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Chronic Active Hepatitis: The Challenge for a New Nomenclature
- Albert J. Czaja, MD
- From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Requests for Reprints: Albert J. Czaja, MD, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. Acknowledgments: The author thanks Linda Grande for preparing the manuscript.
Abstract
Objectives: To review the etiologic agents and pathogenic mechanisms of chronic active hepatitis, to describe the current nomenclature for this disease and highlight its shortcomings, and to propose guidelines for change.
Data Sources: Relevant references were identified through a MEDLINE search (1982 to 1992), through prominent review articles and texts, and through a personal library of journals and reprints. Additional references were selected from the bibliographies of identified articles.
Study Selection: All pertinent articles on the etiologic agents, pathogenic mechanisms, and nomenclature of chronic active hepatitis were studied.
Data Synthesis: Subtypes of chronic active hepatitis can be defined by etiologic agent or immunoserologic marker, and these subtypes may have different clinical features, prognoses, pathogenic mechanisms, and treatments. An unauthorized jargon has evolved to accommodate these subtypes, and it may wrongly or prematurely connote their validity. Patients with cryptogenic disease, mixed viral and immunologic features, and atypical findings lack a formal designation. No established mechanism exists for modification of the nomenclature.
Conclusions: Chronic hepatitis can be subclassified into different subtypes that are defined by etiologic agent or by predominate pathogenic mechanism. A new nomenclature must be based on this knowledge. Formal mechanisms must be established to revise the nomenclature and to promulgate change.
Names are assigned to diseases for practical purposes. They may connote a clinical syndrome, etiologic agent, histologic finding, prognosis, or type of treatment. At best, they facilitate communication by describing a clinical condition that is universally recognizable, and, at worst, they constitute a convenient jargon that promotes stereotypes, perpetuates clinical assumptions, limits critical analysis, and compels therapeutic actions of uncertain efficacy. In the former instance, precise nomenclature ensures a confident diagnosis and a valid treatment decision; in the latter instance, jargon hybridizes fact with hypothesis, confounds research activities, and complicates management strategies.
In liver diseases, individual clinical, laboratory, and histologic features are rarely disease specific. A precise diagnosis, therefore, requires recognition of an etiologic agent or pathogenic mechanism rather than a characteristic but nondiagnostic clinical feature. A precise nomenclature must reflect this fact.
Progress in our understanding of the nature of chronic active hepatitis now compels changes in its nomenclature. Current designations emphasize the clinical and histologic features or cause of the disease, but they do not reflect the pathogenic mechanisms [1-4] (Table 1). The nomenclature for the histologic findings is frequently confused with that of the clinical disease, and diagnoses commonly connote disease severity, prognosis, and need for treatment. Terms such as chronic persistent hepatitis, chronic lobular hepatitis, and chronic active hepatitis are used by clinicians and pathologists to describe different aspects of the same disease, and transitions between different histologic patterns or levels of clinical activity can change the diagnosis [5, 6] (Table 1). Chronicity is defined subjectively by estimates of disease duration that have uncertain reproducibility and the temporal criterion of 6 months is an arbitrary and disputed boundary between acute and chronic illness [3, 4, 6, 7].
Precise etiologic diagnoses can now be made at presentation. Distinctive serologic findings can define different types of chronic active hepatitis, and these types can differ in cause, clinical behavior, and treatment requirements [8-11]. Progress has outdated the current nomenclature, and the accrual of new knowledge has generated a jargon to suit the immediate clinical needs (Table 2). New designations are being created with uncertain justification, whereas important new disease subgroups remain nameless.
It is essential to understand the diversity and complexity of chronic active hepatitis and to forge a new nomenclature based on our current understanding of pathogenic factors. We must also establish an enduring mechanism for the periodic assessment of the terminology. The goals of this review are to provide the basis for this understanding and the impetus for change.
Evolution of the Current Nomenclature
Chronic active hepatitis has been a continuously evolving disease concept since the 1930s [12], and its nomenclature has been remodeled as newer diagnostic technologies have been applied, diagnostic criteria for other similar conditions have been codified, confident exclusion requirements have been established, and advances in molecular biology have permitted identification and isolation of viruses and disease-specific target autoantigens.
Terms Based on Clinical Features
The term active chronic hepatitis was first used in 1953, and it connoted the unresolving nature of the inflammatory process (chronic) as well as the clinical severity of the disease (active) [13]. It accurately described the disorder but it was all-encompassing.
As insights into the nature of the disease accrued, changes in the nomenclature were justified. Lupoid hepatitis was substituted for active chronic hepatitis in 1956 when the disease was associated with the lupus erythematosus cell phenomenon [14]. The original deduction of Joske and King [15] that the lupus erythematosus cell phenomenon was a by-product of excess globulin production yielded to arguments favoring an autoimmune disorder, and, in 1956, the lupus erythematosus cell phenomenon acquired a pathogenic connotation [14]. The findings of cirrhosis, amenorrhea, obesity, and acne in young women constituted the clinical syndrome of lupoid hepatitis [16-19].
In 1961, the concept of lupoid hepatitis was enlarged as studies indicated that the disease could afflict men (33%) and occur early in life (as early as 9 months) [16]. Patients other than obese, amenorrheic, adolescent girls with acne and cirrhosis now qualified for the diagnosis [18, 19], and terms such as juvenile cirrhosis (which had clinical and prognostic connotations) disappeared [20].
In the mid 1960s, the lupus erythematosus cell phenomenon was no longer a prerequisite for the diagnosis of lupoid hepatitis as other autoantibodies, such as smooth-muscle antibodies and antinuclear antibodies, were described and linked to the disease [21, 22]. At this stage of knowledge, the terms autoimmune chronic active hepatitis or idiopathic chronic active hepatitis seemed most appropriate.
Terms Based on Histologic Findings
In the early 1960s, globulin deposits were found in hepatic mesenchymal cells in the periphery of the liver lobule and were associated with lymphocytes, plasma cells, histiocytes, and proliferated bile ductules [23, 24]. The histologic character of an immunologically mediated cytodestructive process was recognized, and this pattern of piecemeal necrosis soon became the sine qua non for the diagnosis. It was at this time that terms such as chronic active hepatitis with bridging necrosis or multilobular collapse, chronic aggressive hepatitis, plasma cell hepatitis, and chronic persistent hepatitis were coined [5, 25-31].
In the late 1960s and 1970s, chronic active hepatitis became a histologic entity and nearly lost its clinical identity. Histologic patterns established the diagnosis, suggested the pathogenesis, implied the prognosis, determined therapeutic strategies, and influenced the nomenclature [5, 27-31]. Terms such as chronic persistent hepatitis and chronic active hepatitis were regarded primarily as histologic diagnoses that connoted prognosis and need for treatment [5, 27-29, 31]. Indeed, the clinical manifestations of these different histologic patterns were frequently secondary considerations, given that the critical element in diagnosis and management was the histologic interpretation. This was the era when inter- and intraobserver variation in the interpretation of histologic features was a key concern, as was the likelihood of sampling error in obtaining representative biopsy specimens [32, 33]. Spontaneous or treatment-associated transitions between chronic active hepatitis and chronic persistent hepatitis were recognized [5, 34], and the limitations of a nomenclature based on histologic patterns became obvious. Chronic active hepatitis that had improved to features of chronic persistent hepatitis was still considered chronic active hepatitis, but this fact was frequently obscured by the nomenclature [34].
Terms Based on Etiologic Considerations
Testing for hepatitis B surface antigen (HBsAg) in the early 1970s showed that at least 25% of patients with chronic active hepatitis had evidence of hepatitis B virus infection [35, 36]. Soloway and colleagues [37] showed that the lupus erythematosus cell phenomenon could be detected in 10% of HBsAg-positive patients and that no difference existed in the laboratory features or frequency of concurrent immunologic diseases in patients with and without the lupus erythematosus cell phenomenon. In addition, various drugs, including oxyphenisatin, -methyldopa, nitrofurantoin, and propylthiouracil, were implicated as causes of chronic active hepatitis [38-40]. The term HBsAg-negative chronic active hepatitis was used to distinguish autoimmune or cryptogenic disease from HBsAg-positive chronic active hepatitis, and, in drug-related cases, an effort was made to indicate the etiologic basis for the condition by coining terms such as methyldopa hepatitis [41]. During this period, etiologic distinctions were recognized, but their importance in defining clinical presentation, prognosis, and therapy was not. Consequently, the nomenclature was inconsistent and varied in accordance with the preference and custom of individual investigators, referral centers, and geographic regions. The lack of a standardized nomenclature reflected the lack of standardized diagnostic criteria. Experiences between research centers and geographic regions could not be readily compared, and the results of clinical trials could not be generalized with confidence.
Terms Based on Compromise
The rubric, chronic active liver disease, was introduced during the early 1970s in an effort to encompass all patients of a similar nature and disease severity and to emphasize their common features regardless of cause [42]. This designation, however, was never fully accepted because clinical experiences continued to indicate significant heterogeneity in various subpopulations of patients with chronic active liver disease. Bulkey and coworkers [43] emphasized the importance of subclassification as a means of identifying patients with different signs and symptoms, prognoses, and pathogenic mechanisms [43], and Schalm and colleagues [44] recognized that patients with HBsAg responded less favorably to corticosteroids than did their HBsAg-negative counterparts. The era of splintering had begun and this effort continues.
Terms Based on Serologic Findings
By the late 1970s, improved virologic assays had diminished but not eliminated the classification of autoimmune chronic active hepatitis. The autoimmune nature of the disease in these patients remained uncertain, and a population of patients who lacked viral and immunoserologic markers remained. The term HBsAg-negative chronic active hepatitis became popular as a result of uncertainties about the nature of non-B disease, and it was promulgated in the literature by editors who preferred neutral, noncontroversial terms [45]. During this period of conservatism (based on ignorance about pathogenic mechanisms), the different types of chronic active hepatitis were designated only by the presence or absence of HBsAg, and terms such as chronic active hepatitis of uncertain etiology and idiopathic chronic active hepatitis were acceptable, albeit bland, synonyms for autoimmune chronic active hepatitis [8, 11]. The quintessence of ambiguity was yet to come, but the stage was set for the acceptance of chronic active hepatitis non-A, non-B.
By the 1980s, the autoimmune nature of some patients with chronic active hepatitis was accepted, and the nomenclature could assume a more robust and informative character. The term autoimmune chronic active hepatitis was resurrected as a clinically useful designation, and the disease became the focus of investigation. The development of an animal model strengthened its validity as a clinical diagnosis [46, 47], and other studies suggested that autoimmune chronic active hepatitis was an antibody-dependent, cell-mediated, cytotoxic reaction [48-50]. With these studies, autoimmune chronic active hepatitis earned its distinction from viral disease.
Terms Based on Pathogenic Considerations
During the 1980s, the number of organ- and nonorgan-specific autoantibodies associated with autoimmune hepatitis proliferated, and the entities of chronic active hepatitis B and non-A, non-B hepatitis acquired greater definition [51-54]. Efforts were focused on the identification and isolation of the target antigens responsible for autoimmune and viral disease. Liver-specific protein, liver membrane antigen, and asialoglycoprotein receptor (hepatic lectin) were proposed as the target autoantigens of autoimmune hepatitis [51, 53, 54], and hepatitis B core antigen was acknowledged as one of the target antigens of chronic active hepatitis B [55]. Investigators were now interested not only in the etiologic classification of chronic active hepatitis but also in the identification of type-specific pathogenic mechanisms.
Dynamics for Change
The modern era of research in chronic active hepatitis began in the late 1980s, when advances in molecular biology permitted the identification of the hepatitis C virus (HCV) as well as the cloning of hepatic autoantigens [56-58]. These developments enhanced diagnostic precision and established the existence of additional subgroups of chronic active hepatitis of differing causes, pathogenic mechanisms, and clinical expression. Re-examination of the histopathologic features of proven cases of chronic hepatitis C confirmed the presence of characteristic but not diagnostic morphologic changes, and it emphasized the difficulty in distinguishing chronic active hepatitis from chronic persistent hepatitis by microscopic examination [59]. These observations, in concert with the advances in diagnostic techniques, heralded the need to eliminate the time-honored classifications of chronic active hepatitis and chronic persistent hepatitis and to replace them with a nomenclature based on cause [59]. Recommendations for change, however, were not implemented, and deficiencies in the nomenclature accrued as research activity burgeoned.
Deficiencies in the Current Nomenclature
Failure To Accommodate Cryptogenic Hepatitis
Chronic hepatitis related to HCV infection is now a well-established, distinct clinical entity, and most patients who had been previously designated as having chronic non-A, non-B hepatitis have been formally reclassified as chronic hepatitis C. Not all patients with chronic non-A, non-B hepatitis, however, can be reclassified, and as many as 20% still lack a formal designation [60]. These patients may have HCV infection that cannot be detected by current methods, another as yet undefined virus (non-A, non-B, non-C) infection, or an autoimmune disease that has escaped detection by conventional immunoserologic testing [60, 61]. Clearly, these patients are not accommodated in the current nomenclature.
Failure To Accommodate Viral Hepatitis with Autoimmune Markers
Patients with serologic markers of autoimmunity may also have evidence of HCV infection [62-67], and it is uncertain whether these patients have concurrent viral disease or a primary HCV infection that has triggered an autoimmune process. Under such circumstances, it is difficult to classify such disease forms as autoimmune or viral, especially because the classification may suggest a treatment strategy that can be ineffective or detrimental if wrongly applied [68, 69]. In some instances, the antibodies detected by enzyme immunoassay are nonspecific for HCV-encoded antigens, but, in other instances, the antibodies correctly define the viral basis for the disease [64-67, 70-74].
Fortunately, only a minority of patients with severe autoimmune hepatitis in the United States are infected with HCV [71, 72, 74], and these patients can usually be identified by second-generation enzyme immunoassay and recombinant immunoblot assay. In Europe, however, 50% to 80% of patients with antibodies to liver-kidney microsome type 1 (anti-LKM1) have evidence of HCV infection [63-65]. Typically, the HCV-infected patients with anti-LKM1 are older men who have less inflammatory activity than their uninfected counterparts [75, 76]. They more closely resemble patients with chronic hepatitis C than autoimmune hepatitis, and most logically they should be classified as such. The designation of type 2b autoimmune hepatitis has been proposed to distinguish these patients from those with type 2a autoimmune hepatitis who are younger, predominantly women, anti-LKM1 positive, and seronegative for HCV infection [76]. Currently, these patients lack an official designation.
Failure To Accommodate Subtypes of Autoimmune Hepatitis
Patients with autoimmune hepatitis may have various autoantibodies, and subclassifications based on these different serologic findings must be considered. Patients with antinuclear antibody and smooth-muscle antibody seropositivity rarely have anti-LKM1 [77], and seropositivity for antibodies to soluble liver antigen (anti-SLA) may define a third subgroup [10]. The jargon of types 1, 2, and 3 autoimmune hepatitis based on these immunoserologic markers is already in use, and the nomenclature of autoimmune hepatitis may well require expansion if the individuality of these subtypes can be established [9, 10, 77]. If so, a foreseeable problem for taxonomists will be the need to ensure universal availability of standardized assays for these novel markers.
Failure To Accommodate Autoimmune Hepatitis with Hybrid Features
Patients with mixed features of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis as well as those with chronic viral infection and concurrent immunologic findings must also be codified. Hybrid syndromes between autoimmune hepatitis and primary biliary cirrhosis have long been recognized [78-82], but such patients have never been formally classified. Similarly, patients with clinical and histologic evidence of autoimmune hepatitis and cholangiographic features of primary sclerosing cholangitis have no designation [83-87]. Terms such as antimitochondrial antibody-positive chronic active hepatitis, autoimmune cholangitis, and small-duct primary sclerosing cholangitis have resulted from attempts to deal with conditions that have a feature inconsistent with a conventional diagnosis [86]. These conditions should be formally designated not simply to give them an identity but to ensure their exclusion from the classic conditions.
Prime Candidates for Inclusion in the Nomenclature
Autoimmune Hepatitis with Disease-specific Autoantibodies
Type 1 autoimmune hepatitis has replaced earlier terms such as lupoid hepatitis, classical hepatitis, and autoimmune chronic active hepatitis in everyday jargon, but the designation has not been formally promulgated. Type 1 disease is the most common form of autoimmune hepatitis in the United States, and it is associated with smooth-muscle antibody or antinuclear antibody seropositivity; hypergammaglobulinemia; concurrent immunologic disorders; HLA positivity for A1, B8, and DR3, or DR4; and responsiveness to corticosteroid therapy [7]. The specificity of smooth-muscle antibody for the diagnosis can be enhanced if antiactin antibodies are sought (especially anti-F actin), and the condition has already been referred to as antiactin hepatitis [9, 88]. Unfortunately, the target autoantigen of type 1 autoimmune hepatitis has not been identified. Smooth-muscle antibodies and antinuclear antibodies lack pathogenicity and are probably not primary immunoreactions to a specific autoantigen [89]. Consequently, the validity of type 1 disease as a distinct immunologic disorder remains uncertain, and its acceptance as a separate designation in the nomenclature has been slow.
Type 2 autoimmune hepatitis is another designation that has entered the hepatologic vocabulary without formal introduction. It refers to patients with anti-LKM1 and, in its purest form, connotes the absence of viral infection [75, 76]. Patients with type 2 autoimmune hepatitis are predominantly children (2 to 14 years old), but adults can also be afflicted [9]. In the United States, the diagnosis is unusual among adults, occurring in only 4% of patients with nonviral chronic hepatitis [77]. Concurrent immunologic disorders are more common in patients with this disorder than in those with type 1 disease (40% compared with 17%). Also, hypergammaglobulinemia is less pronounced, and serum immunoglobulin A levels may be low [9]. Nonorgan-specific autoantibodies are rare, whereas organ-specific antibodies including antithyroid microsome, antithyroglobulin, anti-islets of Langerhans, and antiparietal cell antibodies are common (30%). Preliminary experiences suggest that type 2 autoimmune hepatitis progresses more rapidly to cirrhosis than does type 1 disease (82% compared with 43% within 3 years), although prospective treatment trials using standardized therapies in patients selected by uniform criteria of disease severity have not been done [9].
Importantly, type 2 autoimmune hepatitis has a disease-specific autoantigen, P450 IID6, which can support its candidacy as a distinct subgroup of autoimmune hepatitis [57, 58, 90-93]. The P450 IID6 protein has a small linear 33-amino acid sequence, which is the epitope recognized by anti-LKM1 [58], and it can be expressed on the hepatocytic membrane surface [91, 94]. The T- and B-cell epitopes of this protein have not as yet been defined, but recombinant P450 IID6 is available for mapping studies. Type 2 autoimmune hepatitis has a different clinical presentation and different pathogenic mechanisms than type 1 disease, and its validity as a separate entity should be acknowledged in the nomenclature.
Type 3 autoimmune hepatitis is the most recent and least established of the subclassifications of autoimmune hepatitis [10]. Its credentials as a valid subclassification of autoimmune hepatitis must be developed further, but it is in line as a candidate for inclusion in the nomenclature. Type 3 autoimmune hepatitis is characterized by the presence of anti-SLA. These autoantibodies react with cytokeratins 8 and 18 within the cytoplasm of hepatocytes [10, 93], and the validity of type 3 autoimmune hepatitis as a separate disease entity presumes expression of these cytokeratins on the hepatocyte surface. Unfortunately, surface expression has not as yet been shown.
In the United States, type 3 autoimmune hepatitis constitutes 3% of adult patients with nonviral chronic hepatitis [95]. Patients with type 3 disease are mostly women (91%) with a mean age of 37 years (range, 17 to 67 years) [10]. They lack antinuclear antibodies, anti-LKM1, and antibodies to thyroglobulin and thyroid microsome, but only 26% are seronegative for all immunoserologic markers except anti-SLA. Indeed, smooth-muscle antibody (35%), antibodies to liver membrane antigen (26%), and antimitochondrial antibodies (22%) may be present, and these patients may be indistinguishable from those with type 1 disease except by anti-SLA testing [10, 95]. Consequently, it is uncertain whether anti-SLA is the hallmark of a unique disease with various nonspecific immunoserologic manifestations or an unusual but nonspecific marker of type 1 disease. This uncertainty has delayed the term's introduction into the formal nomenclature.
Cryptogenic Hepatitis
Cryptogenic chronic hepatitis remains an important and common diagnosis in adults [60, 96, 97], and its validity as a clinical entity continues to be enhanced as assays for the detection of viruses and novel autoantigens improve [98]. These patients require an official designation that does not suggest a cause or a treatment strategy. In addition, these patients should not be confused with those with cryptogenic chronic liver disease, which connotes an end-stage, inactive cirrhosis that has lost its identifying features [61]. The term cryptogenic chronic hepatitis is an acceptable designation because it indicates an active disease process of an uncertain nature. The minimum requirements for its diagnosis, however, have not been defined, and the term does not as yet denote a distinct clinical entity.
Portents for Change
On 5 June 1992, an international panel of experts on chronic active hepatitis met in the first of a projected series of regular sessions to standardize terms and to expand the nomenclature. Their focus was on autoimmune hepatitis. The recommendations of this ad-hoc committee (Table 3) constituted the beginnings of a dialogue that must ultimately include national and international scientific societies. The panel exemplified the type of review necessary for all forms of chronic hepatitis. Their recommendations were based on an understanding of pathogenic mechanisms; improvements in diagnostic technologies; and a recognition of the limitations of conventional clinical, biochemical, and histologic criteria for diagnosis. Not only were the terms for autoimmune hepatitis simplified but confusing clinical stereotypes were also eliminated and histologic designations were de-emphasized.
The value of task forces in updating nomenclature and in standardizing terms for all forms of chronic liver disease must be recognized, a method established for their appointment, and a logistic developed for the formal review and promulgation of their findings.
Guidelines for Change
The nomenclature of chronic active hepatitis must abide by the principles of taxonomy, which emphasize identification of genus and species. Although chronic active hepatitis is a generic term, the qualifying word, active, implies that it is a subset of a larger family. Because active no longer has diagnostic specificity and it may wrongly connote clinical features, histologic findings, or prognosis, it should be deleted from the nomenclature. Subsets of the genus, chronic hepatitis, should be defined by species-specific etiologic agents or by pathogenic mechanisms (Figure 1). Subsets of a species may also be included if they have an established clinical identity or distinctive pathogenic features (Figure 1). In Figure 1, chronic hepatitis is used as a collective name, and the various species each have an etiologic designation or connotation.
Implementation of Change
The need for change and the lack of an established method for change must be recognized by the international scientific societies that are dedicated to the study of liver diseases. The leadership of these societies must delegate representatives with established expertise in chronic active hepatitis to a task force that is committed to the standardization of diagnostic criteria and nomenclature. This task force must be able to decide the legitimacy of a subgroup and the appropriateness of its designation. It also must review the old nomenclature, discard archaic classifications, and propose modifications. The task force must also formalize its recommendations with appropriate justifications as a report that is submitted for review and endorsement by each of the executive committees of the sponsoring organizations. The executive committees must agree on a final proposal that can be promulgated to their membership and to the editors of their respective journals. The scientific literature must enforce the recommendations and control the proliferation of novel, unacceptable designations. Standing committees should be established in each of the organizations to review needs for change and to ensure standardization of diagnostic criteria and designations. It is through these standing committees that the call for future task forces must come. Failure to organize the forces for change and ensure the creation of a vocabulary based on deliberation and consensus will continue to allow the evolution of a jargon that will confound rather than illuminate.
- Copyright 2004 by the American College of Physicians
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