Classification of chronic vira! hepatitis: a need for reassessment Peter

J. Schcuer

chronic

The classi5cation of hepatitis proposed ir. 1968 (1) his been used with little modification for over 20 years. Chronic persistent hepatitis (CPH), chronic active hepatitis (CAH) and chronic lobular hepatitis (CLH) (2) are histological patterns associated with a variety of infectivc end non-infective causes. The 1968 Paper served to draw attention to the Tide range of histological appearances which could be found in patients labelled us having chronic hepatitis, and suggested that these correlated with prognosis; CPH, characterised by portal inflammation eithout piecemeal necrosis involving the adjacent hepatic parenchyma, was thought to carry a better progo&s thao CAH in which piecemeal necrosis with its associated fibrosis was considered to be the mechanism whereby some patients gradually developed cirrhosis. At that time, very little was known about the natural history of hepatitis B virus (HBV! infection, and virtually nothing about non-A, non9 hepatitis. Now the agents of hepatitis B, hepatitis D (the delta agent) and hepatitis C have been identified, there is much information on the evolution of these diseases, and many ~controlled therapeutic trials of antiviral agents are in progress. Xx classification of chronic hepatitis needs these developments.

to he reassessed

in the light of

Chronic hepatitis B begins with a phase of high virus replicatkm. with HBeAe and hieh levels of HBV-DNA in the strum; the histolo&d picture during this phase is normally one of mild CAH, CLH or CPH. This is followed by serownversion from e antigen toe antibody (anti-HBe), during which an upsurge of histological activity to severe CAH with prominent lobular activity is characteristic (5). In the subsequent low virus replication phase, the picture is tvoicallv that of CPH. althourh increased necminflam-

..

.

matory activity corresponding 10 CAH or CLH may be seen during periods of virus reactivation or superinfection with another virus. If the patient has been unfortunate enough 10 develop cirrhosis by this time, the picture in the low replication phase will be that of an inactive cirrhosis rather than of CPH. Thus, a single patient with chronic HBV infection may show all the different patterns of chronic hepatitis at various periods during the evolution of the disease. In chronic hepatitis C, the cmnmon form of parenterally transmitted non-A, non-B hepatitis, the histological evolution is not identical but again demonstrates a wide range of appearances in individual patients. Most patients

Are CAH, CPH and CLH differem diseases? At the time of publication of the original classification (I) it was recogniscd that CPH and CAH were not distinct diseases, and that one could change to the other. Howev-

with chronic hepatitis C show a very characteristic pattern of mild chronic hepatitis, often on the borderline of CPH and CAH, with prominent lymphoid follicles in portal tracts and much lobular activity in the form of acidophil body formation and focal hepatocellular necrosis. Yet in spite of this relatively mild picture cirrhosis develops in a substantial proportion of patients, sometimes after a pe-

er. the frequently gwd prognosis of patients with CPH (3.4) led many hepatolagists to regard CPH and CAH as long-term diagnostic labels for individual patients. This view is no longer tenable in the light of the evolution of the various forms of chronic viral hepatitis.

riod of many years (6). The mechanism for this progression is thought to be episodes of lobular necrosis correspending to the observed fluctuations in biochemical activity, although this has not been firmly established. These two examples serve to show that CPH, CAH and

Correspondencr: Pro&ar NW3 ZOG. U.K.

P J Scheuer. Department of Hirtopathology. Royal Free Hospital and School of Medicine, Pond Street, London

CLASStFlCAnON

OF CHRONtC

HEPATlTtS

313

CLH cannot be regarded as separate diseases bur rathe: represent snapshots of the histological pattern of disease et a given moment in time.

reproducibility. The 196X classification (1) already mcorporefed different degrees of severity of CAH. based on the extent of piecemeal necnxis, but other features such as focal and bridging confluent necrosis also have to be

What are the prncrienl implicadons of diagnosing CPH, CAHand CLH? In the individual patient, the milder forms of chronic hepatitis, CPF1 and CLH, usually denote a rrlatwely good prognosis compared with CAH. However, the exact course of the disease varies according to the infecting agent, the phase of virus replication and the nsk factors to which the patient is exposed, especially superinfection with another hepatitis virus. Therefore, for example, one patient with chronic hepatitis Et. biopsied during the high virus replication phase, may have a histological diagnosis of CPH or mild CAH but subsequently develop more 3.e. rious liver disease es a result of seroconverrion, reactiva-

I.&en into account in assessing the results of clinical trials c.i antxiral awnts. One system of quantivdion, now widely used, was proposed by Knodell et al. (NJ). it generates a histological activity index (HAI) on the basis o; inflammation, necrosis, fibrosis sod alteration of architecture. Four indivi&&%l component scores are produced, and may be added IOgethe: !E produce an overall acti-vity score; this addition is temp!ing for those who evaluate new therapy, but is hpt to be misleading in that it combines nesroin~ammatory activity with the effects of such activity, that is lo say tibroris, architectural distortion and cirrhosis. F-orthcrmor?, piecemeal and bridging necrosis are both assessed within one of the subcategories, which may obscure information

tion or superinfection

(7.8). By contrast,

another

patient

to superinfection, is likely to continue to have mild iisease histologically. Thus prognosis depends not only on the histological diagnosis. but also on other factors. A further complication is sampling error. One part of a biopsy

on the separate pathogen& significance of these two forms of liver-cell damage (11.12). A somewhat simpler scoring system WILEused to evaluate the effect of delta agent (HDV) superinfection on chronic hepatitis B (13) and is shown in modified form in Table 1. This swtem scores arivity. but not its effects. From the categories

specimen may show the pattern of CPH, another CAH or CLH. Needle biopsy specimens measuring less than 1.5 cm in leng:h are panic&My unreliable in this respect (9). but even e specimen of this sire represents only one hundred thounandth of the whole liver, and only a small part of the sPecimen is usually viewed under the micro-

given in parentheses in the table. it can be seen that diagnoses of CPH, CAH of various degrees of severity and CLH can be derived from the scores if required. The separation of the ponallperiportal and lobular components of activity enables the impact and behaviour of these to be separately assessed. In addition to the scores derived for

SCQpe. The histologici! label aoplied to an individual biopsy has important clinical impbcations. Some therapeutic trials of new antiviral agents require a histological diagnosis of CAH for entry, so that patients labelled CPH on the basis of a liver biopsy are excluded from the trial. This ignores the observation that the cottrse of patieols with

necroinfiammatory activity, fibrosis and architectural changes can be assessed as shown in Table 2.

with hepatitis B and a similar histological picture, biopsied during the low replication phase and not expixd

CPH or CLH may be essentially similar to that of patients with minimal or mild CAH. Funhermore, patients with CPH due to HBV infection often have verv hick levels of vireemia, and reduction of viraemia and infectivity is an important goal of antiviral therapy. From the point of view of treatment, therefore, the separation of CPH from mild CAH is fundamentally unsound and ethically unacceptable; it betrays misunderstanding of the evolution of chronic viral hepatitis, and may deprive patients of effective treatment. How should liver biopsies bt chronic hepodris be evaluated? The histological semiquantitatively

lesions of chronic viral hepatitis can be assessed with reasonable accuracy and

Should there be a new c/aniJicarion of chronic hepadrix? Any new subdivision should ideally enable aetiology,

P.J. SCHEL’ER

374

each mdividual bmpsy mote complex than at present. It is in line with the vie- expressed at a recent intetnational conference on the nomenclature of liver disease (14). There appear to be three possible choices for the fu0 / 2

nom edarged. fibrotic pond tractr pipona, or portal-ponal septabu,

3

m,rnis wl,h alEhllCCt”iZ!di,lOrtiOnb”I no Ol’Vi-ill~ cirrhosis probab!e ordeflnite nrrbolls

4

f”IC ,fllDC,

adliteC,Y~e

Note: al~~~,twely, wrbosis ran be separatelystored from tibrosis. into rile folloaing categories: probably SbSe.0 dw?lopng; suspetted. present: cannot be awned.

the various forms of necroinffammatory activity and arcbitecmral changes to be documented. Such a classification would be much more comprehensive than the one used at present, but would be more complex and thus less reproducible.

In this, as in any other system of classifica-

(i) Retain the current classification of chronic hepatitis into CPH, CAH and CLH, specifying aetiology, serological data and immunocytochemical results where known. Semiquantitative data could be added if rcquirrd. (ii) Construct an entirely new classification, incorporating not only aetiology but also the different forms of rectoinflammatoty activity (piecemeal, focal, bridging necrosis) as well asserologic~l and immunocytochemical data. (iii) Label patients with chronic hepatitis according to aotioiogy only, hut add verbal or srmiquantitative information an the details of the histological lesion, as well as serological and immunocytochemica: data. These choices need to be discussed

both by clinictans,

tion. seroiogical and immunocytochemical information oti viral markers should be specified. As an alternative to at, extensive subdivision, patients might simoly be diagnosed as having chronic hepatitis, with the aetiology and serological data specified where known, and the histological

diagnosing and treating patients with liver disease, and by the histopathologistr who evaluate liver biopsies. Present circumstances seem to favour the thbd option.

lesion described either varbally or in the form of one of the systems of scmiquarditation outlined above. This

Acknawledgemenl

would overcome the problem of excluding patients from clinical trials on the basis of a diagnosis of CPH rather than CAH, but would make the histological evaluation of

I am grateful to my colleagues, both pathologists and clinicians, who have provided helpful criticism, comment and encouragement.

Classification of chronic viral hepatitis: a need for reassessment.

Classification of chronic vira! hepatitis: a need for reassessment Peter J. Schcuer chronic The classi5cation of hepatitis proposed ir. 1968 (1) hi...
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