Case 1 -

Chronic hepatitis – Update on Terminology and Reporting Julia C. Iezzoni

Clinical History The patient, a 46-year-old African-American female, presented with complaints of a 7-month history of intermittent lethargy and malaise. She denied ethanol abuse and was not on any medications or herbal supplements. Liver function tests demonstrated moderately elevated aminotransferases, and viral serologies were positive for hepatitis C. A liver biopsy was performed. Diagnosis: Chronic hepatitis – Update on Terminology and Reporting Case 1 - Figure 1 - H&E Case 1 - Figure 2 - H&E Case 1 - Figure 3 - Trichrome Pathologic findings: Sections of the liver biopsy show a portal, periportal and lobular inflammatory infiltrate, which is composed mainly of lymphocytes. A portal-based lymphoid aggregate is present, and there is focal interface hepatitis. The lobular inflammatory infiltrate is associated with apoptosis of individual hepatocytes. A trichrome stain demonstrates periportal fibrosis. Discussion Historical Perspective In 1968, when the first classification of chronic hepatitis was proposed, the causes of chronic hepatitis were largely unknown. Most cases were assumed to be autoimmune in nature (so-called "lupoid hepatitis"), and the only virus known to cause hepatitis was the then recently discovered hepatitis B virus. The purpose of this initial classification scheme was to identify subgroups according to the degree of disease activity in order to provide prognostic information and criteria for the use of immunosuppressive therapy. This classification system was based on morphologic criteria, and it originally identified two subgroups of chronic hepatitis – chronic persistent hepatitis and chronic active (aggressive) hepatitis. These two subgroups were differentiated primarily by piecemeal necrosis, which, by definition, was absent in chronic persistent hepatitis and present in chronic active hepatitis. In this classification scheme the terms "chronic persistent hepatitis" and "chronic active hepatitis" referred to degrees of disease activity within a diagnostic category rather than separate disease entities. Shortly thereafter, the term chronic lobular hepatitis was added to indicate a predominantly lobular lesion. The prognostic connotation was that chronic persistent hepatitis was the milder form of the disease, with little risk of progression to cirrhosis, whereas chronic active hepatitis was the more severe form of chronic hepatitis, often associated with progressive disease and cirrhosis. Treatment decisions were based on this morphologic distinction. In the decades since the proposal of this initial classification scheme, significant advances have been made in identifying the causes and understanding the pathogenesis of chronic hepatitis. The terminology and classification of chronic hepatitis, however, largely has failed to keep pace with this progress. As a result, the original classification scheme and terminology has become obsolete and at times, a source of confusion. For example, in clinical practice, the designations of chronic persistent hepatitis and chronic active hepatitis have been misperceived frequently as separate disease entities and not simply as designations of disease severity, as they were intended originally. In addition, the improved understanding of the different causes and varying natural history of chronic hepatitis has brought about a shift of emphasis in the classification from histological features alone to a combination of histologic, clinical and serological factors. Furthermore it has become clear that the single most important determinant of the natural history, prognosis, and choice of therapy in chronic hepatitis is the etiology rather than the histologic pattern. As such, the classification system of chronic hepatitis should be based primarily on etiology. Within each etiologic category, histologic information about the degree of necroinflammatory activity and the extent of the fibrosis is then of use for specific patient management. As a result of this evolution, recommendations for abandoning the original classification of chronic hepatitis began to appear in the 1990's. This has led to the development of new classification systems for chronic hepatitis with more clinically relevant terminology as well as greater standardization of reporting. Specifically, the new classification and reporting scheme for chronic hepatitis has three primary components: 1) etiology (if known); 2) degree of necroinflammatory activity (histologic "grade"); 3) and extent of fibrosis (histologic "stage"). This proposed classification and reporting system for chronic hepatitis is the basis for this discussion. Importantly, the scoring of the degree of necroinflammatory activity and extent of fibrosis has become the standard practice in the evaluation of liver biopsies from patients with chronic hepatitis. Of note, the original classification of chronic hepatitis is no longer supported, and terms that have been designated as obsolete include "chronic active hepatitis", "chronic persistent hepatitis", and "chronic lobular hepatitis". Definitions and etiologic classification of chronic hepatitis Chronic hepatitis is not a single disease but rather a clinicopathologic syndrome that has a variety of causes and is characterized morphologically by varying degrees of inflammation, hepatocellular necrosis, and fibrosis. Accordingly, specific clinical and morphologic criteria must be fulfilled for a case to be classified as chronic hepatitis. For lack of a better definition of "chronicity", chronic hepatitis is still defined as hepatitides or related disorders that presumably have persisted for longer than 6 months. Some cases of chronic hepatitis, however, may be asymptomatic for long periods, especially early in their course. In such cases, histologic evidence of chronicity can be used to infer disease of longer than 6 month's duration and permit classification as chronic disease. Other causes of hepatitis, such as autoimmune hepatitis and metabolic diseases (e.g. Wilson's disease) are a priori regarded as chronic diseases, independent of their clinically apparent duration. From a solely histologic perspective, chronic hepatitis is simply a morphologic pattern of liver injury and is one of the major morphologic categories of liver disease. By definition, the hepatotcytes rather than the biliary structures are the main target of attack of this necroinflammatory process. The different etiologic types of chronic hepatitis share a number of histologic characteristics, which may vary over time in an affected individual. Specifically, the chronic hepatitides are characterized by a portal, periportal, and lobular chronic inflammatory infiltrate. This inflammation is associated with varying degrees of hepatocelllular damage and progressive fibrosis. The term "piecemeal necrosis", which traditionally has been used to designate the extension of portal inflammatory cells into the adjacent liver parenchyma with destruction of the limiting plate and damage to periportal hepatocyes, may no longer be appropriate. In particular, there is increasing evidence that the death of the periportal hepatocytes is mediated through apoptosis rather than necrosis. Furthermore, often it is difficult to distinguish true damage to periportal hepatocytes from simple inflammatory spillover from the portal tract. For these reasons, the term "interface hepatitis" is now used to describe any inflammatory lesion that breaches the interface between portal areas (or fibrous septa) and the adjacent liver parenchyma. Several other liver diseases that are not actual chronic hepatitides may present with histologic and clinical features that mimic chronic hepatitis. Specifically, chronic cholestatic diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis, and metabolic disorders, such as Wilson's disease and alpha-1-antitrypsin deficiency, at various points in their progression, may show morphologic features similar to those of chronic hepatitis. As such, in liver biopsy interpretation, these additional entities should be considered in the differential diagnosis in the evaluation of cases with the morphologic and clinical appearance of chronic hepatitis (Table 1). Table 1: Etiologic Classification of Chronic Hepatitis and Chronic Biliary Disease Chronic (nonbiliary) hepatitis Autoimmune hepatitis Chronic hepatitis B Chronic hepatitis B and D Chronic hepatitis C Chronic drug-related hepatitis Chronic hepatitis, unknown cause Wilson's disease of the liver Alpha-1-antitrypsin disease of the liver Chronic biliary disease Primary biliary cirrhosis Primary sclerosing cholangitis Autoimmune cholangitis Of note, similar to chronic hepatitis, steatohepatitis is a major morphologic category of chronic necroinflammatory liver disease. The histologic features of steatohepatitis, however, are sufficiently different from those of the chronic hepatitides as to preclude it from being placed in the same morphologic category of liver disease. Furthermore, the etiologies, and hence prognosis and treatment of steatohepatitis and chronic (non-steatotic) hepatitis are markedly different. As such, one of the initial determinations that the pathologist must make upon review of a liver biopsy with chronic necroinflammatory hepatocellular injury is to distinguish the histological pattern of chronic hepatitis from steatohepatitis. In practical application, this distinction is usually, but not always, readily apparent. Furthermore, some cases are complicated by the co-existence of both chronic necroinflammatory processes (e.g. hepatitis C and nonalcohol-related steatohepatitis). As mentioned previously, the different causes of chronic hepatitis share many morphologic features. While some histologic findings may suggest a certain etiology, there are no morphologic features that are pathognomic for a specific entity. Accordingly, identification of the etiology in chronic hepatitis typically depends more on the clinical and laboratory data than the histologic features of the liver biopsy. Etiologic evaluation of a liver biopsy with chronic hepatitis, therefore, should be performed in conjunction with complete and thorough clinical and laboratory information. Etiologic evaluation of a liver biopsy for clinically presumed chronic hepatitis proceeds stepwise through the following algorithm. First, does the biopsy have the morphologic appearance of chronic hepatitis? If so, do the histologic features support or exclude the etiology indicated by the clinical and laboratory features? Or do the histologic features provide evidence of an alternative or superimposed process? Once these questions have been addressed, the etiologic portion of the final diagnosis typically is one of the diseases listed in Table 1. If an etiology cannot be determined on the basis of the clinical, laboratory, and histologic features, a descriptive morphologic diagnosis can be used, accompanied by a comment about possible etiologies. Scoring of chronic hepatitis: Grade and Stage Once the etiology is established, histologic information about the degree of necroinflammatory activity and the extent of the fibrosis is important for patient management. The degree of necroinflammatory activity (or histologic "grade") reflects disease activity and potentially is predictive of further fibrosis and/or responsiveness to therapy. The extent of fibrosis (or histologic "stage") is a marker of progressive damage, which may be irreversible, and may have significant therapeutic and prognostic implications. To be meaningful for clinical and/or research purposes, necroinflammatory activity and fibrosis need to be objectively defined and assessed using well-characterized and standardized semiquantitative scoring systems. Essentially, a scoring scheme standardizes the analysis and reporting of this clinically important histologic information. While many schemes, of varying complexity, have been proposed to serve this purpose, no single histologic scoring system for chronic hepatitis has been uniformly accepted. All schemes for scoring chronic hepatitis have advantages and disadvantages, and the choice of a specific scoring scheme must meet the needs of the particular clinical practice or study. For example, in the clinical setting, typically what is needed for patient management is an approximate division of chronic hepatitis into a relatively small number of categories according to the severity of the necroinflammatory activity and fibrosis. Accordingly, simplified schemes for scoring chronic hepatitis, such as the one proposed by Batts and Ludwig (1995), often are appropriate for use in the routine patient care setting (Table 2). Table 2: The Batts and Ludwig System for Grading and Staging Chronic Hepatitis (1995) Grading Terminology Histologic Criteria Grade Descriptive Lymphocytic piecemeal necrosis Lobular inflammation and necrosis 0 Portal inflammation only; no activity None None 1 Minimal Minimal; patchy Minimal; occasional spotty necrosis 2 Mild Mild; involving some or all portal tracts Mild; little hepatocellular damage 3 Moderate Moderate; involving all portal tracts Moderate; with noticeable hepatocellular change 4 Severe Severe; may have bridging necrosis Severe; with prominent diffuse hepatocellular damage Staging Terminology Histologic Criteria Stage Descriptive 0 No fibrosis Normal connective tissue 1 Portal fibrosis Fibrous portal expansion 2 Periportal fibrosis Periportal or rare portal-portal septa; architecture intact 3 Septal fibrosis Fibrous septa with architectural distortion; no obvious cirrhosis 4 Cirrhosis Cirrhosis Simple systems also have the advantages of being easier and quicker to use and associated with less observer variation in comparison to the more detailed scoring schemes. Of note, the Knodell histologic activity index (HAI) is a detailed grading system that has been widely used since it was proposed in 1981. Although relatively comprehensive, this system, with its assignment of four separate scores, often has proved too cumbersome for use in routine clinical practice. Alternatively, a common objective of research studies is the identification of pathogenetically significant histologic features. Since these features only may be detectable through the identification of small differences between cohorts, a more detailed scoring scheme that covers the range of possible histologic findings is necessary to provide the appropriate degree of sensitivity. Accordingly, for research purposes, a more detailed approach, such as the modification of the HAI proposed by Ishak (1995), often is the more suitable scoring system (Table 3). Table 3: The Ishak Modified HAI (1995) Modified HAI Grading: Necroinflammatory scores Score A. Periportal or perispetal interface hepatitis (piecemeal necrosis) Absent 0 Mild (focal, few portal areas) 1 Mild/moderate (focal, most portal areas) 2 Moderate (continuous around <50% of tracts or septa) 3 Severe (continuous around >50% of tracts or septa) 4 B. Confluent necrosis Absent 0 Focal confluent necrosis 1 Zone 3 necrosis in some areas 2 Zone 3 necrosis in most areas 3 Zone 3 necrosis + occasional portal-central bridging 4 Zone 3 necrosis + multiple portal-central bridging 5 Panacinar or multiacinar necrosis 6 C. Focal (spotty) lytic necrosis, apoptosis and focal inflammation Absent 0 One focus or less per 10X objective 1 Two to four foci per 10X objective 2 Five to ten foci per 10X objective 3 More than 10 foci per 10X objective 4 D. Portal inflammation None 0 Mild, some or all portal areas 1 Moderate, some or all portal areas 2 Moderate/marked, all portal areas 3 Marked, all portal areas 4 Maximum possible score for grading 18   Modified Staging: Architectural changes, fibrosis, and cirrhosis Score No fibrosis 0 Fibrous expansion of some portal areas, with or without short fibrous septa 1 Fibrous expansion of most portal areas, with or without short fibrous septa 2 Fibrous expansion of most portal areas, with occasional portal-to-portal bridging 3 Fibrous expansion of portal areas, with marked bridging, portal-to-portal and portal-to-central 4 Marked bridging (portal-to-portal and/or portal-to-central) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 Maximum possible score for staging 6 Ultimately, the primary factor in the choice of a specific scoring system is that it communicates the information that is of clinical, and if applicable, investigational significance necessary for the particular practice or study. As such, the choice of a specific scoring scheme is best made at the local level. Accordingly, the pathologists and clinical and/or research colleagues in the group should decide on the desired objectives and choose a scoring method in accordance with these needs. It is preferred obviously that all biopsies within a practice be evaluated using the same scoring system to provide consistency. Examples of reporting chronic hepatitis As described above, the evaluation and reporting of the liver biopsy findings in chronic hepatitis should systematically address the etiology, the degree of necroinflammatory activity and the extent of fibrosis in each case. As with the application of any scoring system, the specific scheme utilized should be noted in the report. Chronic hepatitis C, with mild necroinflammatory activity (Grade 2) and fibrous portal expansion (Stage 2).* Autoimmune hepatitis with moderate necroinflammatory activity (Grade 3) and bridging fibrosis (Stage 3).* Periportal hepatitis, etiology undetermined, with mild necroinflammatory activity (Grade 2) and periportal fibrosis (Stage 2).* * Batts and Ludwig grading system Limitations of chronic hepatitis scoring Intra- and inter-observer variation: A fundamental limitation of histologic scoring is that it is not objective, and hence, is subject to intra- and inter-observer variation. Specifically, grading and staging are subjective assessments and are inevitably influenced by the observer's experience and bias. The more simple scoring systems tend be associated with less intra- and inter-observer variation than the more complicated schemes. Accordingly, observer variation can be minimized by using the simplest scoring scheme which still provides the information necessary for the specific clinical practice or study. In addition, inter-observer variation can be minimized by clarification and agreement among observers on the scoring criteria for each feature in advance of the actual application of the scheme. Qualitative nature of scoring: The number assigned to each histologic feature does not represent an actual measurement but simply represents a category of severity. This assessment is qualitative not quantitative. The relative numbers applied to specific lesions are arbitrary and are not mathematically valid quantitative measurements. Sampling effect: The average liver biopsy samples approximately 1/50,000 of the total mass of the liver. Chronic liver diseases, including chronic hepatitis, however, typically have an irregular, patchy distribution of lesions within the organ. Accordingly, needle biopsy specimens, the mainstay of histologic evaluation of the liver, are subject to marked sampling variation for both the grade of necroinflammatory activity and the extent of fibrosis in chronic hepatitis. This sampling effect is compounded by small biopsy specimens or specimens obtained with narrow gauge needles. References Batts KP, Ludwig J. Chronic hepatitis: An update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417. Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: The Knodell histology activity index and beyond. Hepatol 2000;31:241-246. Desmet VJ, Gerger M, Hoofnagle JH, et al. Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatol 1994;19:1513-1520. Ferrell L. Nomenclature of chronic hepatitis: The new look. Anat Pathol 1997;2:21-33. Hubscher SG. Histological grading and staging in chronic hepatitis: Clinical applications and problems. J Hepatol 1998;29:1015-1022. Ishak K, Baptista A, Bianchi L, et al. Histologic grading and staging of chronic hepatitis. J Hepatol 1995;22:696-699. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatol 1981;1:431-435. Scheuer PJ. Classification of chronic viral hepatitis: A need for reassessment. J Hepatol 1991;13:372-374.