Liver Failure and Liver Disease
Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis†
Article first published online: 27 MAY 2004
Copyright © 2004 American Association for the Study of Liver Diseases
Volume 39, Issue 6, pages 1631–1638, June 2004
How to Cite
Czaja, A. J. and Carpenter, H. A. (2004), Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. Hepatology, 39: 1631–1638. doi: 10.1002/hep.20235
This study was presented, in part, at the meeting of the American Association for the Study of Liver Diseases, May 17, 2004, New Orleans, LA.
- Issue published online: 27 MAY 2004
- Article first published online: 27 MAY 2004
- Manuscript Accepted: 6 MAR 2004
- Manuscript Received: 20 JAN 2004
Hepatic fibrosis and cirrhosis are possible consequences of corticosteroid-treated autoimmune hepatitis. Our aims were to determine the frequency of progressive fibrosis and the factors associated with this progression. Two hundred seventy-seven liver tissue specimens that had been obtained from 73 patients were interpreted in batch under code by a single pathologist. Fibrosis scores and histological activity indices were determined using the Ishak scoring system, and worsening fibrosis scores were correlated with clinical features, laboratory findings, and treatment responses. Fibrosis scores increased (2.3 ± 0.4 points to 4.2 ± 0.4 points; P < .0001) in 18 patients (25%) during 79 ± 13 months. Only five patients (7%) developed cirrhosis, and 55 patients (75%) had stable (16 patients) or decreased (39 patients) fibrosis scores. Human leukocyte antigen (HLA) DR3/DR4 occurred more frequently in patients with progressive fibrosis than others (23% vs. 2%; P = .03). Patients with progressive fibrosis had higher histological activity indices at last follow-up than patients with stable or reduced fibrosis (3.2 ± 0.7 vs. 1.7 ± 0.2; P = .01), and these indices worsened more commonly during therapy (17% vs. 2%, P = .04). Relapse, treatment failure, and incomplete response did not affect progression of fibrosis. In conclusion, fibrosis progresses in only a minority of patients during corticosteroid therapy. Progression is associated with HLA DR3/DR4 and worsening histological activity. Exacerbations or persistence of disease activity does not increase disease progression after treatment has been instituted. (HEPATOLOGY 2004;39:1631–1638.)
Corticosteroids induce clinical, laboratory, and histological improvement in most patients with autoimmune hepatitis,1, 2 and recent studies have suggested that treatment may decrease hepatic fibrosis by reducing inflammatory activity and/or suppressing the immune mechanisms of liver injury.3 Cirrhosis, however, still develops in as many as 40% within 10 years,4, 5 and the bases for histological progression remain uncertain.
Nine percent of patients with autoimmune hepatitis deteriorate despite compliance with corticosteroid therapy (treatment failure); 13% improve, but not to a degree to satisfy remission criteria (incomplete response); and at least 50% exacerbate after resolution of inflammatory activity and discontinuation of medication (relapse).6 Furthermore, novel treatment strategies using low-dose prednisone7 or azathioprine alone8 have been introduced as long-term maintenance regimens intended to prevent relapse and drug intolerances. Recurrent or incompletely suppressed inflammatory activity as a result of relapse, refractory disease, and/or inadequate primary or maintenance treatments may be other reasons for worsening fibrosis.
Lastly, intrinsic host-specific rather than disease-specific factors may facilitate the development of fibrosis. The principal genetic risk factors for autoimmune hepatitis are human leukocyte antigen (HLA) DR3 and HLA DR4,9 and disease expression and treatment outcome have been associated with these markers.10, 11 Relapse and treatment failure occur more commonly in patients with HLA DR3 than in those with HLA DR4, and HLA DR3–positive patients develop disease at an earlier age. Other autoimmune promoters, including certain polymorphisms of tumor necrosis factor α12 and cytotoxic T lymphocyte antigen-413 genes, are closely associated with HLA DR3, and they may work in synergy (epistasis) with this determinant to affect disease severity and fibrosis.
The progression of fibrosis in autoimmune hepatitis has not been evaluated in a rigorous fashion. Previous studies have assessed the development of cirrhosis in this disease, but they have been limited by sampling and interpretative errors.14, 15 By applying a standardized scoring system, interpreting all specimens in batch under code by a single pathologist, and focusing on changes in fibrosis rather than the complex histological requirements for cirrhosis, the development of fibrosis can be estimated reliably and changes can be correlated with clinical events.3, 16–19
In this retrospective study of tissue samples prospectively acquired to assess treatment response, we evaluated changes in fibrosis in corticosteroid-treated autoimmune hepatitis by applying a standardized scoring system to coded specimens evaluated in batch. We determined the frequency of progressive fibrosis during therapy and correlated progression of fibrosis with clinical features, inflammatory activity, HLA risk factors, management strategies, and treatment outcomes. In this fashion, we determined the factors associated with worsening fibrosis and the adequacy of current management strategies to prevent this progression.
Patients and Methods
Seventy-three patients who satisfied international criteria for definite autoimmune hepatitis pretreatment20 were selected for the study because each had been enrolled in our treatment program, treated with conventional corticosteroid regimens, and monitored through liver biopsy examination. The absence of histological cirrhosis at accession was a requirement for inclusion because progression of fibrosis in patients with preexistent cirrhosis could not be quantified. These patients constituted 54% of the 136 patients in our program who had been treated and followed similarly. Their clinical features at presentation are shown in Table 1. Our investigation was approved by the Institutional Review Board of the Mayo Clinic.
|Clinical Features||Study Population (N = 73)|
|Age (y)||47 ± 2|
|Serum AST (nL, <31 U/L)||596 ± 44|
|Bilirubin (nL, <1.1 mg/dL)||3.9 ± 0.5|
|γ-Globulin (nL, 0.7–1.7 g/dL)||3.3 ± 0.1|
|Immunoglobulin G (nL, 600–1,500 mg/dL)||3100 ± 155|
|SMA- and ANA-positive||43 (59)|
|HLA DR3+/DR4−||25/60 (42)|
|HLA DR4+/DR3−||21/60 (35)|
|HLA DR3+/DR4+||4/60 (7)|
|HLA DR3+ and/or DR4+||50/60 (83)|
The 63 excluded patients had not undergone successive liver biopsy examinations (2 patients), had inadequate tissue specimens for review (4 patients), refused to participate in the study (one patient), had liver tissue slides at another institution (37 patients), had lost biopsy material (5 patients), or had cirrhosis already established at presentation (14 patients).
Clinical and Laboratory Assessments.
All patients had been evaluated at accession and at each follow-up visit by one investigator (A. J. C.). Patients were followed in a systematic fashion according to a previously published protocol.1 Smooth muscle antibodies and antinuclear antibodies were determined in all patients by indirect immunofluorescence as reported previously,21, 22 and antibodies to liver/kidney microsome type 1 (anti-LKM1) were evaluated by a similar method in 61 patients (84%) (see Table 1).23 Serum titers of 1:40 or greater were considered positive for smooth muscle antibodies and antinuclear antibodies, and a serum titer 1:10 or greater was considered positive for anti-LKM1.21–23 One patient had both antinuclear antibodies and anti-LKM1. All individuals were negative for hepatitis B surface antigen and antibodies to hepatitis C virus by a second generation enzyme-linked immunosorbent assay.
Fifty-four patients were initially treated with prednisone in combination with azathioprine (74%), and 19 patients received a higher dose of prednisone alone (26%).1, 2 Both drug regimens had been shown previously to be of comparable efficacy.24 Therapy was continued until previously published criteria for remission or treatment failure had been satisfied.1, 2
Patients entering remission were withdrawn from medication over a 6-week period and monitored for relapse. Relapse connoted reappearance of symptoms and increase in the serum aspartate aminotransferase level to more than threefold the upper limit of normal. Its detection justified reinstitution of the original treatment protocol. The absence of relapse constituted a sustained remission.25
Treatment failure was managed by increasing the dose of prednisone to 60 mg/d or to 30 mg/d in combination with azathioprine 150 mg/d.1, 2, 6 An incomplete response connoted improvements during treatment, but not to a degree to satisfy remission criteria. Treatment was continued long-term at doses that maintained stable laboratory indices.1, 2, 6
Multiple relapses after drug withdrawal or relapse and subsequent intolerance of the medication were managed with long-term maintenance schedules that included low-dose prednisone (0–20 mg/d), azathioprine only (25–150 mg/d), or low-dose prednisone (0–20 mg/d) and azathioprine (0–150 mg/d).1, 2, 6–8, 25 The latter regimen constituted a transition stage from conventional therapy with prednisone and azathioprine to maintenance therapy with azathioprine only.
Liver tissue examinations were performed at accession, prior to discontinuation of medication after remission, and whenever indicated to evaluate treatment failure.1 Two hundred seventy-seven liver tissue specimens from the 73 patients (mean, 3.8 ± 0.3 specimens/patient; range, 2–18 specimens/patient; median, 3 specimens/patient) were interpreted in batch under code by a single liver pathologist (H. A. C.). Two hundred seventy-five specimens had been obtained using 15- to 16-gauge needles; two specimens were surgical wedges.
Stains specific for fibrosis were available in 261 specimens (94%). The mean length of the biopsy core was 1.3 ± 0.04 cm (range, 0.3–4.0 cm; median length, 1.2 cm), and the mean number of portal tracts per specimen was 7.5 ± 0.2 (range, 1–26 portal tracts/specimen; median, 7 portal tracts/specimen). Two hundred one tissue cores (73%) were at least 1.0 cm, and only six (2%) were less than 0.5 cm. One hundred eighty-one specimens (65%) had at least six portal tracts, and all but two had more than one.
The degree of fibrosis and inflammation was graded in accordance with the scoring system of Ishak and colleagues and recorded as the fibrosis score and histological activity index (HAI), respectively.26 The fibrosis score reflected different stages of fibrosis, including none (0 points), fibrous expansion of some portal tracts (1 point), fibrous expansion of most portal tracts (2 points), occasional portal-to-portal bridging (3 points), marked bridging (4 points), bridging with occasional nodules (5 points), and cirrhosis (6 points). The maximum fibrosis score was 6 points. The HAI reflected a composite score of grades for interface hepatitis, confluent necrosis, focal inflammation, and portal inflammation. The maximum HAI was 18 points. The Ishak system is better able to evaluate the mild changes of fibrosis that are unevenly distributed in autoimmune hepatitis14 than the system developed specifically for chronic hepatitis C,17 and its reproducibility18 and validity for staging chronic hepatitis19 are recognized.
Sixty patients (82%) had been evaluated for the class II (DR locus) HLA by a standard microlymphocytotoxicity technique (8 patients), restriction fragment length polymorphism (44 patients), or polymerase chain reaction with sequence specific primers (8 patients), as reported previously.10 All were white North Americans. One hundred two white North American blood donors were similarly typed, and they constituted the normal control population.
The Fisher exact probability test was used to compare dichomotous variables, and the unpaired t test was used to compare differences in the means of continuous variables. The paired t test was used to compare interval changes in the HAI and fibrosis scores in the same patients. For the purposes of this study, only the frequencies of the known susceptibility factors for autoimmune hepatitis, HLA DR3 and HLA DR4, were analyzed. Because the variables for comparison had been formulated a priori and then assessed systematically in the study population, an unadjusted P value of .05 was used to determine statistical significance. Data are presented as the mean ± SEM in tables and text.
Frequency of Increased Fibrosis Scores.
The fibrosis scores increased significantly in 18 patients (25%) during 79 ± 13 months of observation (range, 12–185 months; median, 70 months) (Table 2). Four patients with no fibrosis on initial biopsy samples developed fibrosis, including one patient whose fibrosis score increased to 1, one patient whose fibrosis score increased to 2, one patient whose fibrosis score increased to 3, and one patient whose fibrosis score increased to 6 during 78 ± 25 months of follow-up (range: 24–144 months; median: 72.5 months) (Fig. 1). Five patients increased their fibrosis scores to 6 (cirrhosis) during 88 ± 27 months of observation (range, 12–144 months; median, 112 months), including two patients who had progressed from a fibrosis score of 5, two patients who had progressed from fibrosis scores of 3 and 4, respectively, and one patient who had progressed from a fibrosis score of 0 (see Fig. 1). The frequency of histological progression to cirrhosis was only 7%. Fibrosis scores increased by at least two points (range, 2–4 points) in 12 patients (16%) during 82 ± 16 months of follow-up (range, 12–185 months; median, 70 months) (see Fig. 1).
|Fibrosis Scores||N||Initial Tissue Specimens||Final Tissue Specimens||Follow-up Interval (mo)|
|Worse||18 (25)||2.3 ± 0.4*||4.3 ± 0.4*||79 ± 13|
|Stable||16 (22)||2.1 ± 0.4||2.1 ± 0.4||60 ± 16|
|Improved||39 (53)||3.6 ± 0.2*||1.4 ± 0.2*||56 ± 8|
|Total||73 (100)||2.9 ± 0.2†||2.3 ± 0.2†||64 ± 7|
Frequency of Stable or Improved Fibrosis Scores.
Fifty-five patients (75%) had stable (16 patients) or decreased fibrosis scores (39 patients) during 57 ± 7 months of observation (range, 6–225 months; median, 37 months) (Fig. 2). The 16 patients (22%) with stable fibrosis scores (mean, 2.1 ± 0.4 points; range, 0–5 points; median, 2 points) were observed for 60 ± 16 months (range, 6–200 months; median, 30 months), and they included four patients who failed to develop fibrosis after 11–37 months of observation (mean, 25 ± 11 months; median, 26.5 months) (see Table 2).
Fibrosis scores decreased significantly in 39 patients (53%) during 56 ± 8 months of follow-up (range, 6–225 months; median, 42 months), and the mean decrease in fibrosis score was 2.2 ± 0.2 points (range, 1–5 points; median, 2 points) (see Table 2). Fifteen patients lost all evidence of fibrosis, including one patient who had an initial fibrosis score of 5, five patients who had initial fibrosis scores of 4, and six patients who had initial fibrosis scores of 3. Three other patients who resolved their fibrosis had initial fibrosis scores of 2 (one patient) and 1 (two patients), respectively (see Fig. 2). Fibrosis scores decreased by at least 2 points (range, 2–5 points; median, 3 points) in 23 patients (32%) during 52 ± 9 months of follow-up (range, 12–165 months; median, 44 months). These reductions contributed to a significant overall improvement in fibrosis scores in the entire study population during 64 ± 7 months of treatment (range, 6–225 months; median, 44 months) (see Table 2).
Clinical and Histological Features Associated With Worsening Fibrosis.
Patients who had worsening fibrosis during therapy, including the five patients who progressed to cirrhosis, were indistinguishable at accession from patients with stable or decreased fibrosis by age, gender, duration of illness prior to treatment, and laboratory indices of liver inflammation (Table 3). The initial HAI (8.6 ± 1.3 vs. 7.1 ± 0.7; P = .3) and the degree of interface hepatitis (2.4 ± 0.4 vs. 2.2 ± 0.2; P = .5) or confluent necrosis (1.9 ± 0.5 vs. 1.4 ± 0.3; P = .3) at accession were also similar in the patients who had worsening fibrosis and those who did not. The only finding at entry associated with progression of fibrosis was heterozygosity for HLA DR3/DR4, and this association was strongest among those patients who had increased their fibrosis scores by at least 2 points (see Table 3). HLA DR3/DR4 also occurred more commonly in the patients with progressive fibrosis than in normal subjects (23% vs. 4%; P = .03), and this association strengthened if only patients with fibrosis scores that had increased by 2 or more points were compared with control subjects (30% vs. 4%; P = .01). Homozygosity for HLA DR3 or DR4 was not associated with progressive fibrosis in this small sample (see Table 3).
|Clinical Features at Accession||Increased Fibrosis Scores||Stable or Decreased Fibrosis Scores (N = 55)|
|Total (N = 18)||>2 Points (N = 12)|
|Age (y)||45 ± 4||43 ± 6||48 ± 2|
|Female||14 (78)||8 (67)||47 (85)|
|Duration illness (mo)||11 ± 1||11 ± 2||20 ± 6|
|Serum AST (nL, <31 U/L)||611 ± 90||589 ± 115||592 ± 51|
|Bilirubin (nL, <1.1 mg/dL)||3.6 ± 0.6||3.2 ± 0.7||4 ± 0.6|
|γ-Globulin (nL, 0.7–1.7 g/dL)||3.6 ± 0.2||3.4 ± 0.3||3.2 ± 0.1|
|Immunoglobulin G (nL, 600–1,500 mg/dL)||3493 ± 373||3214 ± 484||2963 ± 161|
|HAI||8.6 ± 1||8.7 ± 1.8||7.1 ± 0.7|
|HLA DR3+/DR4−||4/13 (31)||4/10 (40)||21/47 (45)|
|HLA DR4+/DR3−||4/13 (31)||2/10 (20)||17/47 (36)|
|HLA DR3+/DR4+||3/13 (23)*||3/10 (30)†||1/47 (2)*†|
|HLA DR3+/DR3+||1/13 (8)||1/10 (10)||7/47 (15)|
|HLA DR4+/DR4+||0/13 (0)||0/5 (0)||4/47 (8)|
Worsening Fibrosis and Treatment Outcome.
Treatment outcomes before the last biopsy assessment were similar in patients in whom fibrosis scores had increased and those in whom fibrosis scores had decreased or remained stable (Table 4). HAI at the last biopsy evaluation was significantly higher in the patients with progressive fibrosis, and none of the patients with worsening fibrosis had achieved full resolution of histological activity (see Table 4). Failure to eliminate histological activity, however, was not associated with a significantly higher frequency of progressive fibrosis in this small study population compared with patients who had stable or improved fibrosis (100% vs. 87%; P = .2). Furthermore, reduction in HAI by at least 2 points was as common in patients with and without progressive fibrosis (67% vs. 69%; P < .9) during comparable intervals of observation (see Table 4). An increase in HAI by at least 2 points during therapy, however, was associated with a greater frequency of progressive fibrosis than a stable, improved, or minimally increased HAI (17% vs. 2%; P = .04) (see Table 4).
|Treatment Outcomes Before Last Liver Biopsy Evaluation||Increased Fibrosis Scores||Stable or Decreased Fibrosis Scores (N = 55)|
|Total (N = 18)||>2 Points (N = 12)|
|Remission||15 (83)||11 (92)||47 (85)|
|Relapse||13/15 (87)||10/11 (91)||36/47 (77)|
|Multiple relapses||12/15 (80)||9/11 (82)||26/47 (55)|
|Sustained remission||2/15 (13)||1/11 (9)||11/47 (23)|
|Incomplete response||1 (5)||0 (0)||1 (2)|
|Treatment failure||2 (11)||1 (8)||7 (13)|
|HAI at last tissue examination||3.2 ± 0.7*||3.1 ± 0.9†||1.7 ± 0.2*†|
|HAI resolution (HAI = 0)||0 (0)||0 (0)||7 (13)|
|HAI worse than >2 points||3 (17)‡||2 (17)||1 (2)‡|
|Active inflammation and continued treatment requirement||16 (89)||11 (92)||44 (80)|
|Duration of follow-up (mo)||79 ± 13||82 ± 16||57 ± 7|
Worsening Fibrosis and Inflammatory Activity.
Eleven of the 18 patients (61%) with worsening fibrosis did so after relapse, and five patients (28%) had progressive fibrosis during chronic corticosteroid therapy. Two of these latter patients had been receiving long-term maintenance treatment after relapse, two had been receiving treatment failure regimens, and one had been receiving continuous treatment for an incomplete response. Two other patients increased their fibrosis scores from 4 to 5 and from 1 to 3, respectively, after discontinuation of medication and during a sustained clinical remission.
Sixteen of the 18 patients in whom fibrosis increased (89%) were undergoing treatment for active disease at the time of their last biopsy assessment. Of the five patients who developed cirrhosis, three did so during treatment after relapse, one did so during treatment failure, and one did so during continuous treatment for an incomplete response. Fibrosis did not progress more commonly in patients undergoing corticosteroid therapy for active disease (relapse, treatment failure, incomplete response) than in patients who had been treated to a sustained remission (27% vs. 15%, P = .5). Similarly, cirrhosis did not develop more commonly in the patients undergoing active treatment compared with those who had been treated to remission (8% vs. 0%; P = .6), but the number of patients in each study group was small.
Worsening Fibrosis and Duration of Follow-up.
Patients with progressive fibrosis had longer follow-up than patients with stable or decreased fibrosis scores, but differences were not statistically significant (79 ± 13 months vs. 57 ± 7 months; P = .1) (see Table 4). The frequency of progressive fibrosis was similar in the 28 patients who had been followed for at least 5 years as in the 45 patients who had been followed for 3 years or less (36% vs. 18%; P = .1) and the 24 patients who had been followed for 2 years or less (36% vs. 17%; P = .2).
Specimen Size and Histological Scores.
The HAI (4.2 ± 0.3 points vs. 3.4 ± 0.4 points; P = .1) and fibrosis scores (2.6 ± 0.1 points vs. 2.8 ± 0.2 points; P = .5) were similar between the 201 tissue specimens of 1 cm or greater (mean, 1.5 ± 0.04 cm; range, 1–4 cm; median, 1.4 cm) and the 76 specimens of less than 1 cm (mean, 0.7 ± 0.02 cm; range, 0.3–0.9 cm; median, 0.7 cm) despite the greater number of portal tracts in the longer specimens (8.4 ± 0.3 portal tracts/specimen vs. 5.2 ± 0.3 portal tracts/specimen; P < .0001). Similarly, the histological diagnosis of cirrhosis was made with similar frequency in tissue specimens of at least 1 cm and those less than 1 cm (8% vs. 5%; P > .9).
Analyses based on 53 patients who each had been biopsied at least twice yielding 182 liver specimens of at least 1 cm showed that the frequency of progressive fibrosis increased to only 26%, the occurrence of cirrhosis was still 7%, and the HAI at the end of follow-up was still greater in the patients with progressive fibrosis than in patients with stable or improved fibrosis (3.9 ± 0.9 points vs. 2.0 ± 0.3 points; P < .01). Similar results were obtained when only tissue specimens that were 1 cm or longer containing six or more portal tracts were analyzed. Of 39 patients who had been biopsied at least twice yielding 127 liver specimens of at least 1 cm with at least six portal tracts (9.8 ± 0.3 portal tracts/specimen; range, 6–26 portal tracts; median, 9 portal tracts), the frequency of fibrosis progression was 28%; the occurrence of cirrhosis was 8%; and the HAI at end of follow-up was greater in these patients than in others (4.3 ± 1.1 vs. 2.3 ± 0.4; P = .04). The analyses based on increased sample size did not identify new patients with cirrhosis.
Our study indicates that hepatic fibrosis progresses in only a minority of patients with autoimmune hepatitis who are treated with corticosteroids and that this progression is associated with HLA DR3/DR4 and an increase in HAI by at least 2 points during treatment. Furthermore, cirrhosis develops infrequently in treated individuals who are followed long-term, and the progression of fibrosis is not associated with relapse, treatment failure, duration of follow-up, or need for continuous treatment. These findings suggest that (1) progressive fibrosis is not a common consequence of corticosteroid-treated autoimmune hepatitis, (2) progression of fibrosis relates to genetic as well as inflammatory factors, and (3) treatment schedules that respond to exacerbations or persistence of disease activity are sufficient to prevent disease progression.
Previous studies have indicated that the probability of developing cirrhosis during corticosteroid therapy of autoimmune hepatitis was 40% within 10 years.4, 5 These estimates were based on the assumption that histological cirrhosis was irreversible and that successive biopsy samples showing absence of cirrhosis represented sampling error. Subsequent investigations have indicated that fibrosis can decrease during corticosteroid treatment of autoimmune hepatitis,3, 27–29 and isolated reports have suggested that cirrhosis can disappear.3, 30 Studies that did not account for the possibility that fibrosis could improve may have overestimated the histological consequences of the disease. Our findings suggest that corticosteroid therapy prevents progression of fibrosis in most patients and that fibrosis can diminish during treatment.
Hepatic inflammation stimulates the transformation of perivascular hepatic stellate cells into myofibroblasts, which can then proliferate, migrate, and synthesize fibrillar collagens and matrix proteins.31, 32 Our findings indicate that hepatic inflammation is associated with the progression of fibrosis in autoimmune hepatitis, especially if inflammatory activity increases during corticosteroid therapy. Corticosteroids may prevent or decrease fibrosis by suppressing inflammatory activity,33, 34 promoting disappearance of the tissue inhibitors of fibrinolysis,35 facilitating degradation of the matrix proteins by unrestricted metalloproteinases,36 and stimulating apoptosis of hepatic stellate cells.37 Corticosteroids may also inhibit expression of transforming growth factor-β, which is a powerful activator of hepatic stellate cells.38, 39 Our study suggests that corticosteroids protect against progressive fibrosis in most patients but that worsening histological activity may be a justification for more intense treatment.
Progressive fibrosis was also associated with heterozygosity for HLA DR3/DR4. This phenotype occurred in only four of the 60 patients who underwent HLA typing (7%), but it was found in 23% of the individuals with progressive fibrosis and 30% of those with fibrosis scores that had increased by at least 2 points. HLA DR3 and DR4 are independent susceptibility factors for autoimmune hepatitis in white North American and northern European patients, and HLA DR3 has been associated with treatment failure.9, 11 The HLA DR3/DR4 phenotype, however, has not been ascribed a prognostic importance, and its low frequency in our study population indicates that it is not a major contributor to disease progression. Nevertheless, it may broaden the spectrum of autoantigens that can be displayed by the DR molecules of the major histocompatibility complex, and it may increase the number of autoreactive immunocytes that can extend or perpetuate inflammatory activity.40 Furthermore, other genetic promoters outside the major histocompatibility complex that modulate cytokine production may be linked individually to either HLA DR3 or DR4 and brought into synergy by the heterozygosity.40, 41 Our earlier studies have suggested that the “dose” of susceptibility alleles can affect the occurrence of autoimmune hepatitis11, 42 and its clinical expression.40 The lack of association between homozygosity for HLA DR3 or HLA DR4 and progressive fibrosis (see Table 3) may reflect our small sample size or synergisms with autoimmune promoters that are clustered by the HLA DR3/DR4 phenotype. Future studies are needed in larger numbers of patients to detail the genetic determinants of fibrogenesis.
Our study indicated that adverse treatment outcomes did not increase the frequency of histological progression. These findings suggest that the treatment responses following the adverse outcome were sufficient to suppress inflammatory activity and prevent worsening fibrosis. The degree and duration of inflammation may be more important than its presence in preventing progression. The possibility of a threshold of inflammatory activity below which net collagen deposition is prevented by treatment was supported by another observation. Patients with stable or improved fibrosis scores had an elevated HAI as frequently as patients with increased fibrosis scores.
The continuation of corticosteroid therapy in doses that suppress but not eradicate inflammatory activity may be sufficient to prevent net collagen deposition. This speculation justifies the continued close monitoring of patients during and after treatment and the prompt adjustment of regimens if inflammatory activity worsens. Our study was too small to determine the most effective treatment schedules, but long-term maintenance regimens after relapse appeared to be as effective in preventing fibrosis as conventional dose schedules. Future prospective studies must correlate histological progression with changes in HAI and treatment regimen in a larger number of patients to define optimal maintenance therapy.
We cannot exclude sampling variation as a factor that might have influenced our results, but we estimate that this effect was small. Most of the liver cores were 1.0 cm or longer; methods were applied that have been shown previously to be highly reproducible in the assessment of fibrosis; results were similar if only scoring changes of 2 or more points were analyzed; and fibrosis scores, HAI, and frequencies of cirrhosis were comparable in tissue samples stratified by size. Previous studies have indicated that reductions in the length of the tissue core erroneously decrease the grade and stage of the disease,43, 44 but there has been no consensus about the optimal length, diameter, and number of portal tracts per specimen to assess histological change.45 Studies recommending that tissue cores be at least 2.5 cm long,44 1.4 mm wide,43 and possessing 6–8 portal tracts45, 46 may have set the criteria too high for consistent satisfaction by current biopsy techniques. In our study, the frequency of progressive fibrosis did increase as biopsy length and number of portal tracts were increased, but the number of patients and specimens in these stratifications also diminished. Accordingly, the changes in frequency of progression may have been artifacts of the smaller study population. Importantly, the frequency of disease progression was still low in all the subset analyses, no new patients with cirrhosis were discovered, and the association between progression of fibrosis and increased HAI remained intact. These findings support the likelihood that our observations reflected actual disease behavior rather than sample size. The validation of noninvasive assays for extracellular matrix proteins and/or hepatic stellate cell activity are needed to improve the conventional clinical assessments of fibrosis.31, 32
In conclusion, fibrosis progresses in a minority of patients during corticosteroid therapy, and the frequency of cirrhosis is low. Patients with progressive fibrosis more commonly have HLA DR3/DR4 and an increase in HAI by at least 2 points. Relapse, treatment failure, and incomplete response do not increase the frequency of progression, and corticosteroids may prevent fibrosis by reducing inflammatory activity.
- 34Molecular mechanisms of glucocorticoid effects. Mod Asp Immunobiol 2001; 2: 78–82..
- 36Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem 2002; 277: 11069–11076., , , , , , et al.
- 40Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 2002; 97: 2051–2057., .Direct Link:
- 41Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol 2001; 96: 1224–1231..Direct Link: