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

696
 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
in Grading?
Grading should take into consideration the known and
readily evaluable forms of hepatocellular damage in
hepatitis, together with the extent and distribution of
the predominantly lymphocytic infiltrate characteristic
of those diseases conventionally included under the
heading of chronic hepatitis. These are chronic hepa-
titis of viral cause, autoimmune hepatitis and drug-in-
duced chronic hepatitis, as well as chronic hepatitis of
uncertain cause. We recognise that chronic hepatitis
shares many histological features with certain other
chronic inflammatory liver diseases such as primary
*Does not include diffuse sinusoidal infiltration by inflammatory
cells.
Maximum possible score for grading 18
Additional features which should be noted but not scored:
Bile-duct inflammation and damage
Lymphoid follicles
Steatosis, mild, moderate or marked
Hepatocellular dysplasia, large- or small-cell
Adenomatous hyperplasia
Iron or copper overload
Intra~ll~ar inclusions (e.g. PAS-positive globules, MalIory bodies)
Immunohistochemicaljndings
Information on viral antigens, lymphocyte subsets or other features,
when available, should be recorded and may be semi-quantitatively
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
separate consideration. They are therefore not included
in the present discussion. Alcohol abuse may also
cause histological features of chronic hepatitis, in some
instances related to infection with a hepatitis virus, but
classical alcoholic steatohepatitis is not included be-
cause of its essentially different histological character-
istics.
In our view, grading should include assessment of
portal, periportal and intra-acinar inflammatory cell
infiltration, and various forms of liver cell damage and
necrosis (Table 1): spotty {focal) lytic necrosis and
apoptosis with liver cell drop-out, piecemeal necrosis
(interface hepatitis), simple con&rent necrosis (death
of groups of adjacent hepatocytes without clear zonal
location or bridging), zonal confluent necrosis (zone
3), bridging necrosis linking vascular structures, and
panacinar or multiacinar necrosis. We support the use
of the term interface hepatitis rather than piecemeal
necrosis, because the main form of liver-cell damage in
this process is thought to be apoptosis rather than lytic
necrosis (5).
The designation of bridging necrosis should in our
view be restricted to bridging between portal tracts and
terminal hepatic venules as reflected in the term portal-
central (P-C) bridging. This form of bridging, which

697
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-
port
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-
quantitative?
The need for critical evaluation of histological features
in clinical trials of therapeutic regimes has led to the
generation of numerical grading and staging systems.
In everyday practice, however, as already noted above,
simple recording of the relevant histological features in
words rather than numbers is usually more appropriate
(Table 3). An overall assessment of the severity of
chronic hepatitis may be made by way of summary
(e.g. minimal, mild, moderate or severe chronic hepa-
titis), but this should be done and evaluated with cau-
tion, since it involves the morphological integration by
the pathologist of many different individual features.
TABLE 2
Modified staging: architectural changes, fibrosis and cirrhosis
Validation of Systems of Grading and Staging
An acceptable system of grading and staging must
have several characteristics. First, as already indicated
above, it must include all features known to be of value
in the assessment of the severity and extent of the dis-
ease, as well as those believed to have prognostic poten-
tial for useful future evaluation. Secondly, the system
must be practical and not cumbersome to use, and
must be shown to be reasonably reproducible, both by
one pathologist at different times (low intra-observer
variation) and by different pathologists (low inter-ob-
server variation), as has been exemplified for chronic
hepatitis C recently (7). Thirdly, the system must be
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-
cibility.

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:

698

1. The first three categories of the HAI
(periportal t: bridging necrosis, intralobular degenera-
tion and focal necrosis, and portal inflammation) rep-
resent a system of grading, and the scores generated
should therefore not be added to that of the fourth
category (fibrosis), which is a criterion of staging.
2. The first category includes both piecemeal and
bridging necrosis, whereas we now believe that these
forms of liver cell damage should be separately as-
sessed.
3. In all four categories, a range of scores from 0 to 10
or 0 to 4 is given, but some of the numbers are omitted.
For instance, where scores of 0, 1, 3 and 4 are specified
but 2 is omitted, pathologists are left in doubt as to
whether an intermediate score of 2 is permissible.
4. In some instances, scores are defined by a combi-
nation of extent and severity of a feature. This causes
difficulty in cases where extent and severity (e.g. of por-
tal inflammation) do not correspond.
5. It must be remembered that the scores generated are
discontinuous variables, and must therefore be treated
as such in statistical analyses.
What Scoring System Should be Used in
Future?
The Histological Activity Index of Knodell et al. (8)
has the advantage over other systems of widespread
use. It also generates a substantial range of numbers,
giving a helpful spread of scores for the evaluation of
treatments. We therefore wish to suggest a modification
of the HAI cables 1 and 2), taking the above criticisms
into account. Each pathologist is, however, free to use
whatever system he or she wishes. Indeed, there are
many situations where scoring systems need to be indi-
vidually constructed to answer specific questions. An
HAI, modified along the lines suggested in this paper,
may then be seen as a model which can be used for the
evaluation of chronic hepatitis in general, supple-
mented if desired by the recording of specific features
such as lymphoid follicles and bile-duct damage. We
Grading and staging of hepatitis
consider it a suitable tool for the semi-quantitative
evaluation of liver biospies in therapeutic trials.
Acknowledgements
This paper summarizes the views of a meeting held at
Rheinfelden, Switzerland from May 8-12, 1994 and
supported by Abbott AG, Cham; Ciba-Geigy AG, Ba-
sel; Falk-Foundation, Freiburg i. Br.; Giuliani S.A.,
CastagnolalLugano; Glaxo AG, S~h~nb~hl/Bern;
Hoffmann-La Roche AG, Basel; Immuno AG, Wien;
Medichemie/Phardi Foundation, Ettingen and Sandoz
AG, Basel.
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