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Journal of Hepatology 1995; 22: 69fX99 Copyright 0 Journal of HepatologyI995

Printed in Denmark . All rights reserved

Journal of Hepatology
ISSN 0168-8278

Special Article

Histological grading and staging of chronic hepatitis

Kamal Ishak’, Amelia Baptista2, LeonardoBianchi3, Francesco Callea4, Jan De Grootes, Fred Gudat6,
Helmut Denk7, Valeer Desmet*, Gerhard Korb9, Roderick N. M. MacSweeni”, M. James Phillips”“,
Bernard G. Portmannl*, Hemming Paulsen I3 , Peter J . Scheuer14, Martin Schmid15 and Heribert Thaler16
‘Armed Forces instifute of Pathology, Washington, USA, 2University of Lisbon. Lisbon, Portugal, -‘Hofstetten, Switzerland, 4Servizio di Anatomia
e Istologia Patologica. Spedali Civili, Brescia, Italy, 5Department of Medicine, University of Leuven, Leaven, Belgium, 61nstitute for Pathology,
University of Basel, Basel, Switzerland, 7Department of Pathology, University of Graz. Graz, Austria, 8Department of Pathology, University of
Leuven, Leuven, Belgium. 9 Weiden, Germany, ‘ODepartment of Pathology, Western Infirmary, University of Glasgow, Glasgow, UK,
“Department of Pathology, ~osp~talfor Sick Children, University of Toronto, Toronto, Canada, ~‘~nstitute of Liver Studies, King’s College
Hospital, London, UK, 13Frederiksberg, Denmark, Is Watt, Switzerland, “Vienna, Austria

ERE has been much recent discussion of the no- morphological lesions is meaningfully conveyed to the
T menclature and classification of chronic hepatitis. clinician. The ways in which this information can best
be organised are also discussed in the following para-
Since the proposal for a simple histological grading
system by this group in 1968 (1), substantial infor- graphs.
mation has been gained on the viral and other causes
of chronic hepatitis, necessitating a review of the way Grading and Staging
in which liver biopsies in patients with chronic hepa- The concepts of grading and staging have traditionally
titis are evaluated and reported. We do not wish to been applied to neoplasms. Grading describes the de-
comment in detail on the most appropriate nomencla- gree of differentiation of a neoplasm, while staging de-
ture for the 1990s but recognise that several authors notes the extent of its spread. The same principles can
have recommended that the simple subdivision of be applied, however, with some modifications, to non-
chronic hepatitis into chronic persistent (CPH), neoplastic conditions such as chronic hepatitis (3).
chronic active (CAH) and chronic lobular forms Grading may be used to describe the intensity of necro-
(CLH) should no longer form the principal basis for inflammatory activity in chronic hepatitis. Staging, on
classification (24). We agree with the view that, from the other hand, is a measure of fibrosis and architec-
the standpoint of the clinician, the most important tural alteration, i.e. structural progression of the dis-
single factor in diagnosis and evaluation of therapy is ease; these features are currently believed to be the
the cause of the hepatitis. Once the aetiology is estab- consequence of the necroin~ammatory process.
lished, however, histological data continue to provide The purpose of staging and grading is to record
the clinician with information essential for manage- those histological features which are thought to indi-
ment of the patient. cate the severity and the progression of chronic hepa-
The purpose of the present paper is to outline the titis, and which might also be of prognostic signifi-
morphological features which are of importance in cance. In addition, numerical scores can be attributed
undertaking grading and staging in chronic hepatitis to both staging and grading, thus providing a semi-
and to make suggestions with respect to the semi- q~ntitative assessment of the observed histological
quantification of these features so as to produce a nu- features. The extent to which grading and staging can
merical index of histological activity. In addition, we be accurately performed in a single biopsy is limited
suggest ways in which these data can be incorporated by potential sampling error, so that grading and sta-
into histological reports so that the significance of the ging must be regarded as approximations, depending
to some extent on the size and quality of the sample.
Received 2 January 1995 Where many biopsies are evaluated, however, as for in-
C~rresp~~d~~~g: Prof. E Gudat, Institute for Pathology, stance in a clinical trial of an antiviral therapy, a
SchBnbeinstr. 40, CH-4003 Basel, Switzerland greater degree of accuracy can be achieved. We do not

Grading and staging of hepatitis

believe that semi-quantitative grading and staging, as TABLE 1

opposed to simple descriptions of biopsies, are necess- Modified HA1 grading: n~roinfl~matory scores
ary in routine practice. However, trials of new thera- Score
peutic agents and regimes have increased the demand A. Periportal or periseptal interface hepatitis (piecemeal necrosis)
for their use, because they enable different series of pa- Absent 0
Mild (focal, few portal areas) I
tients and therapies to be compared. 2
Mild/moderate (focal, most portal areas)
In addition, grading and staging may have some Moderate (continuous around 60% of tracts or septa) 3
prognostic significance, and may also influence the way Severe (continuous around >50% of tracts or septa) 4
in which a patient is managed. For example, chronic B. Confluent necrosis
hepatitis with a low grading score, in other words a Absent 0
Focal confluent necrosis 1
mild chronic hepatitis, often has a better prognosis in Zone 3 necrosis in some areas 2
a given patient than one with a high score, denoting Zone 3 necrosis in most areas 3
a severe hepatitis. On the other hand, the course and Zone 3 necrosis+occasional portal-central (P-C) bridging 4
Zone 3 necrosis+multiple P-C bridging 5
prognosis of chronic hepatitis cannot be determined Panacinar or multiacinar necrosis 6
without reference to cause, state of viral replication C. Focal (spotty) lytic necrosis, apoptosis and focal inflammation*
and immune response, response to therapy and pres- Absent 0
ence or absence of superinfection. One focus or less per 1OXobjective 1
Two to four foci per lOXobjective 2
Furthermore, grading and staging may provide Five to ten foci per lOXobjective 3
valuable research data. Accurate recording of individ- More than ten foci per fOXobjective 4
ual histological features may give insight into their D. Portal inflammation
interrelationships. An example of such potentially im- None 0
Mild, some or all portal areas 1
portant data is the significance of bridging necrosis in 2
Moderate, some or all portal areas
the initiation and progression of cirrhosis in hepatitis Moderate/marked, all portal areas 3
C virus infection. Marked, all portal areas 4

What Histological Features Should be Included *Does not include diffuse sinusoidal infiltration by inflammatory
in Grading?
Maximum possible score for grading 18
Grading should take into consideration the known and
Additional features which should be noted but not scored:
readily evaluable forms of hepatocellular damage in
Bile-duct inflammation and damage
hepatitis, together with the extent and distribution of Lymphoid follicles
the predominantly lymphocytic infiltrate characteristic Steatosis, mild, moderate or marked
of those diseases conventionally included under the Hepatocellular dysplasia, large- or small-cell
Adenomatous hyperplasia
heading of chronic hepatitis. These are chronic hepa- Iron or copper overload
titis of viral cause, autoimmune hepatitis and drug-in- Intra~ll~ar inclusions (e.g. PAS-positive globules, MalIory bodies)
duced chronic hepatitis, as well as chronic hepatitis of
uncertain cause. We recognise that chronic hepatitis Information on viral antigens, lymphocyte subsets or other features,
shares many histological features with certain other when available, should be recorded and may be semi-quantitatively
chronic inflammatory liver diseases such as primary expressed.

biliary cirrhosis, primary sclerosing cholangitis and

sometimes Wilson’s disease and alpha- 1-antitrypsin de-
ficiency, but we believe that these latter entities need (interface hepatitis), simple con&rent necrosis (death
separate consideration. They are therefore not included of groups of adjacent hepatocytes without clear zonal
in the present discussion. Alcohol abuse may also location or bridging), zonal confluent necrosis (zone
cause histological features of chronic hepatitis, in some 3), bridging necrosis linking vascular structures, and
instances related to infection with a hepatitis virus, but panacinar or multiacinar necrosis. We support the use
classical alcoholic steatohepatitis is not included be- of the term interface hepatitis rather than piecemeal
cause of its essentially different histological character- necrosis, because the main form of liver-cell damage in
istics. this process is thought to be apoptosis rather than lytic
In our view, grading should include assessment of necrosis (5).
portal, periportal and intra-acinar inflammatory cell The designation of bridging necrosis should in our
infiltration, and various forms of liver cell damage and view be restricted to bridging between portal tracts and
necrosis (Table 1): spotty {focal) lytic necrosis and terminal hepatic venules as reflected in the term portal-
apoptosis with liver cell drop-out, piecemeal necrosis central (P-C) bridging. This form of bridging, which

K. Ishak et al.

probably represents necrosis of acinar zones 3 often TABLE 3

starting as perivenular necrosis, is thought to have dif- Example of conventional verbal and semi-numerical liver biopsy re-
ferent prognostic and pathogenetic significance from
linking of portal tracts; the latter is usually the result “This liver biopsy shows preserved acinar architecture, but portal
tracts appear enlarged and short septa extend from them without
of portal expansion by piecemeal or sleeve necrosis (for forming bridges between vascular structures. Portal tracts are infil-
detailed definition of this and other morphological trated by lymphocytes, and lymphoid follicles with germinal centres
terms see (6)). have formed. Interface hepatitis (piecemeal necrosis) is minimal.
There is mild bile-duct damage, as shown by epithelial swelling and
the presence of occasional intra-epithelial lymphocytes. Within the
acini there are a few small foci of liver cell drop-out and infiltration
What Histological Features Should be Included
by lymphoid cells and macrophages. A few acidophil bodies are seen.
in Staging? Confluent and portal-central bridging necrosis are not seen. Fatty
The features to be considered include fibrosis, architec- change is mild. There is no haemosiderosis. Alpha-I-antitrypsin glob-
ules are absent.
tural disturbance and cirrhosis (Table 2). In the case of
the latter there may be considerable difficulty in as- Summary: Mild chronic hepatitis with a lobular component but no
bridging necrosis, compatible with but not diagnostic of hepatitis C
sessing a small biopsy specimen, and the problem of virus infection.”
potential sampling error must therefore be considered The scores appropriate for this report (Tables 1 & 2) would be:
in all cases. For this reason, the staging categories are Grading (A)l+(B)O+(C)2+(D)3; Total=6
so worded that staging scores can be allotted, even if a Staging = 2

diagnosis of cirrhosis is not completely certain.

Should Grading and Staging be Semi- Validation of Systems of Grading and Staging
quantitative? An acceptable system of grading and staging must
The need for critical evaluation of histological features have several characteristics. First, as already indicated
in clinical trials of therapeutic regimes has led to the above, it must include all features known to be of value
generation of numerical grading and staging systems. in the assessment of the severity and extent of the dis-
In everyday practice, however, as already noted above, ease, as well as those believed to have prognostic poten-
simple recording of the relevant histological features in tial for useful future evaluation. Secondly, the system
words rather than numbers is usually more appropriate must be practical and not cumbersome to use, and
(Table 3). An overall assessment of the severity of must be shown to be reasonably reproducible, both by
chronic hepatitis may be made by way of summary one pathologist at different times (low intra-observer
(e.g. minimal, mild, moderate or severe chronic hepa- variation) and by different pathologists (low inter-ob-
titis), but this should be done and evaluated with cau- server variation), as has been exemplified for chronic
tion, since it involves the morphological integration by hepatitis C recently (7). Thirdly, the system must be
the pathologist of many different individual features. useful to the clinician or evaluator of a clinical trial;
reproducibility is not in itself valuable if the data gen-
erated cannot be used by the clinician. This often re-
quires a compromise between complexity and reprodu-
Modified staging: architectural changes, fibrosis and cirrhosis

Change Score What Semi-quantitative Systems are Currently

No fibrosis 0 Available?
Fibrous expansion of some portal areas, with or without 1
Several systems have been used or proposed (6,8-10).
short fibrous septa
Fibrous expansion of most portal areas, with or without 2 Of these, the most widely used throughout the world
short fibrous septa is undoubtedly the Histological Activity Index (HAI)
Fibrous expansion of most portal areas with occasional 3
of Knodell et al. (8). Its widespread use has already
portal to portal (P-P) bridging
Fibrous expansion of portal areas with marked bridging 4 enabled series of patients with chronic viral hepatitis
(portal to portal (P-P) as well as portal to central (P-C)) to be compared, and it is likely that many pathologists
Marked bridging (P-P and/or P-C) with occasional nodules 5
and hepatologists will wish to continue to use this scor-
(incomplete cirrhosis)
Cirrhosis, probable or definite 6 ing method.
Maximum possible score 6
Several problems have, however, arisen in its use (3),
and we therefore wish to suggest modifications which
Additional features which should be noted but not scored:
Intra-acinar fibrosis, perivenular (‘chicken wire’ fibrosis). Phlebo-
could usefully be made. The problems discussed by De-
sclerosis of terminal hepatic venules. smet et al. (3) include the following:

Grading and staging of hepatitis

1. The first three categories of the HAI consider it a suitable tool for the semi-quantitative
(periportal t: bridging necrosis, intralobular degenera- evaluation of liver biospies in therapeutic trials.
tion and focal necrosis, and portal inflammation) rep-
resent a system of grading, and the scores generated Acknowledgements
should therefore not be added to that of the fourth This paper summarizes the views of a meeting held at
category (fibrosis), which is a criterion of staging. Rheinfelden, Switzerland from May 8-12, 1994 and
2. The first category includes both piecemeal and supported by Abbott AG, Cham; Ciba-Geigy AG, Ba-
bridging necrosis, whereas we now believe that these sel; Falk-Foundation, Freiburg i. Br.; Giuliani S.A.,
forms of liver cell damage should be separately as- CastagnolalLugano; Glaxo AG, S~h~nb~hl/Bern;
sessed. Hoffmann-La Roche AG, Basel; Immuno AG, Wien;
3. In all four categories, a range of scores from 0 to 10 Medichemie/Phardi Foundation, Ettingen and Sandoz
or 0 to 4 is given, but some of the numbers are omitted. AG, Basel.
For instance, where scores of 0, 1, 3 and 4 are specified
but 2 is omitted, pathologists are left in doubt as to References
whether an intermediate score of 2 is permissible. 1. De Groote J, Desmet V, Gedigk P, Korb G, Popper H, Pouls-
4. In some instances, scores are defined by a combi- en H, S&mid M, Uehl~nger E, Wepler W. A classification of
chronic hepatitis. Lancet 1968; ii: 626-28.
nation of extent and severity of a feature. This causes
2. Ludwig J. The nomenclature of chronic active hepatitis: an
difficulty in cases where extent and severity (e.g. of por- obituary. Gastroenterology 1993; 105: 274-78.
tal inflammation) do not correspond. 3. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer
5. It must be remembered that the scores generated are PJ. Classification of chronic hepatitis: diagnosis, grading and
discontinuous variables, and must therefore be treated staging. Hepatology 1994; 19: 1513-20.
4. Ishak KG. Chronic hepatitis. Morphology and nomencla-
as such in statistical analyses.
ture. Modern Path01 1994; 7: 690-713.
5. Powell LW. The nature of cell death in piecemeal necrosis: is
What Scoring System Should be Used in order emerging from chaos? Hepatology 1987; 7: 794-96.
Future? 6. Bianchi L, Gudat E Chronic hepatitis. In: MacSween RNM,
The Histological Activity Index of Knodell et al. (8) Anthony PP, Scheuer PJ, Portmann B, Burt AD, eds. Pathol-
ogy of the Liver; 3rd Edn: Edinburgh: Churchill Livingstone,
has the advantage over other systems of widespread
1994; 349-95.
use. It also generates a substantial range of numbers, I. Bedossa P Bioulac-Sage P Callard P Chevallier M, Degott
giving a helpful spread of scores for the evaluation of C, Deugnier Y, Fabre M, Reynes M, Voigt JJ, Zafrani ES.
treatments. We therefore wish to suggest a modification Intraobserver and interobserver variations in liver biopsy
of the HAI cables 1 and 2), taking the above criticisms interpretation in patients with chronic hepatitis C. Hepa-
tology 1994; 20: 15-20.
into account. Each pathologist is, however, free to use
8. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Ka-
whatever system he or she wishes. Indeed, there are plowitz N, Kiernan TW, Wollman J. Formulation and appli-
many situations where scoring systems need to be indi- cation of a numerical scoring system for assessing histologi-
vidually constructed to answer specific questions. An cal activity in asymptomatic chronic active hepatitis. Hepa-
HAI, modified along the lines suggested in this paper, tology 1981; 1: 431-35.
9. Lok ASF, Lindsey I, Scheuer P, Thomas HC. Clinical and
may then be seen as a model which can be used for the
histological features of delta inf~tion in chronic hepatitis B
evaluation of chronic hepatitis in general, supple- virus carriers. J Clin Path01 1985; 38: 530-33.
mented if desired by the recording of specific features 10. Scheuer PJ. Classification of chronic viral hepatitis: a need
such as lymphoid follicles and bile-duct damage. We for reassessment. J Hepatol 1991; 13: 372-74.