Recent Developments in Liver Pathology
Moderator: Dr. Helmut Denk
Section 1 -
Current Nomenclature of Chronic Hepatitis and Staging/grading Systems
Department of Pathology, Medical University of Graz,
The liver biopsy is still the gold standard, particularly in the assessment of chronic liver disease
following a subclinical course. It is a reliable procedure to confirm the clinical diagnosis, assess the
severity of necroinflammation, type and extent of fibrosis and related architectural alterations, to
uncover concomitant diseases and to evaluate the effect of therapy. The histologic classification of
chronic hepatitis proposed in 1968 by an international group of liver pathologists  has proved to be a
valuable basis for the clinic at a time when many aspects of etiology, natural history and pathogenesis
were still unclear. However, the terminology proposed, i.e. chronic active or aggressive (CAH) and
chronic persistent (CPH) hepatitis, although not intended by the authors, sometimes led to
misinterpretation in the sense that clinical hepatologists regarded CPH and CAH as long-term
diagnostically and prognostically relevant labels for individual patients and thus as distinct entities
rather than only different grades of necroinflammatory activity . Particularly in chronic hepatitis
C, progression to cirrhosis occurs in a substantial proportion of patients, even despite relatively mild
activity in the biopsy. Moreover, the term "piecemeal necrosis" indicating erosion of the limiting plate
is now obsolete and replaced by "interface hepatitis" because the mechanism of this type of liver cell
damage is predominantly apoptosis rather than necrosis. The traditional evaluation of liver biopsies is
based on the identification of morphologic features of proven or suggested clinical (prognostic and
therapeutic) relevance in correlation with clinical findings. Etiology is most important with respect to
diagnosis, prognosis, natural history and therapeutic options, which may, in certain instances, be
recognized on the basis of morphologic features of the biopsy. The descriptive approach of liver biopsy
interpretation can be supplemented by semiquantitative scoring of morphologic features with major
emphasis on necroinflammatory activity (grading) and fibrosis (staging). Grading and staging with
resulting numerical scores seem to satisfy clinicians better than purely descriptive histologic reports
and are more amenable to statistical evaluation. Therefore, semiquantitative grading and staging has its
place in clinical trials, enabling comparison of different series of patients and therapy regimens, as
well as in research. In the daily practice, however, semiquantitative scoring can be avoided. Several
histological scoring systems for different types of chronic liver diseases have been proposed.
In the Knodell system  periportal and bridging
necrosis, intralobular liver cell damage, portal inflammation and fibrosis are assessed and by adding up
scores for the individual categories an overall histologic activity index (HAI) is calculated. However,
despite other problems (e.g. combination of different types of necrosis in one category), the combination
of scores representing grading (intensity of necroinflammation) and staging (measure of fibrosis and
architectural alteration) can be misleading. In other scoring systems, fibrosis is considered separately
and grading is either simplified or types of necrosis are more individualized
in the Ishak system  the modified HAI reflects the intensity of periportal and periseptal interface
hepatitis, confluent and bridging necrosis, spotty lytic necrosis, apoptosis and focal inflammation in
the lobule and portal inflammation. The modified staging is based on the degree of portal and septal
fibrosis and related architectural alterations.
Histological scoring systems have also been
proposed for non-alcoholic steatohepatitis (NASH) taking into account amount of steatosis, hepatocyte
ballooning, lobular and portal inflammation and Mallory body formation (grading) as well as staging of
fibrosis (zone 3 perivenular perisinusoidal/pericellular, periportal, bridging, cirrhosis) resulting in
a numerical activity score (NAS) as the sum of the scores for steatosis, lobular inflammation and
Chronic Cholestatic Conditions.
Staging of chronic biliary diseases,
like primary biliary cirrhosis and primary sclerosing cholangitis, has been described based on portal and
periportal inflammation with accompanying periportal fibrosis, bridging fibrosis (fibrous septa) and
bridging fibrosis with nodular regeneration (cirrhosis)
Advances in our understanding of etiology and evolution
of chronic hepatitis and other chronic liver diseases require a reassessment of our traditional
morphologic classification with the goal to closer correlate morphology with clinical presentation,
serologic and immunohistochemical data, etiology and possible therapeutic strategies. A semiquantitative
scoring system including stage and grade of the disease is helpful for overall assessment. Several
problems are inherent to all scoring systems; they include sampling and inter- and intra-observer
variations. Moreover, it has to be kept in mind that, in contrast to biochemical measurements, the
numbers generated by scoring represent only categories of severity and non-parametric tests are necessary
for statistical analysis. It should always be borne in mind that scores are added-up numbers of
variables with quite different biologic and clinical significance. Thus, in patients with different
histologic changes the same total score may be obtained, but the total score may be differently composed
and thus of different clinical significance. Therefore, particularly in clinical trials individual
components of grading have to be separately studied. Finally, etiologically different types of liver
diseases may show differences in evolution (natural history, behaviour) and response to therapy, without
close correlation with morphology.
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