrous tissue. The development of established cirrhosis usually takes several years. However, in some situations (e.g. viral hepatitis recurring following
Scoring Systems Currently in Use Many histological scoring systems for chronic hepatitis have been proposed. Some evaluate histological features which are present in all forms of chronic hepatitis, while others incorporate changes which are more or less specific for a particular aetiology. A detailed evaluation of all of the scoring systems which have been proposed is beyond the scope of this paper. How-
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S. G. Hu¨bscher TABLE 1 Histological Activity Index (Knodell et al. 1981) (10) Periportal∫bridging necrosis 0ΩNone 1ΩMild piecemeal necrosis 3ΩModerate piecemeal necrosis (∞50% of circumference of most tracts) 4ΩMarked piecemeal necrosis (±50% of circumference of most tracts) 5ΩModerate piecemeal necrosis and bridging necrosis 6ΩMarked piecemeal necrosis and bridging necrosis 10ΩMultilobular necrosis Intralobular degeneration and focal necrosis 0Ω None 1Ω Mild (acidophilic bodies, ballooning degeneration and/or scattered foci of necrosis in ∞1/3 of lobules or nodules) 3Ω Moderate (involvement of 1/3–2/3 lobules or nodules) 4Ω Marked (involvement of ±2/3 of lobules or nodules) Portal inflammation 0Ω None 1Ω Mild (few inflammatory cells in ∞1/3 of tracts) 3Ω Moderate (increased inflammatory cells in 1/3–2/3 of tracts) 4Ω Marked (numerous inflammatory cells in ±2/3 of tracts) Fibrosis 0Ω No fibrosis 1Ω Fibrous portal expansion 3Ω Bridging fibrosis (Portal-Portal or Portal-Central) 4Ω Cirrhosis
ever, it is worth briefly reviewing three papers which represent ‘‘landmarks’’ in the field. ‘‘Histological Activity Index’’ (Knodell et al. 1981) (Table 1) (10) The Knodell system was the first formal numerical scoring system to be proposed. It involves assessment of four main histological features, as summarised in Table 1. Scores for the individual categories can be added to produce an overall ‘‘histological activity index’’ ranging from 0–22. The Knodell system has been widely used in many studies throughout the world. A number of criticisms can be made of the Knodell system. Firstly, the original study was based on a small number of specimens – 14 biopsies from five patients with ‘‘asymptomatic chronic active hepatitis’’. Although good observer agreement was obtained amongst the six participants in the original study, no attempt was made to validate the reproducibility of the Knodell system subsequently. Two recent studies evaluating the Knodell system have shown good observer agreement for scores relating to fibrosis, but less good agreement for the inflammatory components (11,34). A second criticism relates to the way in which scoring is carried out. A discontinuous scale (0,1,3,4) is used for each of the histological features assessed. The rea-
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sons for this idiosyncratic scoring system are not clearly explained in the original paper. Thirdly, scores for inflammatory activity are combined with scores for fibrosis. For reasons discussed earlier, it is more logical to separate inflammatory ‘‘grade’’ from fibrosis ‘‘stage’’. Combining scores for these two separate processes may produce a misleading picture, as illustrated by the example in Table 2. Fourthly, scores for portal inflammation involve combining assessments relating to the density of inflammation within individual portal areas and the overall proportion of portal tracts involved. A biopsy in which a small proportion of portal tracts (less than one third) contained a moderately dense infiltrate of inflammatory cells (not uncommon in cases of chronic hepatitis C infection) would be difficult to score using this system. Finally, the first category assessed in the Knodell system combines piecemeal necrosis (interface hepatitis) with bridging necrosis. The latter is now generally regarded as a manifestation of lobular activity and should therefore be assessed separately (5). A Simplified System for Scoring in Chronic Viral Hepatitis (Scheuer 1991) (Tables 3 and 4) (4) In this simplified system two main components of necroinflammatory activity are assessed, each on a scale of 0–4 (Table 3). Fibrosis is assessed separately, again on a scale of 0–4 (Table 4). This simplified system has a number of advantages over the Knodell system. Firstly a continuous scale of 0–4 is used for both components of necroinflammatory activity. By using this simplified approach, scores for portal/periportal activity can readily be ‘‘translated’’ to the old terminology of CPH and varying degrees of CAH. Secondly, inflammatory activity and fibrosis are considered separately, in line with current concepts of these being two distinct processes. Thirdly, bridging necrosis is now considered under lobular activity rather than in the same category as piecemeal necrosis.
TABLE 2 An example of how two hypothetical patients with quite different histological changes may obtain the same Knodell score. Patient 1 has an established cirrhosis with mild inflammatory activity. Patient 2 has chronic hepatitis with moderate ongoing inflammatory activity, but no fibrosis. Prognosis and suitability for antiviral therapy are likely to be quite different in these two cases Periportal∫ Intralobular Portal Fibrosis Total bridging degeneration inflammanecrosis and focal tion necrosis Patient 1 Patient 2
1 3
1 1
2 4
4 0
8 8
Histological grading and staging in chronic hepatitis TABLE 3
TABLE 5
A simple system for scoring necroinflammatory activity in chronic hepatitis (Scheuer 1991) (4)
Modified HAI grading: necroinflammatory scores (Ishak et al. 1995) (13)
Grade
Portal/periportal activity
0 1
none or minimal portal inflammation (CPH)
2 3 4
Lobular activity
none inflammation but no necrosis mild piecemeal necrosis (mild focal necrosis or CAH) acidophil bodies moderate piecemeal necrosis severe focal cell damage (moderate CAH) severe piecemeal necrosis damage includes bridging (severe CAH) necrosis
TABLE 4 A scoring system for fibrosis and cirrhosis (Scheuer 1991) (4) Grade
Fibrosis
0 1 2 3
none enlarged, fibrotic portal tracts periportal or portal-portal septa but intact architecture fibrosis with architectural distortion but no obvious cirrhosis probable or definite cirrhosis
4
The main criticism of the Scheuer system is that it produces a narrower range of potential scores (0–8 for necroinflammatory activity) than was possible using the Knodell system. This limits its usefulness in the context of monitoring response to therapy in clinical trials. Another potential problem is that the criteria used to define different grades of necroinflammatory activity (particularly periportal inflammation) are not clearly stated. This might lead to problems with interobserver reproducibility. However, a recent multi-observer study showed better observer agreement for inflammatory activity using the Scheuer system compared with the Knodell system (34). Histological Grading and Staging of Chronic Hepatitis (Ishak et al. 1995) (Tables 5 and 6) (13) This scheme represents an extension of the original Knodell system, with a number of minor modifications. Firstly, a continuous scale is used for scoring each of the features assessed. Secondly necroinflammatory activity and fibrosis are considered as separate categories. Thirdly, confluent necrosis is separated from periportal hepatitis and is included as a separate category of necroinflammatory activity. By combining scores for each of the four individual necroinflammatory categories, histological grading scores ranging from 0–18 can now be achieved. Fibrosis is staged separately on a scale of 0–6.
Score A. Periportal or periseptal interface hepatitis (piecemeal necrosis) Absent Mild (focal, few portal areas) Mild/moderate (focal, most portal areas) Moderate (continuous around ∞50% of tracts or septa) Severe (continuous around ±50% of tracts or septa)
0 1 2 3 4
B. Confluent necrosis Absent Focal confluent necrosis Zone 3 necrosis in some areas Zone 3 necrosis in most areas Zone 3 necrosisπoccasional portal-central (P-C) bridging Zone 3 necrosisπmultiple P-C bridging Panacinar or multiacinar necrosis
0 1 2 3 4 5 6
C. Focal (spotty) lytic necrosis, apoptosis and focal inflammation Absent One focus or less per 10¿ objective Two to four foci per 10¿ objective Five to ten foci per 10¿ objective More than ten foci per 10¿ objective
0 1 2 3 4
D. Portal inflammation None Mild, some or all portal areas Moderate, some or all portal areas Moderate/marked, all portal areas Marked, all portal areas
0 1 2 3 4
Maximum possible score
18
TABLE 6 Modified staging: architectural changes, fibrosis and cirrhosis (Ishak et al. 1995) (13) Change
Score
No fibrosis Fibrous expansion of some portal areas, with or without short fibrous septa Fibrous expansion of most portal areas, with or without short fibrous septa Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging Fibrous expansion of portal areas with marked bridging (portal to portal (P-P) as well as portal to central (P-C)) Marked bridging (P-P and/or (P-C) with occasional nodules (incomplete cirrhosis) Cirrhosis, probable or definite
0 1
Maximum possible score
2 3 4 5 6 6
Each of the systems currently in use has strengths and weaknesses. All suffer from problems which apply to any form of histological scoring of liver biopsies in chronic hepatitis. These problems are discussed further below. The system proposed by Ishak et al. incorporates current concepts relating to the pathogenesis of
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liver damage in chronic hepatitis, has the backing of a distinguished panel of internationally renowned liver pathologists, and, by providing a wide range of possible scores, is also likely to be popular with clinicians managing patients with chronic hepatitis and with members of the pharmaceutical industry. The Ishak system is already used in many centres and it is likely that it will be more widely used in the future.
Problems with Histological Scoring There are a number of problems which apply to all of the scoring systems currently in use. Lack of scientific validation A fundamental problem with histological ‘‘scoring’’ is that the numbers which are generated do not represent measurements of a continuous variable (34–36). Instead, they simply represent different categories of severity. To illustrate this general point with a specific example, panacinar necrosis would score 10 points compared to 1 point for focal (spotty) lobular necrosis in the Knodell system, 4 points versus 1 point in the Scheuer system, and 6 points versus 1 point in the Ishak system. Whilst all scoring systems recognise that panacinar necrosis is a more severe lesion than spotty lobular necrosis, the relative scores applied to these two lesions are entirely arbitrary and cannot be regarded as mathematically valid. This contrasts with biochemical measurements, for example, serum transaminases, for which a numerical progression can be more readily justified. Because the data generated by histological scoring do not represent a true numerical progression, nonparametric techniques are required for statistical analysis. This point has been overlooked in many studies (34). The problems outlined above are compounded if scores for individual categories (which may have different pathogenetic mechanisms and prognostic significance) are added together. As an example, Table 7
TABLE 7 An example of how two hypothetical patients with quite different histological changes may obtain the same total score for histological inflammatory grade when the Ishak system is used. Patient 1 has ‘‘acute’’ lobular hepatitis with spotty and confluent necrosis. Patient 2 has chronic hepatitis with severe periportal inflammatory activity (‘‘chronic active hepatitis’’)
Patient 1 Patient 2
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Periportal/ periseptal interface hepatitis
Confluent necrosis
Focal spotty necrosis
Portal inflammation
Total score
1 4
2 0
4 1
2 4
9 9
shows how two biopsies with quite different histological appearances can achieve the same overall grading score using the Ishak system. Observer variation There are problems in obtaining reproducible results, even when scoring systems are applied by experts in the field of liver pathology (11,34). In general, better reproducibility has been obtained for scoring fibrosis than for scoring inflammatory activity. The problems stem partly from the imprecise terminology which is used in defining individual histological features. Terms such as ‘‘occasional’’, ‘‘some’’ and ‘‘most’’ or ‘‘mild’’, ‘‘moderate’’ and ‘‘severe’’ are used without defining precisely what these mean. Problems of inter-observer variation can be largely overcome if pathologists participating in a multicentre study discuss in detail how they will actually apply the scoring system to be used before the study commences (11,12). Circulation of one or more sets of slides for scoring, followed by open discussion of areas where disparities exist, also help in achieving a uniform approach. Better intraobserver reproducibility can be obtained if slides are assessed by a pair of pathologists rather than by a single person (11). Sampling variation The problem of sampling variation in needle biopsies is one which receives too little attention. Much of the knowledge regarding this problem has come from the examination of hepatectomy specimens obtained at liver transplantation (37). Sampling variations exist, both for the grade of necroinflammatory activity and for the stage of fibrosis. For example, small areas of multiacinar necrosis can often be found in a liver which otherwise shows a relatively inactive cirrhosis. These areas are typically subcapsular in location but may also be present elsewhere. If a needle biopsy is taken from one of these areas, a ‘‘falsely high’’ inflammatory score may be obtained. Similarly, widely divergent fibrosis scores have been identified in samples taken simultaneously from different areas of livers with primary biliary cirrhosis (37) and primary sclerosing cholangitis (38). Whilst other forms of chronic liver disease (e.g. chronic viral hepatitis) may affect the liver more uniformly, considerable variation in the severity of fibrosis can still be seen when whole livers are available for examination. Aetiological considerations The scoring systems currently in common use incorporate histological features which may be seen in all
Histological grading and staging in chronic hepatitis
forms of chronic hepatitis. However, it is quite clear that different types of chronic hepatitis have marked differences in natural history and response to therapy. These differences in behaviour may be reflected by different patterns of histological damage. For example, ballooning, rosetting and giant cell transformation may be regarded as signs of severe damage in cases of autoimmune hepatitis, even in the absence of conspicuous inflammatory activity. Direct cytopathic damage (e.g. hepatocyte ballooning or fatty change) may be important in the pathogenesis of fibrosis in chronic hepatitis C infection (39). Immunohistochemical staining for viral antigens, including identification of superinfection with delta virus, may be important as an adjunct to conventional histological assessment in classifying liver damage in chronic hepatitis B infection. Some local scoring systems have incorporated additional features relevant to particular causes of chronic hepatitis, but this approach has not been widely accepted.
Conclusions Numerical scoring of liver biopsies will continue to have a place in the context of clinical trials. In order to obtain meaningful, reproducible results, assessments should be carried out by a small number of experienced liver pathologists who have preferably worked together to develop a uniform approach to scoring histological features in liver biopsies. Histological scoring is less relevant in routine clinical practice. Traditional descriptive reports (including specific comments relating to aetiology, necroinflammatory activity and fibrosis) should remain the basis for routine histological assessments. For clinical colleagues who are insistent on having histological ‘‘scores’’ for their patients, an attempt should be made to indicate clearly how the final scores have been achieved. This can be done simply by appending a proforma including boxes for each of the categories assessed to the conventional histology report. The occasional application of histological scoring by pathologists with little experience in the field of liver pathology (and the interpretation of these ‘‘results’’ by similarly inexperienced clinicians) should be strongly discouraged. In the future, it is to be hoped that more attention will be paid to assessing individual components of inflammatory activity rather than concentrating on overall scores. With such an approach, it might be easier to decide which histological features are important in terms of prognosis and in determining response to therapy. Based on such an improved understanding, new models for deciding on appropriate therapy may be devised.
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Journal of Hepatology 1998; 29: 1015–1022 Printed in Denmark ¡ All rights reserved Munksgaard ¡ Copenhagen
Journal of Hepatology ISSN 0168-8278
Special Article
Histological grading and staging in chronic hepatitis: clinical applications and problems Stefan G. Hu¨bscher Department of Pathology, University of Birmingham, Birmingham, UK
years there has been a marked change in the approach to the histological classification of chronic hepatitis. The terms ‘‘chronic active hepatitis’’ (CAH), ‘‘chronic persistent hepatitis’’ (CPH) and ‘‘chronic lobular hepatitis’’ (CLH), which have been in use for almost 30 years, were proposed at a time when little was known about the aetiology or pathogenesis of chronic hepatitis (1,2). With better understanding of the different causes and varying natural history of chronic hepatitis, several deficiencies in the old system of classifying chronic hepatitis were identified (3,4). A new approach to classifying chronic viral hepatitis was proposed by Scheuer in 1991 (4) and is now widely accepted for classifying other types of chronic hepatitis also (5–7). The new approach to classifying chronic hepatitis involves three separate considerations. The first is a comment on the aetiology. Frequently, this cannot be determined with certainty on the basis of histological appearances alone, and the diagnosis is made on the basis of other laboratory investigations. The second assessment relates to the severity and distribution of necroinflammatory activity (histological ‘‘grade’’). This component of the disease can be regarded as potentially treatable. Thirdly, an attempt should be made to assess the degree of fibrosis (histological ‘‘stage’’). Fibrosis is considered to be a marker of progressive damage, which is less likely to be reversible. As a consequence of these developments, the terms CAH, CPH and CLH can now be regarded as obsolete, and their use is no longer recommended. The reasons for the demise of the old system of classifying chronic hepatitis and the advantages of the new approach have been extensively discussed elsewhere (4–9) and will therefore not be considered in further detail here. The traditional method of reporting on liver biopsies
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Correspondence: Stefan G. Hu¨bscher, Department of Pathology, University of Birmingham, Birmingham, B15 2TT, UK. Tel: 44 (0) 121 414 4005. Fax: 44 (0) 121 414 4019. E-mail: s.g.hubscher/bham.ac.uk
from patients with chronic hepatitis (and other liver diseases) involves identifying histological features which are thought to be clinically relevant and then interpreting any abnormalities identified in the light of clinical findings and other laboratory investigations. This descriptive approach can be supplemented by semi-quantitative assessments of one or more histological features. Terms such as ‘‘minimal’’, ‘‘mild’’, ‘‘moderate’’ and ‘‘severe’’ may be used to describe the degree of necroinflammatory activity or the extent of fibrosis. Severity of necroinflammatory activity can be expressed as an overall grade or subdivided according to individual histological components (see below). A number of attempts have been made to convert these subjective semi-quantitative assessments into formal numerical scores (4,10–13). Histological scoring systems are now widely used as a supplement to conventional histopathological reporting of liver biopsies from patients with chronic hepatitis, particularly from patients involved in clinical trials assessing the efficacy of new therapeutic agents. In these circumstances, descriptive histological reports (on which it is difficult to make direct comparisons or carry out statistical analysis) are sometimes replaced by numerical scores, which are much more amenable to statistical manipulation. Whilst pressure from clinical colleagues and members of the pharmaceutical industry will no doubt ensure that scoring systems will continue to be used, there are several problems (both theoretical and practical) which will be considered in further detail here. The majority of activity relating to the histological scoring of chronic hepatitis is in the field of chronic viral hepatitis. However, similar approaches may also be applied to other forms of chronic hepatitis, such as autoimmune hepatitis, drug-induced chronic hepatitis and chronic hepatitis of undetermined cause.
Patterns of Necroinflammatory Activity Inflammatory activity in the liver can be divided into two main components. The first involves portal tracts
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simple ‘‘inflammatory spillover’’ in which destruction of periportal hepatocytes does not occur. For these reasons the term ‘‘interface hepatitis’’ is now used to describe any inflammatory lesions which breach the interface between portal areas (or fibrous septa) and the adjacent liver parenchyma. Fig. 1. Pathways of lymphocyte migration to the liver. Three main pathways whereby circulating lymphocytes can gain access to the liver are illustrated in this figure: (i) through portal vessels into portal tracts, (ii) across sinusoidal endothelium into liver parenchyma and (iii) via hepatic venules into perivenular regions (acinar zone 3).
(‘‘portal hepatitis’’) with variable extension into the adjacent periportal regions (‘‘periportal hepatitis’’). The second involves the liver parenchyma (‘‘lobular hepatitis’’). These different patterns of inflammation are probably related to the different pathways whereby circulating inflammatory cells can gain access to the liver (Fig. 1) (14). Portal/periportal hepatitis Inflammatory cells migrating across the endothelium of portal vessels pass into portal connective tissue which is rich in antigen presenting dendritic cells (15,16). A predominantly portal inflammatory infiltrate is one of the characteristic histological features of chronic hepatitis. However, it should be borne in mind that portal hepatitis by itself does not necessarily indicate a diagnosis of chronic hepatitis. Mild portal inflammatory changes, indistinguishable from low-grade chronic viral hepatitis, can be seen in a variety of conditions including systemic illness (7), nearby space-occupying lesions and even in some livers which otherwise would be considered as normal (17). Furthermore, a predominantly portal inflammatory infiltrate is sometimes present in cases of acute viral hepatitis (18), without any implications for chronicity. Considerable attention has focused on the extension of portal inflammatory cells into the adjacent liver parenchyma associated with destruction of the limiting plate and damage to periportal hepatocytes. The terms ‘‘piecemeal necrosis’’ (PMN) or ‘‘lymphocytic piecemeal necrosis’’ have traditionally been used to describe this process. There are two reasons why these terms may no longer be appropriate. Firstly, there is increasing evidence to suggest that death of periportal hepatocytes is mediated via apoptosis rather than necrosis (19–21). Secondly, there are often difficulties in distinguishing ‘‘true’’ piecemeal necrosis (in which there is presumed damage to periportal hepatocytes), from
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Lobular hepatitis Inflammatory cells migrating across the endothelium of hepatic sinusoids can gain direct access to the liver parenchyma causing lobular (or acinar) inflammation. Typically this is present as ‘‘spotty’’ inflammation dispersed randomly throughout the liver parenchyma. In some cases, inflammatory changes are more pronounced in perivenular (acinar zone 3) regions. One possible explanation for this zonal accentuation might be the migration of lymphoid cells across the endothelium of hepatic venules into perivenular areas which are rich in antigen-presenting dendritic cells (22) (Fig. 1). Other functional differences which exist between different acinar zones could also play a role in this respect. In some cases zone 3 damage may be more severe and is associated with areas of confluent necrosis. When areas of zone 3 necrosis link vascular structures (in particular portal tracts to hepatic venules), the term ‘‘bridging’’ necrosis is used. Rarely, in severe cases, there may be complete destruction of hepatocytes in one or more acini (panacinar necrosis or multiacinar necrosis). Functional significance of necroinflammatory activity The main purpose in identifying different patterns of necroinflammatory activity is that these may have differerent functional and prognostic significance in terms of progression to fibrosis and ultimately cirrhosis. Similar comments apply to the numerical scoring of necroinflammatory activity. Piecemeal necrosis (interface hepatitis) has long been considered as an important lesion in the evolution of chronic hepatitis to cirrhosis. In the original classification proposed by de Groote et al. (1), chronic persistent hepatitis (portal inflammation without PMN) was thought to have a favourable prognosis, whereas chronic active hepatitis (portal inflammation with PMN) was regarded as having a substantial risk of progression to cirrhosis. Whilst interface hepatitis (with associated periportal liver cell loss and collapse of the reticulin framework) can readily be visualised as a mechanism for the development of periportal fibrosis (23), there have been few attempts to validate this lesion as a prognostic feature in serial biopsies. One study by Mattsson et al. (24) showed that the presence of PMN in initial biopsies from patients with chronic
Histological grading and staging in chronic hepatitis
post-transfusion non A, non B hepatitis (presumably hepatitis C) correlated with the subsequent development of cirrhosis. Two more recent studies (again in cases of chronic hepatitis C) have demonstrated an association between the severity of necroinflammatory activity (including PMN as a major component) in an initial biopsy and the development of fibrosis or cirrhosis in follow-up biopsies (25,26). The possible role of lobular inflammatory lesions in the progression of chronic hepatitis to cirrhosis has been recognised more recently. Bridging necrosis was noted as a risk factor for the development of cirrhosis by Boyer & Klatskin (27) and this observation was confirmed in a subsequent study by Cooksley et al. (28). Bursts of lobular inflammatory activity are thought to be particularly important in the pathogenesis of chronic hepatitis C infection, where progression to cirrhosis is common despite the lack of interface activity (3,12,29–31). For these reasons it has been suggested that the pattern and severity of lobular inflammation should be taken into account in assessing the likely outcome in some cases of chronic hepatitis (3,23). It is clear that factors other than histological severity of inflammation must play a role in the development of fibrosis. Perhaps the best evidence for this comes from studies on patients with chronic hepatitis C infection. Chronic HCV infection is characterised by low-grade inflammatory changes, which would be classified as CPH or very mild CAH using the old system. Interface activity is seldom conspicuous and bridging necrosis is very rarely seen. Despite these ‘‘favourable’’ histological appearances, a substantial proportion of patients develop progressive fibrosis leading eventually to cirrhosis. As noted above, it is possible that transient bursts of lobular inflammatory activity (not necessarily seen in liver biopsies), are important in the pathogenesis of fibrosis in chronic HCV infection. However, other factors including direct cytopathic damage to hepatocytes or activation of hepatic stellate cells by non-inflammatory pathways may also have an important role in the development of liver damage in this situation.
liver transplantation), cirrhosis can develop much more quickly (within a few months). Parenchymal fibrosis can also occur in the wake of lobular inflammation, particularly in areas of bridging necrosis. This may be responsible for the formation of portal-central septa (28), which have been regarded as more significant in the development of cirrhosis than portal-portal linkages (5). Connective tissue stains are essential for the accurate assessment of liver architecture and hepatic fibrosis. A distinction should be drawn between areas of recent collapse (demonstrated by reticulin staining) and the development of mature fibrous septa (demonstrated by trichrome methods or Orcein staining for elastic fibres) (32). The former lesions are potentially recoverable by hepatocellular regeneration, whereas the latter are more likely to be associated with progressive architectural disturbance.
Other Histological Findings In addition to the basic patterns of necroinflammatory activity and fibrosis described above, there may be other histological abnormalities reflecting different aetiological factors. Some of these factors may have an additional role in the development of chronic liver damage. Hepatitis B virus (HBV) infection is characterised by features such as nuclear pleomorphism, cytoplasmic eosinophilia and acidophil bodies surrounded by inflammatory cells (satellitosis) (33). Immunohistochemical staining for HBV-associated antigens is useful in confirming the presence of viral infection in tissue sections and may provide additional information on the likely state of viral replication. Characteristic histological features of hepatitis C virus (HCV) infection include portal lymphoid aggregates, bile duct damage and fatty change (29,30). A variety of techniques have been used to identify HCV antigens in tissue sections. These include immunohistochemistry, in-situ hybridization and in-situ polymerase chain reaction. However, none of these approaches is sufficiently reliable to be used in routine diagnosis. Diagnostic features relating to other causes of chronic hepatitis will not be considered in further detail here.
Assessment of Hepatic Fibrosis In the majority of cases fibrosis begins as expansion of portal tracts occurring in association with interface hepatitis. As fibrosis progresses, there is formation of septa with the development of portal-portal linkages. Eventually hepatocyte nodules are completely surrounded by fibrous tissue. The development of established cirrhosis usually takes several years. However, in some situations (e.g. viral hepatitis recurring following
Scoring Systems Currently in Use Many histological scoring systems for chronic hepatitis have been proposed. Some evaluate histological features which are present in all forms of chronic hepatitis, while others incorporate changes which are more or less specific for a particular aetiology. A detailed evaluation of all of the scoring systems which have been proposed is beyond the scope of this paper. How-
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S. G. Hu¨bscher TABLE 1 Histological Activity Index (Knodell et al. 1981) (10) Periportal∫bridging necrosis 0ΩNone 1ΩMild piecemeal necrosis 3ΩModerate piecemeal necrosis (∞50% of circumference of most tracts) 4ΩMarked piecemeal necrosis (±50% of circumference of most tracts) 5ΩModerate piecemeal necrosis and bridging necrosis 6ΩMarked piecemeal necrosis and bridging necrosis 10ΩMultilobular necrosis Intralobular degeneration and focal necrosis 0Ω None 1Ω Mild (acidophilic bodies, ballooning degeneration and/or scattered foci of necrosis in ∞1/3 of lobules or nodules) 3Ω Moderate (involvement of 1/3–2/3 lobules or nodules) 4Ω Marked (involvement of ±2/3 of lobules or nodules) Portal inflammation 0Ω None 1Ω Mild (few inflammatory cells in ∞1/3 of tracts) 3Ω Moderate (increased inflammatory cells in 1/3–2/3 of tracts) 4Ω Marked (numerous inflammatory cells in ±2/3 of tracts) Fibrosis 0Ω No fibrosis 1Ω Fibrous portal expansion 3Ω Bridging fibrosis (Portal-Portal or Portal-Central) 4Ω Cirrhosis
ever, it is worth briefly reviewing three papers which represent ‘‘landmarks’’ in the field. ‘‘Histological Activity Index’’ (Knodell et al. 1981) (Table 1) (10) The Knodell system was the first formal numerical scoring system to be proposed. It involves assessment of four main histological features, as summarised in Table 1. Scores for the individual categories can be added to produce an overall ‘‘histological activity index’’ ranging from 0–22. The Knodell system has been widely used in many studies throughout the world. A number of criticisms can be made of the Knodell system. Firstly, the original study was based on a small number of specimens – 14 biopsies from five patients with ‘‘asymptomatic chronic active hepatitis’’. Although good observer agreement was obtained amongst the six participants in the original study, no attempt was made to validate the reproducibility of the Knodell system subsequently. Two recent studies evaluating the Knodell system have shown good observer agreement for scores relating to fibrosis, but less good agreement for the inflammatory components (11,34). A second criticism relates to the way in which scoring is carried out. A discontinuous scale (0,1,3,4) is used for each of the histological features assessed. The rea-
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sons for this idiosyncratic scoring system are not clearly explained in the original paper. Thirdly, scores for inflammatory activity are combined with scores for fibrosis. For reasons discussed earlier, it is more logical to separate inflammatory ‘‘grade’’ from fibrosis ‘‘stage’’. Combining scores for these two separate processes may produce a misleading picture, as illustrated by the example in Table 2. Fourthly, scores for portal inflammation involve combining assessments relating to the density of inflammation within individual portal areas and the overall proportion of portal tracts involved. A biopsy in which a small proportion of portal tracts (less than one third) contained a moderately dense infiltrate of inflammatory cells (not uncommon in cases of chronic hepatitis C infection) would be difficult to score using this system. Finally, the first category assessed in the Knodell system combines piecemeal necrosis (interface hepatitis) with bridging necrosis. The latter is now generally regarded as a manifestation of lobular activity and should therefore be assessed separately (5). A Simplified System for Scoring in Chronic Viral Hepatitis (Scheuer 1991) (Tables 3 and 4) (4) In this simplified system two main components of necroinflammatory activity are assessed, each on a scale of 0–4 (Table 3). Fibrosis is assessed separately, again on a scale of 0–4 (Table 4). This simplified system has a number of advantages over the Knodell system. Firstly a continuous scale of 0–4 is used for both components of necroinflammatory activity. By using this simplified approach, scores for portal/periportal activity can readily be ‘‘translated’’ to the old terminology of CPH and varying degrees of CAH. Secondly, inflammatory activity and fibrosis are considered separately, in line with current concepts of these being two distinct processes. Thirdly, bridging necrosis is now considered under lobular activity rather than in the same category as piecemeal necrosis.
TABLE 2 An example of how two hypothetical patients with quite different histological changes may obtain the same Knodell score. Patient 1 has an established cirrhosis with mild inflammatory activity. Patient 2 has chronic hepatitis with moderate ongoing inflammatory activity, but no fibrosis. Prognosis and suitability for antiviral therapy are likely to be quite different in these two cases Periportal∫ Intralobular Portal Fibrosis Total bridging degeneration inflammanecrosis and focal tion necrosis Patient 1 Patient 2
1 3
1 1
2 4
4 0
8 8
Histological grading and staging in chronic hepatitis TABLE 3
TABLE 5
A simple system for scoring necroinflammatory activity in chronic hepatitis (Scheuer 1991) (4)
Modified HAI grading: necroinflammatory scores (Ishak et al. 1995) (13)
Grade
Portal/periportal activity
0 1
none or minimal portal inflammation (CPH)
2 3 4
Lobular activity
none inflammation but no necrosis mild piecemeal necrosis (mild focal necrosis or CAH) acidophil bodies moderate piecemeal necrosis severe focal cell damage (moderate CAH) severe piecemeal necrosis damage includes bridging (severe CAH) necrosis
TABLE 4 A scoring system for fibrosis and cirrhosis (Scheuer 1991) (4) Grade
Fibrosis
0 1 2 3
none enlarged, fibrotic portal tracts periportal or portal-portal septa but intact architecture fibrosis with architectural distortion but no obvious cirrhosis probable or definite cirrhosis
4
The main criticism of the Scheuer system is that it produces a narrower range of potential scores (0–8 for necroinflammatory activity) than was possible using the Knodell system. This limits its usefulness in the context of monitoring response to therapy in clinical trials. Another potential problem is that the criteria used to define different grades of necroinflammatory activity (particularly periportal inflammation) are not clearly stated. This might lead to problems with interobserver reproducibility. However, a recent multi-observer study showed better observer agreement for inflammatory activity using the Scheuer system compared with the Knodell system (34). Histological Grading and Staging of Chronic Hepatitis (Ishak et al. 1995) (Tables 5 and 6) (13) This scheme represents an extension of the original Knodell system, with a number of minor modifications. Firstly, a continuous scale is used for scoring each of the features assessed. Secondly necroinflammatory activity and fibrosis are considered as separate categories. Thirdly, confluent necrosis is separated from periportal hepatitis and is included as a separate category of necroinflammatory activity. By combining scores for each of the four individual necroinflammatory categories, histological grading scores ranging from 0–18 can now be achieved. Fibrosis is staged separately on a scale of 0–6.
Score A. Periportal or periseptal interface hepatitis (piecemeal necrosis) Absent Mild (focal, few portal areas) Mild/moderate (focal, most portal areas) Moderate (continuous around ∞50% of tracts or septa) Severe (continuous around ±50% of tracts or septa)
0 1 2 3 4
B. Confluent necrosis Absent Focal confluent necrosis Zone 3 necrosis in some areas Zone 3 necrosis in most areas Zone 3 necrosisπoccasional portal-central (P-C) bridging Zone 3 necrosisπmultiple P-C bridging Panacinar or multiacinar necrosis
0 1 2 3 4 5 6
C. Focal (spotty) lytic necrosis, apoptosis and focal inflammation Absent One focus or less per 10¿ objective Two to four foci per 10¿ objective Five to ten foci per 10¿ objective More than ten foci per 10¿ objective
0 1 2 3 4
D. Portal inflammation None Mild, some or all portal areas Moderate, some or all portal areas Moderate/marked, all portal areas Marked, all portal areas
0 1 2 3 4
Maximum possible score
18
TABLE 6 Modified staging: architectural changes, fibrosis and cirrhosis (Ishak et al. 1995) (13) Change
Score
No fibrosis Fibrous expansion of some portal areas, with or without short fibrous septa Fibrous expansion of most portal areas, with or without short fibrous septa Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging Fibrous expansion of portal areas with marked bridging (portal to portal (P-P) as well as portal to central (P-C)) Marked bridging (P-P and/or (P-C) with occasional nodules (incomplete cirrhosis) Cirrhosis, probable or definite
0 1
Maximum possible score
2 3 4 5 6 6
Each of the systems currently in use has strengths and weaknesses. All suffer from problems which apply to any form of histological scoring of liver biopsies in chronic hepatitis. These problems are discussed further below. The system proposed by Ishak et al. incorporates current concepts relating to the pathogenesis of
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liver damage in chronic hepatitis, has the backing of a distinguished panel of internationally renowned liver pathologists, and, by providing a wide range of possible scores, is also likely to be popular with clinicians managing patients with chronic hepatitis and with members of the pharmaceutical industry. The Ishak system is already used in many centres and it is likely that it will be more widely used in the future.
Problems with Histological Scoring There are a number of problems which apply to all of the scoring systems currently in use. Lack of scientific validation A fundamental problem with histological ‘‘scoring’’ is that the numbers which are generated do not represent measurements of a continuous variable (34–36). Instead, they simply represent different categories of severity. To illustrate this general point with a specific example, panacinar necrosis would score 10 points compared to 1 point for focal (spotty) lobular necrosis in the Knodell system, 4 points versus 1 point in the Scheuer system, and 6 points versus 1 point in the Ishak system. Whilst all scoring systems recognise that panacinar necrosis is a more severe lesion than spotty lobular necrosis, the relative scores applied to these two lesions are entirely arbitrary and cannot be regarded as mathematically valid. This contrasts with biochemical measurements, for example, serum transaminases, for which a numerical progression can be more readily justified. Because the data generated by histological scoring do not represent a true numerical progression, nonparametric techniques are required for statistical analysis. This point has been overlooked in many studies (34). The problems outlined above are compounded if scores for individual categories (which may have different pathogenetic mechanisms and prognostic significance) are added together. As an example, Table 7
TABLE 7 An example of how two hypothetical patients with quite different histological changes may obtain the same total score for histological inflammatory grade when the Ishak system is used. Patient 1 has ‘‘acute’’ lobular hepatitis with spotty and confluent necrosis. Patient 2 has chronic hepatitis with severe periportal inflammatory activity (‘‘chronic active hepatitis’’)
Patient 1 Patient 2
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Periportal/ periseptal interface hepatitis
Confluent necrosis
Focal spotty necrosis
Portal inflammation
Total score
1 4
2 0
4 1
2 4
9 9
shows how two biopsies with quite different histological appearances can achieve the same overall grading score using the Ishak system. Observer variation There are problems in obtaining reproducible results, even when scoring systems are applied by experts in the field of liver pathology (11,34). In general, better reproducibility has been obtained for scoring fibrosis than for scoring inflammatory activity. The problems stem partly from the imprecise terminology which is used in defining individual histological features. Terms such as ‘‘occasional’’, ‘‘some’’ and ‘‘most’’ or ‘‘mild’’, ‘‘moderate’’ and ‘‘severe’’ are used without defining precisely what these mean. Problems of inter-observer variation can be largely overcome if pathologists participating in a multicentre study discuss in detail how they will actually apply the scoring system to be used before the study commences (11,12). Circulation of one or more sets of slides for scoring, followed by open discussion of areas where disparities exist, also help in achieving a uniform approach. Better intraobserver reproducibility can be obtained if slides are assessed by a pair of pathologists rather than by a single person (11). Sampling variation The problem of sampling variation in needle biopsies is one which receives too little attention. Much of the knowledge regarding this problem has come from the examination of hepatectomy specimens obtained at liver transplantation (37). Sampling variations exist, both for the grade of necroinflammatory activity and for the stage of fibrosis. For example, small areas of multiacinar necrosis can often be found in a liver which otherwise shows a relatively inactive cirrhosis. These areas are typically subcapsular in location but may also be present elsewhere. If a needle biopsy is taken from one of these areas, a ‘‘falsely high’’ inflammatory score may be obtained. Similarly, widely divergent fibrosis scores have been identified in samples taken simultaneously from different areas of livers with primary biliary cirrhosis (37) and primary sclerosing cholangitis (38). Whilst other forms of chronic liver disease (e.g. chronic viral hepatitis) may affect the liver more uniformly, considerable variation in the severity of fibrosis can still be seen when whole livers are available for examination. Aetiological considerations The scoring systems currently in common use incorporate histological features which may be seen in all
Histological grading and staging in chronic hepatitis
forms of chronic hepatitis. However, it is quite clear that different types of chronic hepatitis have marked differences in natural history and response to therapy. These differences in behaviour may be reflected by different patterns of histological damage. For example, ballooning, rosetting and giant cell transformation may be regarded as signs of severe damage in cases of autoimmune hepatitis, even in the absence of conspicuous inflammatory activity. Direct cytopathic damage (e.g. hepatocyte ballooning or fatty change) may be important in the pathogenesis of fibrosis in chronic hepatitis C infection (39). Immunohistochemical staining for viral antigens, including identification of superinfection with delta virus, may be important as an adjunct to conventional histological assessment in classifying liver damage in chronic hepatitis B infection. Some local scoring systems have incorporated additional features relevant to particular causes of chronic hepatitis, but this approach has not been widely accepted.
Conclusions Numerical scoring of liver biopsies will continue to have a place in the context of clinical trials. In order to obtain meaningful, reproducible results, assessments should be carried out by a small number of experienced liver pathologists who have preferably worked together to develop a uniform approach to scoring histological features in liver biopsies. Histological scoring is less relevant in routine clinical practice. Traditional descriptive reports (including specific comments relating to aetiology, necroinflammatory activity and fibrosis) should remain the basis for routine histological assessments. For clinical colleagues who are insistent on having histological ‘‘scores’’ for their patients, an attempt should be made to indicate clearly how the final scores have been achieved. This can be done simply by appending a proforma including boxes for each of the categories assessed to the conventional histology report. The occasional application of histological scoring by pathologists with little experience in the field of liver pathology (and the interpretation of these ‘‘results’’ by similarly inexperienced clinicians) should be strongly discouraged. In the future, it is to be hoped that more attention will be paid to assessing individual components of inflammatory activity rather than concentrating on overall scores. With such an approach, it might be easier to decide which histological features are important in terms of prognosis and in determining response to therapy. Based on such an improved understanding, new models for deciding on appropriate therapy may be devised.
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