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HEPATOLOGY, August 1998, p. 360-365, Vol. 28, No. 2

Original Articles

Frequency and Nature of the Variant Syndromes of Autoimmune Liver Disease

Albert J. Czaja

From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN.

ABSTRACT

To determine the frequency and nature of variant syndromes in autoimmune liver disease, 162 patients with type 1 autoimmune hepatitis, 37 patients with primary biliary cirrhosis, and 26 patients with primary sclerosing cholangitis were assessed in a uniform fashion, and the strength of the original diagnosis was evaluated by use of a scoring system. Variant forms, including syndromes with autoimmune hepatitis and primary biliary cirrhosis (7%) or primary sclerosing cholangitis (6%) and autoimmune cholangitis (11%), were common in the 225 patients (18%). Individuals with autoimmune hepatitis and primary biliary cirrhosis entered remission during corticosteroid therapy as commonly as individuals with definite autoimmune hepatitis (75% vs. 64%, P = .5), and they responded better than patients with autoimmune hepatitis and primary sclerosing cholangitis (75% vs. 22%, P = .03) or autoimmune cholangitis (75% vs. 0%, P = .009). Patients with autoimmune hepatitis and primary sclerosing cholangitis had a higher frequency of a poor result than other variants (78% vs. 17%, P = .04), and they died of liver failure or required liver transplantation more often than patients with definite autoimmune hepatitis (33% vs. 8%, P = .05). None of the patients entering remission had serum alkaline phosphatase levels greater than twofold the reference value. In conclusion, variants of autoimmune liver disease are common. Corticosteroid therapy can be effective in patients with features of autoimmune hepatitis and primary biliary cirrhosis. A serum alkaline phosphatase level of less than twofold the reference value characterizes corticosteroid-responsive individuals. (HEPATOLOGY 1998;28:360-365.)

INTRODUCTION

The criteria for autoimmune hepatitis have been codified,1 and its definite diagnosis requires confident demonstration of a nonviral, immunity-mediated, hepatocellular inflammation.1-3 Variant syndromes have been described that have autoimmune features, but their findings are either insufficent for the definite diagnosis of autoimmune hepatitis or they suggest the presence of a coexistent different liver disease.4 These patients may have autoimmune cholangitis4-9 or an overlap syndrome between autoimmune hepatitis and primary biliary cirrhosis (PBC)4,10 or primary sclerosing cholangitis (PSC).4,11-16

The diagnostic criteria for these variant forms have not been standardized, nor have the frequencies of each syndrome and its appropriate treatment strategy been established.4 Because their diagnosis implies a resemblance to autoimmune hepatitis, empirical therapy with corticosteroids has frequently been instituted.4,6-8,13,15-19 Ursodeoxycholic acid has also been administered in anecdotal reports, especially in patients unresponsive to corticosteroid therapy and/or in those with marked cholestatic features.4,7,8,20 In each instance, clinical, laboratory, and histological improvements have been variable, and treatment guidelines have lacked confidence.4

A scoring system has been proposed by the International Autoimmune Hepatitis Group,1 and the validity of a modification of this system for the diagnosis of autoimmune hepatitis has been demonstrated.3 By grading each manifestation of the disease in accordance with its diagnostic importance, a numerical score is generated that reflects the net strength of the diagnosis. The composite score indicates the degree of difference between patients with various immune findings, and it permits a quantitative comparison between patients with classical features of autoimmune hepatitis and those with atypical or less pronounced findings.1,3The scoring system provides a mechanism by which variant syndromes can be evaluated and compared with each other and to definite autoimmune hepatitis in a consistent fashion.3,4,14

In this report, the frequencies of autoimmune cholangitis, autoimmune hepatitis and PBC, and autoimmune hepatitis and PSC are determined among patients with the clinical diagnoses of autoimmune hepatitis, PBC and PSC. Distinctive findings are sought between each of the variant syndromes and between the variant syndromes and patients with definite autoimmune hepatitis by scoring criteria. Responses to corticosteroid therapy are assessed in a retrospective fashion, and factors influencing treatment outcome are evaluated.

PATIENTS AND METHODS

Study Population. One hundred sixty-two patients with type 1 autoimmune hepatitis, 37 patients with PBC, and 26 patients with PSC constituted the study population. All patients had been evaluated in a uniform fashion by one investigator (A.J.C.), and each satisfied conventional clinical criteria that justified their diagnosis.1,21-23 Antimitochondrial antibody (AMA) was present in each patient with PBC, and diagnostic cholangiographic changes were present in each patient with PSC. The study was part of a research project approved by the Institutional Review Board of the Mayo Clinic.

Modified Scoring System. A scoring system modified from that proposed by the International Autoimmune Hepatitis Group1 and subsequently validated for the diagnosis of autoimmune hepatitis3 was applied to each of the 225 patients in the study population (table 1). Thirty items in 11 categories were scored, and an aggregate score of greater than 15 before therapy justified a definite diagnosis of autoimmune hepatitis.1,3 Scores between 10 and 15 indicated probable autoimmune hepatitis, and scores of less than 10 were nondiagnostic1,3 (table 1).

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table 1. Modified Scoring System for the Diagnosis of Autoimmune Hepatitis

Criteria for the Variant Syndromes. The designation of autoimmune hepatitis and PBC was made in all patients originally diagnosed as having type 1 autoimmune hepatitis or PBC who had aggregate scores of 10 or greater and seropositivity for AMA.

The designation of autoimmune hepatitis and PSC was made in all patients who had characteristic cholangiographic changes of PSC and aggregate scores of 10 or greater, indicating a concurrent probable or definite autoimmune hepatitis.

The designation of autoimmune cholangitis was made in all AMA-negative patients with clinical diagnoses of type 1 autoimmune hepatitis who had cholestatic clinical, laboratory, and/or histological changes and in whom inflammatory bowel disease was either absent or in whom results of cholangiography were normal.

Clinical Assessments. Comprehensive clinical histories, emphasizing drug use, parenteral inoculations, alcohol consumption, and familial illnesses; complete physical examination; and laboratory assessments, including standard liver-related biochemical indices, serum protein electrophoresis, and serum immunoglobulin concentrations by immunonephelometry, were performed at presentation. Serum levels of aspartate aminotransferase, alkaline phosphatase, and -globulin were determined in each patient, and immunoglobulin concentrations were assessed in 208 patients (92%).

Concomitant extrahepatic disorders of an immune nature were sought in accordance with previously published guidelines.25,26 The presence of thyromegaly, synovitis, colitis and skin lesions was recorded systematically, and additional studies were performed as indicated to characterize the finding.

Immunoserological Assessments. Smooth muscle antibody (SMA), antinuclear antibody (ANA), antibody to liver/kidney microsome type 1 (anti-LKM1), and AMA were sought by indirect immunofluorescence on murine tissue sections as described previously.18,24,27,28 A serum titer of 1:40 or higher was considered positive for SMA, ANA, and AMA. A serum titer of 1:10 or higher was considered positive for anti-LKM1.

Two hundred twenty-three patients (99%) were tested for SMA, and 225 patients were each tested for ANA (100%) and AMA (100%). Two hundred thirteen patients (95%) were tested for anti-LKM1, and all immunoreactions were negative (183 patients) or indeterminate (30 patients). The confounding effects of AMA positivity on the indirect immunofluorescence assay for anti-LKM1 accounted for the indeterminate reactions.28

Virological Assessments. All patients except 1 with PSC were tested for antibodies to Hepatitis C virus (anti-HCV) by a second-generation enzyme-linked immunosorbent assay (ELISA; Ortho Diagnostic Systems, Inc., Raritan, NJ) and/or for HCV RNA in serum by polymerase chain reaction.29 Similarly, all patients except 1 with autoimmune hepatitis were tested for Hepatitis B surface antigen by ELISA (Abbott Laboratories, North Chicago, IL). None of the patients had epidemiological or serological evidence of viral infection.

Histological Assessments. Liver tissue specimens were obtained from each patient by needle biopsy, and the histological findings were interpreted under code by experienced hepatopathologists at the Mayo Clinic. Each examiner reported the features in a standard fashion, and each adhered to conventional histological criteria for a tissue diagnosis.30,31 The designation of cirrhosis required fibrosis and a complete regenerative nodule. The individual histological changes were graded in accordance with the modified scoring system (table 1), and incompatible findings were downgraded.3

HLA Determinations. All patients were evaluated for class II (DR locus) HLA by use of a standard microlymphocytotoxicity technique as described elsewhere.26Restriction fragment length polymorphism was also used to define class II HLA in 141 patients (63%), and polymerase chain reaction with sequence-specific primers was used to confirm class II HLA status in 68 patients (30%).32 All individuals were white.

Treatment Responses. One hundred fifty-three patients (68%) were treated with prednisone alone (59 patients) or a higher dose of prednisone in combination with azathioprine (94 patients). Each of these therapies has been shown previously to be equally effective in the management of autoimmune hepatitis.33 Alternative therapies, including ursodeoxycholic acid alone (24 patients), prednisone and ursodeoxycholic acid (5 patients), prednisone, azathioprine, and ursodeoxycholic acid (1 patient), prednisone in varying doses (1 patient), and diverse investigational agents (6 patients), were administered to other patients. Institution of therapy was an independent clinical decision affecting patients similarly in all diagnostic categories.

To assess treatment outcomes retrospectively between variant groups and to compare results between variant syndromes and autoimmune hepatitis, only the responses to conventional corticosteroid regimens were analyzed.33,34Furthermore, only patients with a definite diagnosis of autoimmune hepatitis by scoring criteria constituted a confident comparison population.3 Accordingly, treatment results were assessed in 113 of the treated patients, including 86 individuals with definite autoimmune hepatitis.

Remission, treatment failure, and incomplete response constituted the treatment outcomes, and patients were classified in accordance with these previously published criteria.34 An incomplete response was declared only after at least 6 months of conventional corticosteroid therapy. Recrudescence of disease after remission and withdrawal of medication connoted relapse, and the development of fibrosis with a complete regenerative nodule in sequential liver tissue samples indicated progression to cirrhosis.34 Treatment failure and incomplete response were designated as a poor result. Death from hepatic failure and/or liver transplantation was not included as a poor result unless it occurred during immediate therapy and was categorized as a treatment failure.

Statistical Analyses. Fisher’s Exact Test was used to compare dichotomous variables, and the unpaired t test was used to compare differences in the means of continuous variables. Nonparametric variables in independent samples were compared by use of the Mann-Whitney test. A P value of .05 was required for statistical significance. Data are presented as means ± SEM in tables and text.

RESULTS

Frequency of the Variant Syndromes. Of 162 patients with the clinical diagnosis of type 1 autoimmune hepatitis, 11 (7%) satisfied criteria for autoimmune cholangitis and 8 (5%) were redesignated as having autoimmune hepatitis and PBC (table 2). Seven of the 37 patients with PBC (19%) satisfied criteria for autoimmune hepatitis and PBC, and 14 of the 26 patients with PSC (54%) were redesignated as having autoimmune hepatitis and PSC (table 2). Variant syndromes were found more commonly in patients with the original clinical diagnosis of PSC than in patients with the original clinical diagnosis of type 1 autoimmune hepatitis or PBC (table 2). The frequency of the variant syndromes in the entire study population of 225 patients was 18%, and each variant form occurred with similar frequency within this group (table 2).

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table 2. Frequencies of the Variant Syndromes in Autoimmune Chronic Liver Disease

Importantly, patients initially categorized as having type 1 autoimmune hepatitis who were subsequently reclassified as having autoimmune hepatitis and PBC were indistinguishable from those originally categorized as having PBC and then reclassified as having autoimmune hepatitis and PBC. Both groups were similar by age (46 ± 5 years vs. 58 ± 5 years, P = .1), female composition (75% vs. 100%, P= .5), serum levels of aspartate aminotransferase (698 ± 269 U/L vs. 413 ± 150 U/L, P = .4), alkaline phosphatase (461 ± 112 U/L vs. 400 ± 77 U/L, P = .7), bilirubin (6.9 ± 2.2 mg/dL vs. 5.8 ± 3.4 mg/dL, P = .8), and immunoglobulin M (382 ± 69 mg/dL vs. 692 ± 204 mg/dL, P = .1), and each group had comparable mean aggregate scores for autoimmune hepatitis (13 ± 1 vs. 16 ± 1, P = .09).

Distinctive Clinical Features. Patients with autoimmune hepatitis and PBC were distinguished from those with definite autoimmune hepatitis by having lower serum levels of immunoglobulin G, higher serum concentrations of immunoglobulin M, and a lower occurrence of SMA (table 3). Importantly, these patients were indistinguishable from those with definite autoimmune hepatitis by serum aspartate aminotransferase, bilirubin, alkaline phosphatase, and -globulin concentrations (table 3).

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table 3. Features of Variant Syndromes Compared With Definite Autoimmune Hepatitis

Patients with autoimmune hepatitis and PSC had concurrent immune diseases more frequently than patients with definite autoimmune hepatitis (79% vs. 38%, P= .007), but this difference reflected mainly the close association of PSC with inflammatory bowel disease. Serum concentrations of aspartate aminotransferase, -globulin, and immunoglobulin G were lower in these patients than in those with definite autoimmune hepatitis, whereas serum levels of alkaline phosphatase were higher (table 3). Furthermore, autoantibodies occurred less frequently, and HLA-DR4 was detected less often (table 3).

Patients with autoimmune cholangitis were distinguished from those with definite autoimmune hepatitis by lower serum levels of aspartate aminotransferase, -globulin, and immunoglobulin G at accession, higher serum concentrations of alkaline phosphatase, and a lower frequency of SMA (table 3). Importantly, these patients had the lowest mean aggregate score compared with each of the other syndromes, and they were more widely separated from definite autoimmune hepatitis (table 3). Only 1 patient with autoimmune cholangitis had inflammatory bowel disease (Crohn’s disease), and findings on cholangiography in this patient were normal. Five other patients underwent retrograde endoscopic cholangiography as part of their routine assessment, and results of these studies were also normal. Eight of the 11 patients had histological changes of ductopenia and/or cholangitis. Three patients had nondiagnostic liver tissue specimens but cholestatic clinical and/or laboratory features.

Treatment Results. Conventional corticosteroid regimens were administered to 12 patients with autoimmune hepatitis and PBC, 9 patients with autoimmune hepatitis and PSC, and 6 patients with autoimmune cholangitis (table 4). Only patients with the overlap syndrome of autoimmune hepatitis and PBC entered remission as commonly as the 86 treated patients with definite autoimmune hepatitis during comparable periods of follow-up. These patients also had a lower frequency of progression to cirrhosis (table 4).

View This table table 4. Results of Corticosteroid Therapy

Remission was less common in patients with autoimmune hepatitis and PSC than in patients with definite autoimmune hepatitis and patients with autoimmune hepatitis and PBC (table 4). Furthermore, the frequency of a poor result was higher in these patients than in each variant syndrome and definite autoimmune hepatitis. Patients with autoimmune hepatitis and PSC also died of liver failure or required liver transplantation more often than patients with classical autoimmune hepatitis (table 4).

Remission was not achieved in any of the patients with autoimmune cholangitis, but the mean duration of treatment and follow-up was short (table 4).

Factors Affecting Results of Corticosteroid Therapy. The frequencies of HLA-DR3 (36% vs. 56%, P = .4) and DR4 (45% vs. 38%, P = .7) were similar in patients with and without remission regardless of variant type. The aggregate score also did not predict treatment response, because patients with remission, treatment failure, and an overall poor result had similar scores (table 5). Furthermore, the number of patients with scores of 15 or greater was similar in each response category (table 5).

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table 5. Features Associated With Corticosteroid Responses in the Variant Syndromes

Remission during corticosteroid therapy was associated with lower serum levels of alkaline phosphatase and higher serum concentrations of -globulin and immunoglobulin G (table 5). Indeed, none of the patients with variant syndromes and serum alkaline phosphatase levels of more than twofold the reference value responded to corticosteroid treatment. The degree of hypergammaglobulinemia did not have a similar discriminatory effect (table 5).

DISCUSSION

Variant forms of immunity-mediated chronic liver disease are common, and they are frequently assimilated into conventional diagnostic categories. In this study, 18% of patients originally designated as having type 1 autoimmune hepatitis, PBC, and PSC had features of autoimmune cholangitis or autoimmune hepatitis and PBC or PSC (table 2). Detection depends on the diagnostic criteria that are applied, and these syndromes lack an established identity, official designation, and assessment algorithm.2,4 Consequently, their prevalence and behavior can vary between studies, and regional results may not be generalizable. A scoring system (table 1) was used in this report mainly to ensure uniformity of assessment and diagnosis. The specificity of this scoring system for autoimmune hepatitis has been established,3 and it provides a template that can be refined with experience or replaced as variant forms are better characterized and diagnostic criteria are codified.

Patients with PSC more commonly had concurrent features of autoimmune hepatitis than patients with PBC (table 2). HLA-DR3, ANA, and/or SMA seropositivity, and extrahepatic immune diseases, including inflammatory bowel disease, are common in both PSC and autoimmune hepatitis.3,14,25 These similarities may have accounted for the high occurrence of features associated with autoimmune hepatitis in the PSC group. The scoring system may overvalue nonspecific clinical features that are common in different diseases and undervalue or neglect to weigh truly discriminative findings, such as cholangiographic changes.3,14 Future studies must refine the diagnostic indices for the PSC variant by demonstrating that this syndrome is different from either primary disease and by tailoring the scoring system to recognize only this form.

Patients with autoimmune hepatitis and PBC or PSC differed from patients with definite autoimmune hepatitis, and the principal areas of difference reflected features particular to the PBC or PSC components of the syndrome (table 3). Autoimmune cholangitis had the lowest net aggregate score, and it was most distantly removed from the diagnosis of autoimmune hepatitis. None of the syndromes, however, could be distinguished from the others by individual findings or aggregate scores (table 3), and their existence as distinct clinical entities could not be established. Larger numbers of patients are required to fully assess the issue of independent existence.

Only patients with autoimmune hepatitis and PBC responded as commonly to corticosteroid therapy as patients with definite autoimmune hepatitis, and these individuals progressed to cirrhosis less frequently than patients with autoimmune hepatitis and PSC and patients with definite autoimmune hepatitis during comparable periods of observation (table 4). Previous studies have indicated that patients with autoimmune hepatitis, AMA seropositivity, and/or histological features of cholangitis frequently respond to corticosteroid therapy,17,18 and our current analysis reconfirms this potential benefit.

Importantly, patients with autoimmune hepatitis and PBC had serum aspartate aminotransferase, bilirubin, alkaline phosphatase, and -globulin levels that were similar to those in patients with definite autoimmune hepatitis, and the frequencies of HLA-DR3 and DR4 were also comparable (table 3). Mean aggregate scores were higher in these patients than those of the other conditions, and although these differences were not statistically significant, they indicated a stronger kinship with autoimmune hepatitis than was evident in the other variants. This greater resemblance may have contributed to the better outcome.

In contrast, none of the patients with autoimmune cholangitis and only 2 of the 10 treated patients with autoimmune hepatitis and PSC entered remission during corticosteroid therapy (table 4). Remission occurred less frequently in these variant conditions than in patients with definite autoimmune hepatitis, and a poor result was especially common in patients with autoimmune hepatitis and PSC (table 4).). Other studies have indicated a similar recalcitrance to corticosteroid therapy in autoimmune cholangitis6,8 and PSC,15,16,25 especially in regard to histological improvement, and this study extends these observations to the variant categories.

Unfortunately, the appropriate therapy for each of the variant syndromes remains uncertain, and treatment strategies are empirical. In this study, responsiveness to corticosteroid therapy was associated with a serum alkaline phosphatase level of less than twofold the reference value (table 5). Improvement during corticosteroid therapy is uncommon in chronic cholestatic liver disease,17,25 and the magnitude of serum alkaline phosphatase elevation may be the most useful laboratory test to differentiate variant syndromes that have predominant cholestatic or hepatocellular features. Further assessment of this laboratory parameter as an index for treatment selection is warranted.

In summary, variant syndromes of immunity-mediated chronic liver disease are common, and they should be sought in all such patients. Only individuals with autoimmune hepatitis and PBC respond well to corticosteroids. Individuals with autoimmune hepatitis and PSC have an especially poor treatment outcome. Normal or near-normal serum alkaline phosphatase levels characterize the treatment responders. The frequency of the variant syndromes and their variable response to corticosteroids justify continued efforts to define their character, establish their validity, codify diagnostic criteria, and determine effective therapies. A greater understanding of shared pathogenic mechanisms and/or host predispositions and a better explanation of unsuccessful treatment in patients with presumed autoimmune hepatitis should result from this effort. Indeed, the recognition and separate categorization of these syndromes may be essential in ensuring accurate depictions of the natural history and prognosis of autoimmune hepatitis.

References

Footnotes

Acknowledgement: Linda Grande provided secretarial assistance. Abbreviations: PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; AMA, antimitochondrial antibody; SMA, smooth muscle antibody; ANA, antinuclear antibody; anti-LKM1, antibody to liver/kidney microsome type 1; anti-HCV, antibody to Hepatitis C virus; ELISA, enzyme-linked immunosorbent assay.

Presented in part at the meeting of the American Association for the Study of Liver Diseases, May 19, 1998, in New Orleans, LA

Received January 14, 1998; accepted April 7, 1998.

Address reprint requests to: Albert J. Czaja, M.D., Mayo Clinic, 200 First St. S.W., Rochester, MN 55905. Fax: (507) 284-0538.

Copyright © 1998 by the American Association for the Study of Liver Diseases.