We describe eight patients with autoimmune, steroid-responsive hepatitis in whom cirrhosis or extensive fibrosis was confirmed on liver biopsy at diagnosis but disappeared or was markedly reduced in response to effective treatment.

Methods

Top Methods Case Reports Results Discussion Author & Article Info References

Study Sample

Eight patients were retrospectively selected because they had extensive scarring or cirrhosis on liver biopsy or laparotomy at time of diagnosis; responded to treatment with glucocorticoids, immunosuppressive drugs, or both; and had liver biopsy some years after treatment began. They were part of a group of 97 patients with a diagnosis of autoimmune hepatitis who were seen at New England Medical Center between 1966 and 1996. The other 89 patients did not have cirrhosis at diagnosis (n = 55), had cirrhosis at diagnosis but did not have liver biopsy after successful medical treatment (n = 25), had cirrhosis at diagnosis and still had extensive fibrosis on liver biopsy despite symptomatic and biochemical response to treatment (n = 6), or did not have a liver biopsy specimen of adequate size (>5 mm) at diagnosis or follow-up (n = 3). The diagnosis of autoimmune hepatitis was based primarily on a complete response to steroids [6], increased aminotransferase and total globulin levels, chronic active hepatitis on histologic study of the liver, and exclusion of other causes of hepatitis (such as alcohol or viral infection) [7]. Patients given a diagnosis before 1989 were not tested for hepatitis C virus.

Histologic Assessment

All liver biopsy specimens were measured; those 5 mm or less in length were excluded. All slides were coded in an unpaired manner and read blindly and independently by a hepatologist and a liver pathologist using the Knodell scoring system [8].

Case Reports

Top Methods Case Reports Results Discussion Author & Article Info References

Patient 1

A 40-year-old man had surgical cholecystectomy and wedge liver biopsy in 1970 because of fever and abnormal results on liver function tests. His aspartate aminotransferase (AST) level was 7.50 µkat/L, and his alanine aminotransferase (ALT) level was 4.33 µkat/L. The liver was nodular. Liver biopsy showed portal and lobular inflammation with extensive fibrosis (Figure 1, part A). The patient was treated with prednisone, 30 mg/d. His ALT and AST levels returned to normal within 6 months. Prednisone therapy was tapered and discontinued after 2 years. Blood test results remained normal for 8 years, after which time autoimmune hepatitis recurred. The patient noted fatigue and fever, and his ALT and AST levels were elevated sevenfold. Response to prednisone was again rapid. Liver biopsy done 2 years later had normal results with the exception of minimal portal fibrosis (Figure 1, part B). The patient had additional relapses while not receiving treatment 12 and 20 years after diagnosis. Each relapse responded quickly to prednisone therapy. An attempt to use azathioprine for maintenance therapy was unsuccessful because of an idiosyncratic reaction.

View larger version (125K): [in this window] [in a new window]   Figure 1. Liver biopsy specimens. A. Patient 1. Surgical liver biopsy specimen obtained at diagnosis. The liver was reported to be macroscopically nodular, and there are extensive portal fibrosis and linkage of portal triads by bands of connective tissue. (Masson trichrome; original magnification, x74.) B. Patient 1. Percutaneous liver biopsy specimen obtained 10 years after diagnosis. The parenchyma and portal triads are normal. (Masson trichrome; original magnification, x74.) C. Patient 2. Percutaneous liver biopsy specimen obtained 2.5 years after diagnosis and just before compliance with treatment. There is obvious cirrhosis with islands of parenchyma between bands of connective tissue. (Masson trichrome; original magnification, x74.) D. Patient 2. Percutaneous liver biopsy specimen obtained after 5.5 years of immunosuppressive therapy. Results were normal except for minimal portal fibrosis. (Gomori trichrome; original magnification, x74.) E. Patient 3. Percutaneous liver biopsy specimen obtained before treatment. There are dense bands of connective tissue that disrupt parenchyma and extensive piecemeal necrosis. (Masson trichrome; original magnification, x74.) F. Patient 3. Percutaneous liver biopsy done after 2 years of prednisone treatment. Portal triads are minimally enlarged, but no piecemeal necrosis or bridging fibrosis is seen. (Gomori trichrome; initial magnification, x74.).

Patient 2

A 17-year-old man presented with jaundice, an AST level of 20.25 µkat/L, an ALT level of 22.09 µkat/L, and hyperglobulinemia (globulin level, 62 g/L). He received prednisone, 20 mg/d, and azathioprine, 100 mg/d. After 6 months, his ALT level was 0.98 µkat/L and his AST level was 1.20 µkat/L. The patient discontinued treatment against medical advice and was untreated for 2 years. His ALT level increased to 19.09 µkat/L, and his AST level increased to 25.42 µkat/L. Liver biopsy showed chronic hepatitis and cirrhosis (Figure 1, part C). The patient resumed treatment with prednisone, 30 mg/d, and azathioprine, 100 mg/d. His ALT level decreased to 0.27 µkat/L, and his AST level decreased to 0.45 µkat/L. Prednisone therapy was discontinued after 2 years, and the patient remained in remission with azathioprine alone. Liver biopsy done 8 years after diagnosis showed no sign of hepatitis and minimal fibrosis (Figure 1, part D).

Patient 3

A 34-year-old woman had been told that her liver function test results were abnormal 17 years earlier. Her ALT level was 8.30 µkat/L at time of referral. Liver biopsy showed chronic active hepatitis and cirrhosis (Figure 1, part E). The patient began receiving prednisone, 20 mg/d, and her aminotransferase levels returned to normal. Attempts to taper steroid dose and maintain the patient with azathioprine or 6-mercaptopurine were unsuccessful because of adverse reactions. After 2 years of prednisone therapy, the ALT level was 0.28 µkat/L and the AST level was 0.33 µkat/L. Repeated liver biopsy showed nearly normal results with minimal portal inflammation and marked regression of fibrosis (Figure 1, part F). The patient remained well while receiving prednisone for 8 years.

Results

Top Methods Case Reports Results Discussion Author & Article Info References

The final study group included six male and two female patients. The median age at presentation was 36 years (range, 8 to 61 years). At presentation, all patients had elevated ALT levels (median, 10.30 µkat/L [range, 4.33 to 36.26 µkat/L]), AST levels (median, 12.79 µkat/L [range, 5.15 to 35.42 µkat/L]), and globulin levels (median, 43 g/L [range, 31 to 62 g/L]) (Table 1). The median albumin level was 34 g/L (range, 31 to 42 g/L), and the median platelet count was 143 000 cells/mm³ (range, 103 000 cells/mm³ to 200 000 cells/mm³). All patients received steroids; four also received 6-mercaptopurine and four also received azathioprine. At the time of the final biopsy, ALT levels were significantly lower than at presentation (median, 0.37 µkat/L [range, 0.17 to 1.50 µkat/L]), as were AST levels (median, 0.35 µkat/L [range, 1.33 to 0.25 µkat/L]) and globulin levels (median, 25 U/L [range, 20 to 34 U/L]). Serum albumin levels increased during therapy (median, 43 g/L [range, 39 to 48 g/L]), as did platelet counts (median, 200 000 cells/mm³ [range, 110 000 to 364 cells/mm³]) (Table 1). The median duration of follow-up was 9.5 years (range, 4 to 28 years). After follow-up, four patients were in remission while receiving no treatment, two were receiving 6-mercaptopurine, and two were receiving prednisone.

The median length of biopsy specimens at presentation was 15 mm (range, 13 to 25 mm for seven of the eight specimens; one specimen was from a wedge biopsy). The median length of final biopsy specimens was 21 mm (range, 6 mm to 32 mm for all eight specimens). The median Knodell score at presentation was 14.0, with a median fibrosis grade of 3.3 (Table 1). The median Knodell score on the final set of biopsy specimens was 1.3, with a median fibrosis grade of 0.8 (Table 1). The median interval between initial and final biopsy was 47 months (range, 13 to 118 months). There was good concordance between the pathologists, as shown in the (Table 1).

Discussion

Top Methods Case Reports Results Discussion Author & Article Info References

We describe eight patients who had documented cirrhosis or extensive fibrosis at the time of diagnosis of autoimmune hepatitis. Blood test results became normal in response to medical therapy, and subsequent biopsies showed complete regression of hepatic fibrosis. Several trials have reported the successful long-term treatment of autoimmune hepatitis and commented on the induction of clinical, biochemical, and histologic remission. None, to the best of our knowledge, has discussed the reversibility of fibrosis.

Fibrosis results from the accumulation of connective tissue and implies an imbalance between the deposition and the degradation of that tissue. The pathogenesis of progressive scarring seems similar for different types of hepatic injuries. Schematically, lipocytes activated by cytokines, such as transforming growth factor ß1, degrade the normal extracellular matrix and replace it with fibril-forming collagens types I and III [9]. Less is known about fibrolysis. The liver contains metalloproteinases and collagenases capable of degrading extracellular matrix. Collagen degradation is a slow process, however, and collagen I, after its deposition, sustains extensive cross-linking and becomes more resistant to collagenases over time [10].

Regression of hepatic fibrosis has been seen in animal models. In rats, functional and structural recovery occurred with partial reversibility of fibrosis 1 month after decompression of chronic bile duct obstruction [11]. In rabbits, liver fibrosis due to Schistosoma japonicum infection regressed after parasitologic cure [12]. In humans, liver fibrosis and cirrhosis are generally believed to be irreversible. At the same time, anecdotal reports suggest improvement of cirrhosis in patients treated for hemochromatosis [3] and Wilson disease [4]; we recently documented regression of fibrosis in several patients with primary biliary cirrhosis [5]. In autoimmune hepatitis, effective therapy rapidly controls hepatic inflammation and hepatocellular necrosis. Treatment may decrease the inciting stimulus for fibrogenesis and unmask or upregulate the fibrolytic side of the dynamic matrix remodelling process. However, cirrhosis seems to be reversible only in patients who are in the early clinical stages of disease. Our eight patients were Child-Pugh class A or B. Cirrhosis is probably irreversible in patients with advanced liver disease (Child-Pugh class C with portal hypertension).

Our study has some limitations. This was a small group of selected patients studied retrospectively, and sampling artifacts of the liver biopsy specimens (despite the generous size of the specimens) may account for the differences in fibrosis [13]. To minimize bias, liver biopsy specimens were read under code and were not paired by patient. In line with the results of the METAVIR study [14], we found excellent concordance among observers for the grading of portal fibrosis and cirrhosis [14]. The observed decrease in connective tissue is therefore unlikely to be due to subjective histologic interpretation. The fact that serial liver biopsies, when available, showed a consistent decrease in scarring supports our hypothesis that hepatic fibrosis may be reversible in patients with liver disease for which effective therapy is available.

Dr. De Lellis: Clinical Pharmacology, University of Bern, 35 Murtenstrasse, 3010 Bern, Switzerland.

Dr. Kaplan: Box 233, Division of Gastroenterology, New England Medical Center, 750 Washington Street, Boston, MA 02111.