Hepatitis B Annual

REVIEW ARTICLE
Year
: 2004  |  Volume : 1  |  Issue : 1  |  Page : 92--112

Histopathological scoring of chronic viral hepatitis


Gupta S Datta 
 Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

Correspondence Address:
Gupta S Datta
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029
India




How to cite this article:
Datta GS. Histopathological scoring of chronic viral hepatitis.Hep B Annual 2004;1:92-112


How to cite this URL:
Datta GS. Histopathological scoring of chronic viral hepatitis. Hep B Annual [serial online] 2004 [cited 2020 Nov 28 ];1:92-112
Available from: https://www.hepatitisbannual.org/text.asp?2004/1/1/92/27921


Full Text

One of the important features of science is that scientific data is invariably quantifiable. Data that may be sequential or from similar but different sources or even from dissimilar observations, can be compared if these are numerical. Undoubtedly it is easier to apply this principle to mathematics, physics, chemistry and a host of similar disciplines that have traditionally been associated with precision - phenomena seemingly governed by laws and less subject to variability. On the other hand, biological sciences have fascinated the world by their variability. The challenge in medicine lies in treating patients with similar diseases, using similar therapy but realizing that different patients are as similar to each other as their individual fingerprints! Nevertheless medical literature is full of examples that attempt to quantify observations and use them to predict prognosis and response to therapy. While quantification is easy as far as laboratory parameters, physiological responses and measurements using instruments are concerned, quantification is difficult in the case of subjective observations. However, subjectivity has its inherent problems. In order to avoid semi-quantitative measurements of such observations, various pathologists have attempted to make these observations more objective. Thus, invariably numbers are assigned to pre-determined nature of observations so that a final score can be arrived at. [It would not be out of place to reiterate that not everything in medicine can be quantified and the subjective 'art' of medicine cannot be written off. 'Gut-feelings' may have saved several lives inspite of accurately determined numerical or objective scores!] These systems of scoring that are in use in several conditions have been repeatedly validated, are of undoubted utility and of proven significance. For example, the gastroenterologist is well versed with utility of the Child-Pugh score. For the past two decades, there have been several attempts to score the histological features of chronic viral hepatitis. The importance of these scoring systems is being appreciated with the availability of effective therapy. The current scoring systems have evolved over time with the changes in the nomenclature and classification of chronic viral hepatitis. Hence it would not be out of place to recapitulate the evolution of the nomenclature of chronic viral hepatitis.

 NOMENCLATURE OF CHRONIC VIRAL HEPATITIS



The nomenclature and classification of chronic viral hepatitis has been repeatedly revised over the past four decades. Since the earliest systematic classification, the nomenclature of chronic viral hepatitis is primarily based on histological features. This nomenclature and classification is also used in the clinical context and today this forms the basis of all interactions between the practising hepatologist and his or her patient. The changes that have occurred have attempted to include the enormous information on the etiology, molecular biology, the prognosis, treatment and various modifying factors of chronic hepatitis that have accumulated in the last 25-30 years.

Although there were several reports of what appears to be acute hepatitis ever since the description of jaundice by Hippocrates in 5th century AD, the observation of the entity of chronic hepatitis occured much later. After World War II, between 1945-1948, there were reports of epidemics of hepatitis in soldiers with possible long-term sequelae[1],[2],[3]. However follow-up studies in 1950's on epidemics of acute hepatitis, including the historic epidemic in Delhi, did not provide evidence of chronicity.[6] Unfortunately, at that time the viral etiology of hepatitis was not proven and hence the natural history associated with individual viruses were not known. The first of the hepatitis viruses to be discovered was Hepatitis B in 1965.[4] This was followed by identification of hepatitis A in 1973.[5] For a long time the remaining group of hepatitis was attributed to the non-A non-B hepatitis viruses. That this group was heterogenous was apparent. It was known what these viruses were not, but it was not known what these viruses were! At least it was expected that the major types of viruses would be two: one due to parenteral transmission and thus resembling hepatitis B and another transmitted enterically and thus resembling hepatitis A. Subsequently Hepatitis C (1987) and Hepatitis E viruses were found to correspond to the two non-A and non-B hepatitis viruses. Today we know that acute hepatitis due to Hepatitis A and hepatitis E (frequent cause of epidemic hepatitis such as the one in Delhi) are generally not known to result in chronic hepatitis. On the other hand hepatitis B (such as some of the epidemics reported earlier) and hepatitis C virus infection result in chronic hepatitis in a sizeable proportion of patients.

Chronic hepatitis is now a well accepted entity and is essentially a clinical, biochemical and histopathological syndrome characterized by varying degrees of hepatocellular necrosis and inflammation continuing without improvement for at least six months[7]. This definition although old has ripened over the years (since the late 1960s) and is acceptable even today. The distinction between acute and chronic hepatitis has been arbitrarily fixed at six months because it was observed that histological changes of conventional acute hepatitis do not persist beyond this period.

The earliest practical classification of chronic hepatitis that was in use for several decades was reported by an international group of hepatologists and histopathologists in 1968.[8] This was done on the basis of a proposal for this classification put forth by one of the members of this group in 1966.[9] This classification was formulated at a time when hepatitis B virus had just been discovered and many cases of chronic hepatitis were presumed to be autoimmune in etiology (lupoid hepatitis).[10] Originally two subgroups were identified depending on the severity of disease. Cirrhosis was accepted as the end stage of progression of chronic hepatitis. Chronic persistent hepatitis (CPH) implied a milder disease and chronic aggressive hepatitis (CAH) implied a more severe form of disease with a definite potential for the development of cirrhosis. The term chronic active hepatitis initially used in a clinical context eventually replaced the term chronic aggressive hepatitis.[11] The term 'aggressive' that was used by histopathologists may have appeared rather sinister to some patients and was mellowed to the more acceptable 'active'! Although the two terms had a clinical connotation, the distinction between chronic persistent hepatitis and chronic active hepatitis was essentially histological. The corner stone of this distinction was the identification of "piece-meal" necrosis or the necrosis at the interface between the parenchyma and the mesenchyma of the liver. In simple terms, this interface hepatitis would mean the necrosis of hepatocytes at the junction between the portal tracts and the lobule. The layer of hepatocytes that is adjacent to the portal tract is known as the limiting plate and therefore the preservation of the limiting plate distinguished chronic persistent from chronic active hepatitis. Subsequently two other types of chronic hepatitis were introduced: chronic lobular hepatitis (CLH) characterized by a predominantly lobular or acinar inflammation,[12] and chronic septal hepatitis (CSH) wherein scarring and fibrosis followed inflammation of septae without piece-meal necrosis.[13] Clinically these cases were associated with a better prognosis than chronic active hepatitis. It was soon realized that practically a majority of the cases of chronic hepatitis were either of the chronic persistent hepatitis or chronic aggressive hepatitis types. Hence the other types faded into oblivion due to disuse.

It must be reiterated that the original classification into chronic persistent hepatitis and chronic active hepatitis described different grades of severity rather than separate disease entities[12],[13] based on morphological features. However over a period of time due to its simplicity, clinically cases were classified into seemingly two types of separate entities: a relatively "good" non-progressive from (CPH) and a relatively "bad" form (CAH) which would progress to cirrhosis. Unfortunately, this simplification was in reality a misinterpretation of the original classification that resulted in problems.

Subsequently, with the discovery of other hepatitis viruses such as hepatitis C and D and E, better understanding of the hepatitis viruses was inevitable. Several features that were hitherto poorly understood came to light. For example, it was soon realised that cases of CPH due to HBV, despite having a good prognosis[16] could progress to CAH and cirrhosis, and this was dependent on whether the hepatitis B virus was replicative or non-replicative. Similarly, cases of chronic hepatitis due to hepatitis C virus invariably showed histological features of CPH or a mild CAH,[19],[20],[21] but did not share the "good prognosis" (lack of progression to cirrhosis) generally associated with this histology. The distinction between mild CAH and CPH was therefore questioned.[14] The paper by Boyer and Klatskin highlighted the importance of bridging necrosis in prognosis,[23],[24] and it soon became apparent that, in addition to piece-meal necrosis, other types of necrosis were also important.[25] Finally, a variety of associated factors seemed to affect the progression of chronic hepatitis to cirrhosis such alcoholism, HIV infection, metabolic liver disease, to name a few. With the development of reasonably effective therapy and consequent clinical trials, it was realized that the response to treatment was also influenced by factors such as genotype of the virus.[27] Eventually, over the years it was accepted that chronic viral hepatitis could not be compartmentalized into "black and white" but instead was a continuous spectrum of shades of grey.

The landmark 1968 classification[8] of chronic hepatitis nevertheless formed the basis for subsequent reviews. Another attempt at revision was made by the same international group in 1977[11] but it soon became obsolete in the next decades due to the resurgent interest in the subject, culminating in an explosion of knowledge that had accumulated rapidly. A series of proposals were put forth through editorials and commentaries (beginning especially with Scheuer in 1991[14] and Ludwig in 1993[15]) that would suit present day.[14],[15],[26],[28],[29],[30] Desmet et al too made some significant recommendations in 1994.[29] Subsequently another international working group comprising of distinguished histopathologists, including many of those who were responsible for the original and revised nomenclature of chronic hepatitis in 1968[8] and 1977[11] proposed a nomenclature of chronic hepatitis in 1995. This nomenclature not only took care of most of the criticisms, but also retained the important features of the earlier classification,[31] and currently this is the nomenclature that is being universally followed.

Presently, chronic hepatitis is labeled as such, and sub divisions such as chronic persistent hepatitis (CPH) and chronic active hepatitis (CAH) are considered to be obsolete and are no longer recommended. Thus a major change has been made in this regard. Therefore histopathological diagnosis and clinical diagnosis should be restricted to the use of the term Chronic Hepatitis and this should not be qualified further into any subgroup.

Further qualification of Chronic Hepatitis is essentially based on etiology. This is because etiology of the chronic hepatitis is an important factor in diagnosis, therapy and prognosis. Therefore the histopathology report should contain an etiological label as far as possible. Ground glass hepatocytes, orcein staining and immunohistochemistry would aid in the identification of HBV etiology. HBsAg immunostaining would indicate HBV infection and HBcAg staining by immunohistochemistry would be consistent with a replicative HBV infection. In case these are not available, the etiological diagnosis could be made on the basis of available serological (HBsAg, Anti-HCV) or molecular biology data (HBV DNA, HCV RNA) with a compatible histology. Therefore the histopathology report could read as:

"Chronic hepatitis (HBV etiology). " (If there is histological evidence by way of stains/immunohistochemistry)

"Chronic hepatitis (compatible with HCV etiology). " [If there are histological features that support the clinical diagnosis and laboratory evidence of HCV infection (HCV RNA etc)]

 GRADING AND STAGING OF CHRONIC HEPATITIS



The diagnosis of Chronic hepatitis is often reliably made on the basis of clinical and laboratory data. This also includes the etiology as well as the replicative status of HBV infection. However the time-honoured method of assessing the extent of liver injury, despite advances in imaging and other non-invasive techniques, has been morphological. Thus liver biopsy not only helps in confirming the diagnosis of chronic hepatitis but also provides information on the extent of hepatic injury. In addition, any other associated diseases not suspected clinically (tuberculosis for example) could be identified too. Further sequential liver biopsies is an effective and accepted investigation to determine the progress (improvement or deterioration) of chronic hepatitis with or without therapy. For the purpose of comparison of different liver biopsies it was necessary to make the subjective observations of histopathologists more objective. With the advent of therapy and understanding of the natural history of this disease, the histological severity of disease became important. It appears that at least some form of therapy may be dependent on the severity of histological changes. Thus it became necessary to determine how severe the disease was before a particular therapy could be started and how severe the disease should be when it would appear that current therapy would not be effective and some other form of management should be tried. The degree of histological severity of disease (especially if translated into numbers) is in essence the scoring of chronic hepatitis.

The earliest form of quantifying severity was by an overall assessment of the histological features and expressing these as mild, moderate or severe changes. Therefore depending on the severity of interface hepatitis and other necroinflammatory changes, chronic active hepatitis could be mild, moderate or severe. This is still being followed, and chronic hepatitis could be histologically mild, moderate or severe. However, although this is practical, the drawback of this system is that there are only three broad categories. Therefore if there were some differences in the histological changes that may not amount to reclassification into another group, it would cause difficulties. For example if the changes following therapy in a case of moderate chronic hepatitis were less severe but still insufficient to assign these as mild chronic hepatitis it might result in problems in comparison of changes. Of course, by reading the description of the histological observations some inferences could be drawn (for example in comparison to the earlier biopsy the interface hepatitis or piece-meal necrosis and spotty necrosis could be less and so on). However if there were some mechanism to further subdivide the three semiquantitative categories further, it would appear more reasonable and acceptable. In essence, this would be like the face of two clocks where the hours in one are distinctly divided into five-minute markings only and another where the minutes are also denoted in between the five-minute markings! Both are similar but the details are different. Perhaps if there were sufficient reasonable words to describe subdivisions of mild, moderate and severe this might have been used; but nevertheless it would be simpler to use numbers!

A landmark in the introduction of the concept of numerical scoring of chronic hepatitis was the introduction of Hepatic Activity Index (HAI) by Knodell et al in 1981.[32] The hallmark of the HAI was providing numerical categories for the severity of different histological features in chronic active hepatitis. Adding the numerical scores of four features [Table 1] generated the HAI. The HAI laid the foundation of the current scoring system and formed the basis of numerical scoring of chronic hepatitis for a decade. The HAI thus added a new dimension to the histopathology reports of liver biopsies of chronic hepatitis. While the utility of HAI was beyond doubt, some shortcomings were identified subsequently.[14],[15],[28],[29]

The HAI consists of a sum total of three major components of histological changes: necrosis, inflammation and fibrosis. All the three are not similar. While necrosis and inflammation are the direct result of liver injury, fibrosis is a consequence of necrosis and inflammation. Hence necroinflammation and fibrosis should be assessed or scored separately.The first category included two important types of necrosis: piecemeal necrosis and bridging necrosis. While subgroups B, C and D score piecemeal necrosis, subgroups E and F refer to a combination of piecemeal necrosis and bridging necrosis. Thus, bridging necrosis cannot be scored separately.One of the major criticisms was that the categories had scores ranging from 0-10 for I, and 0-4 for II to IV but several numbers were omitted. In category I, there are 7 subgroups (A-G) but the scores 2,7,8 and 9 are missing. Similarly categories II to IV have 4 subgroups (A-D) with the score 2 missing in all of them.

Based on previous suggestions,[14],[15],[29],[30] the HAI was subsequently modified by an International Liver Group of distinguished liver histopathologists. The salient features of the new system of scoring [Table 2][Table 3] are given below.

Necroinflammation and fibrosis have been separated. Deriving the concept from oncology, wherein Grading is used to describe the degree of differentiation, and staging the extent of anatomical spread or dissemination, this has been adopted in the histological scoring of chronic hepatitis. Grading is used to describe the severity or intensity of necrosis and inflammation, while Staging is used to indicate the extent of fibrosis, architectural alteration and progression to cirrhosis.For the purpose of grading, standard forms of hepatocellular damage are taken into account. These include: [A] interface hepatitis (piecemeal necrosis); [B] confluent necrosis (including portal-central bridging necrosis); [C] focal (spotty) necrosis, apoptosis, focal lobular inflammation and [D] portal inflammation. Categories A, C and D are given a score of 0-4, while category B is scored 0-6. The sum scores of A, B, C and D give the Histological Activity Grade (also called "Ishak score"). The total possible score of this grading is 0-18. Actually this score is similar to the total of categories I to II (necrosis and inflammation) of the original HAI. This grading can be roughly subcategorized as :

0 : None

1-4 : Minimal

5-8 : Mild

9-12 : Moderate

13-18 : Severe

Features such as bile duct damage, lymphoid follicles, steatosis, iron or copper overload, intracellular inclusions etc. are recorded in the report but are not included in the grading. Therefore, the grading is in a way "standardized", irrespective of the etiology and does not include features that may be characteristic of a particular etiology.Similarly, for the purpose of staging, fibrosis, architectural changes and cirrhosis are included to give scores from 0-6 (none to definite cirrhosis). Features such as intra acinar fibrosis, perivenular "chicken wire" fibrosis and phlebosclerosis of terminal hepatic venule are noted but not used for staging chronic hepatitis.It must be emphasized that the numbers that are generated are discontinuous variables. The numbers are separate categories and neither linear or identical like the rungs of a ladder. Thus for interface hepatitis (A) a score of 4 is not four times that of 1 and a score of 2 does not mean interface hepatitis that is twice that of 1 or half that of 4. Similarly a score of 6 for confluent necrosis (B) does not mean six times the necrosis in a case with 1. Also a grade of 8 in three different cases may be dependent on totally different scores for A, B, C and D categories.

The above system introduced by the international liver group allows the recording of important pathological features, and is hence useful in clinical trials of therapy. If a simple stratification of cases is required then simpler systems[14] of scoring may be used. [Tables 4][14] and 5[33] are examples of such scoring systems.

The METAVIR Alogirthm[33] is designed to score Chronic Hepatitis C [Table 5]. Whatever be the system employed, it must be clear and understood by the histopathologist as well as the clinician so that confusions are avoided.

The real value of semi quantitative assessment is in comparision of histological changes in serial biopsies, to evaluate therapy and regimens and to provide research data.[31] Thus, in some clinical trials patients are enrolled for therapy only at a predetermined grade or stage (Grade 4 or Stage 1usually). A change in the grade of 2 or stage of 1 is considered significant in serial biopsies. Thus if the initial grade was 6, a subsequent grade of 4 would indicate improvement, a grade of 9 would indicate deterioration while a grade of 5 or 7 would indicate the absence of any significant change in the grade. Nevertheless, as the international group has cautioned, the value of such semi quantification is limited when performed in a single biopsy. Therefore while this form of assessment would be useful for comparing different series of patients and therapies, its use in routine reporting may not be absolutely necessary in every case. It must be mentioned that the scoring systems described have been formulated for chronic viral hepatitis (proven or presumed viral etiology). Chronic hepatitis due to other etiology is generally not scored by this method; but there is no reason why this could form the basis of scoring other diseases with appropriate modifications and adequate validations.

Therefore a histopathological report should be descriptive. The final impression should ideally include the etiology (either based on the demonstration of viral antigens in the biopsy or due to compatible histology). The severity of chronic hepatitis may be graded semiquantitatively (mild, moderate severe, with or without bridging or periportal necrosis). Similarly, the extent of fibrosis should be indicated. Finally, the scoring for the histological activity grading and staging should be mentioned (and the scoring system used should be indicated with the maximum possible scores).

Reproducibility of scoring

Certain issues regarding the reproducibility of scores always crop up when grading and staging of chronic hepatitis are discussed. A detailed analysis of such contentious issues is beyond the scope of this article. The interested reader may refer to a recent review[34] on this subject. Only some of the salient features are summarized here.

Firstly, it must be appreciated that percutaneous blind needle biopsies are the preferred specimens for scoring chronic hepatitis. Wedge biopsies if available should be deep (like a cup and not a saucer) because the subcapsular region gives a false impression of fibrosis due to septae extending into the subjacent parenchyma to a depth of around 5mm from the Glisson's capsule.[35] Further, for unknown reasons, the subcapsular region tends to show an unduly extensive necrosis in some cases, in comparison to the deeper tissue. The type of needle used depends on the operator's convenience. However the cutting type of needles (Trucut) is preferred to the aspiration type (Menghini) when fibrosis is marked.

The needle biopsy samples about 1/50000 of the liver. Hence there may be variability in assessment due to sampling. Studies entailing a number of biopsies from the same case indicate that there may be problems in the assessment of cirrhosis due to sampling errors.[36],[37],[38],[39],[40] The discrepancy in grading (of at least 2 scores) may be as high as 33%[41] or 69%.[42] For fibrosis, the discrepancy could be 25%[41] or 62%.[42] When the right and left lobes are biopsied, a difference in both - the grade and stage of I-score has been reported in 24.2% and 30.6% by Regev et al.[43] Thus increasing the number of samples should increase the likelihood of accuracy. This unfortunately is not a practical proposition! Chronic hepatitis is a diffuse disease and hence given the limitation of this variability decisions based on grading and staging are likely to continue without recourse to increasing the current method of sampling.

As a corollary to the above, the size of the sample of liver biopsy should be important. The size of the needle biopsy that was traditionally considered adequate was 1.5cms in length and containing four to six portal tracts.[44] However it has recently been observed that thin needle biopsies (1mm wide, less than 21G needle) were inadequate and an adequate biopsy should be at least 2cm in length, and 1.4mm wide so as to contain 11 to 15 portal tracts.[45] Such a biopsy is considered ideal for grading and staging chronic hepatitis. A small biopsy tends to under-grade the chronic hepatitis.Thus it is truly a case of more the merrier as far as portal tracts are concerned (amongst several other things!). It must be realized that grading and staging on an inadequate sample of the liver biopsy is the signature step towards an inadequate report and if accepted by the clinician and the histopathologist reflects on the inadequate care the patient is subjected to.

Finally intraobserver and interobserver variability of scoring liver biopsies have fortunately been low especially amongst histopathologists with an interest in liver diseases. It is advisable that whenever more than one histopathologist is involved in scoring biopsies, the histopathologists agree upon the criteria employed for such scoring. This would reduce interobserver variation. By and large, the agreement has been more perfect for fibrosis (staging) than for necrosis and inflammation (grading).[46],[47],[48],[49],[49]

The new nomenclature for chronic viral hepatitis, a landmark in hepatology, made possible by the numerous contributions over the years that provided a better understanding of viral hepatitis has laid due emphasis on histology and etiology and introduced grading and staging. Scoring systems are important and form an important part of the report. A close cooperation between the histopathologist and the clinician is necessary in understanding the utility of such scoring in the diagnosis, management and follow-up of cases of chronic viral hepatitis. The scores provided by the histopathologist are not mere numbers but a measure of hope (and despair) clinicians and perhaps to a greater extent patients look forward to.

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