Preventing and Reversing Fibrosis in Autoimmune Hepatitis
Reductions in hepatic fibrosis and reversal of cirrhosis in autoimmune hepatitis were initially inconceivable. Histological assessments that disclosed such improvements were ascribed to sampling errors associated with needle biopsy of the liver and erroneous histological interpretations. Nevertheless, creditable clinical reports emerged that affirmed the reversal of hepatic fibrosis in autoimmune hepatitis after immunosuppressive therapy, and the demonstration of this reversal in tissue samples of adequate size was compelling. Furthermore, studies in animal models and patients with diverse forms of advanced fibrotic liver disease supported this possibility.
The reversal of hepatic fibrosis is now recognised as an achievable objective in the treatment of chronic liver disease, and autoimmune hepatitis is a prime candidate in which to seek this result. The first experience demonstrating this possibility in autoimmune hepatitis was a retrospective analysis of paired liver tissue specimens obtained by needle biopsy from 28 treated patients (Table 1). Fifty-seven per cent improved their hepatic fibrosis, and 9 of 14 patients (64%) with cirrhosis lost this histological finding. The regression of fibrosis was associated with the suppression of liver inflammation, and the findings justified the recommendation that immunosuppressive therapy be started early in the course of the disease.
These early observations were supported by a later experience in eight patients with autoimmune hepatitis and cirrhosis who had responded fully to immunosuppressive therapy (Table 1). Liver tissue specimens obtained by needle biopsy after an interval of 13–118 months (median interval between tissue samples, 47 months) were evaluated for liver inflammation and fibrosis by the Knodell score. The median Knodell score decreased from 14 to 1.3; the median fibrosis score decreased from 3.3 to 0.8; and cirrhosis disappeared in all follow-up tissue specimens (median sample length, 21 mm; range, 6–32 mm).
Subsequent studies not only demonstrated the anti-fibrotic effects of immunosuppressive therapy in autoimmune hepatitis but strengthened the association between the indices of hepatic inflammation and the progression of liver fibrosis (Table 1). Fibrosis scores by the Ishak system improved in 46 of 87 treated patients (53%) with autoimmune hepatitis during 63 ± 6 months of observation, and the histological activity index (HAI) decreased concurrently. Improvements in the HAI occurred more commonly in patients whose fibrosis scores improved than in patients whose HAI remained stable or increased (61% vs. 32%), and histological cirrhosis disappeared in 8 of 14 patients (57%) with cirrhosis at presentation. Furthermore, fibrosis scores did not worsen in 23 patients (26%) during 62 ± 12 months of observation. In contrast, patients whose fibrosis progressed during therapy had worsening HAIs (17% vs. 2%). These findings suggested that improvement or stabilisation of hepatic fibrosis was possible in 79% of treated patients with autoimmune hepatitis and that failure to suppress liver inflammation worsened fibrosis.
Similar findings were described in 19 patients treated with either ciclosporin or corticosteroids (Table 1). Mean fibrosis scores by the Ishak system improved in needle biopsy specimens obtained after a mean interval of 3.4 ± 2.3 years, and the improvement was associated with a reduction in HAI. Reduced fibrosis occurred in 13 patients (70%), remained unchanged in five patients (25%) and worsened in only one patient (5%). Furthermore, histological cirrhosis disappeared in four of seven patients (57%). This experience suggested that the anti-fibrotic effects were not regimen specific and that the reduction or prevention of hepatic fibrosis depended more on the suppression of liver inflammation than the nature of the immunosuppressive agent. Emerging new drugs for autoimmune hepatitis, including budesonide and mycophenolate mofetil, have anti-inflammatory and immunosuppressive actions similar to those of prednisone (prednisolone) and azathioprine, but their anti-fibrotic actions are unmeasured, preliminary, or manifest in animal studies and limited human experiences (Table 1).
A key concept to emerge from these clinical reports was that the prevention of progressive hepatic fibrosis is strongly influenced by the rapidity and degree of disease suppression during immunosuppressive therapy. Patients who experienced laboratory and histological resolution of inflammatory manifestations within 12 months of therapy had lower frequencies of progression to cirrhosis than patients requiring longer durations of treatment (18% vs. 54%) and lower frequencies of death from hepatic failure or need for liver transplantation (2% vs. 15%). Furthermore, the rapidity of the response was greater in patients aged ≥60 years than in those aged <40 years (18% vs. 2%), and the response rate was negatively associated with HLA DRB1*03. These findings suggested that current management strategies could be improved by identifying critical patient-related factors that presaged slow treatment responses and progressive fibrosis. Theoretically, treatments could then be individualised, and medication schedules could be adjusted to optimise the speed and degree of response.
The causes of progression or regression of hepatic fibrosis in autoimmune hepatitis and the anti-fibrotic actions of the conventional therapies in this disease are uncertain. Observational studies cannot exclude the possibility that the progression or regression of hepatic fibrosis determines the treatment response rather than vice versa. Hepatic inflammation may be the most obvious driver of hepatic fibrosis in autoimmune hepatitis, but it may not be the most important or sole factor. Many other chronic liver diseases can have progression or regression of hepatic fibrosis in the absence of hepatic inflammation, and a greater understanding of the pro-fibrotic mechanisms involved in autoimmune hepatitis is required before developing a reliable anti-fibrotic strategy.
Reversal of Hepatic Fibrosis in Autoimmune Hepatitis
Reductions in hepatic fibrosis and reversal of cirrhosis in autoimmune hepatitis were initially inconceivable. Histological assessments that disclosed such improvements were ascribed to sampling errors associated with needle biopsy of the liver and erroneous histological interpretations. Nevertheless, creditable clinical reports emerged that affirmed the reversal of hepatic fibrosis in autoimmune hepatitis after immunosuppressive therapy, and the demonstration of this reversal in tissue samples of adequate size was compelling. Furthermore, studies in animal models and patients with diverse forms of advanced fibrotic liver disease supported this possibility.
The reversal of hepatic fibrosis is now recognised as an achievable objective in the treatment of chronic liver disease, and autoimmune hepatitis is a prime candidate in which to seek this result. The first experience demonstrating this possibility in autoimmune hepatitis was a retrospective analysis of paired liver tissue specimens obtained by needle biopsy from 28 treated patients (Table 1). Fifty-seven per cent improved their hepatic fibrosis, and 9 of 14 patients (64%) with cirrhosis lost this histological finding. The regression of fibrosis was associated with the suppression of liver inflammation, and the findings justified the recommendation that immunosuppressive therapy be started early in the course of the disease.
These early observations were supported by a later experience in eight patients with autoimmune hepatitis and cirrhosis who had responded fully to immunosuppressive therapy (Table 1). Liver tissue specimens obtained by needle biopsy after an interval of 13–118 months (median interval between tissue samples, 47 months) were evaluated for liver inflammation and fibrosis by the Knodell score. The median Knodell score decreased from 14 to 1.3; the median fibrosis score decreased from 3.3 to 0.8; and cirrhosis disappeared in all follow-up tissue specimens (median sample length, 21 mm; range, 6–32 mm).
Subsequent studies not only demonstrated the anti-fibrotic effects of immunosuppressive therapy in autoimmune hepatitis but strengthened the association between the indices of hepatic inflammation and the progression of liver fibrosis (Table 1). Fibrosis scores by the Ishak system improved in 46 of 87 treated patients (53%) with autoimmune hepatitis during 63 ± 6 months of observation, and the histological activity index (HAI) decreased concurrently. Improvements in the HAI occurred more commonly in patients whose fibrosis scores improved than in patients whose HAI remained stable or increased (61% vs. 32%), and histological cirrhosis disappeared in 8 of 14 patients (57%) with cirrhosis at presentation. Furthermore, fibrosis scores did not worsen in 23 patients (26%) during 62 ± 12 months of observation. In contrast, patients whose fibrosis progressed during therapy had worsening HAIs (17% vs. 2%). These findings suggested that improvement or stabilisation of hepatic fibrosis was possible in 79% of treated patients with autoimmune hepatitis and that failure to suppress liver inflammation worsened fibrosis.
Similar findings were described in 19 patients treated with either ciclosporin or corticosteroids (Table 1). Mean fibrosis scores by the Ishak system improved in needle biopsy specimens obtained after a mean interval of 3.4 ± 2.3 years, and the improvement was associated with a reduction in HAI. Reduced fibrosis occurred in 13 patients (70%), remained unchanged in five patients (25%) and worsened in only one patient (5%). Furthermore, histological cirrhosis disappeared in four of seven patients (57%). This experience suggested that the anti-fibrotic effects were not regimen specific and that the reduction or prevention of hepatic fibrosis depended more on the suppression of liver inflammation than the nature of the immunosuppressive agent. Emerging new drugs for autoimmune hepatitis, including budesonide and mycophenolate mofetil, have anti-inflammatory and immunosuppressive actions similar to those of prednisone (prednisolone) and azathioprine, but their anti-fibrotic actions are unmeasured, preliminary, or manifest in animal studies and limited human experiences (Table 1).
A key concept to emerge from these clinical reports was that the prevention of progressive hepatic fibrosis is strongly influenced by the rapidity and degree of disease suppression during immunosuppressive therapy. Patients who experienced laboratory and histological resolution of inflammatory manifestations within 12 months of therapy had lower frequencies of progression to cirrhosis than patients requiring longer durations of treatment (18% vs. 54%) and lower frequencies of death from hepatic failure or need for liver transplantation (2% vs. 15%). Furthermore, the rapidity of the response was greater in patients aged ≥60 years than in those aged <40 years (18% vs. 2%), and the response rate was negatively associated with HLA DRB1*03. These findings suggested that current management strategies could be improved by identifying critical patient-related factors that presaged slow treatment responses and progressive fibrosis. Theoretically, treatments could then be individualised, and medication schedules could be adjusted to optimise the speed and degree of response.
The causes of progression or regression of hepatic fibrosis in autoimmune hepatitis and the anti-fibrotic actions of the conventional therapies in this disease are uncertain. Observational studies cannot exclude the possibility that the progression or regression of hepatic fibrosis determines the treatment response rather than vice versa. Hepatic inflammation may be the most obvious driver of hepatic fibrosis in autoimmune hepatitis, but it may not be the most important or sole factor. Many other chronic liver diseases can have progression or regression of hepatic fibrosis in the absence of hepatic inflammation, and a greater understanding of the pro-fibrotic mechanisms involved in autoimmune hepatitis is required before developing a reliable anti-fibrotic strategy.
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