Editorial
Acute autoimmune hepatitis: Many open questions Christina Weiler-Normann, Ansgar W. Lohse⇑ 1st Dept. of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
See Article, pages 876–882
Autoimmune hepatitis (AIH) is more variable than other liver diseases. Autoimmune hepatitis can present in young infants [1] and in octogenarians [2]. AIH can be a slowly progressive smouldering condition, or it can run an acute fluctuating course characterized by flares and spontaneous apparent remission, albeit usually associated with scarring and progressive fibrosis. AIH can present as a subclinical condition diagnosed on routine blood tests in an asymptomatic person, and it can present as acute liver failure [3]. It is the acute and hyper-acute presentation of AIH that remains the greatest challenge in this disease and at the same time has the least evidence basis to guide diagnosis and management. Key issues are the definition of diagnostic criteria, the need for prognostic parameters, and the therapeutic approach to acute AIH. The report by the King’s College group in this issue of the Journal [4] summarizing their experience in a series of 32 patients with acute severe AIH is thus an important attempt to answer some of these questions. This study only looks at patients with a severe impairment of liver function using an international normalized ratio (INR) of >1.5 as their cut-off, a limit also used as the cut-off for acute liver failure in the large American Acute Liver Failure (ALF) study group [5]. This definition is helpful to allow some comparison between the King’s data and the report of the ALF consortium looking at features of autoimmunity in patients presenting with cryptogenic acute liver failure, and it is the main reason why it was used in the study. This INR definition of liver failure does, however, have an important limitation: patients were included, if at ‘‘any time during the index presentation’’ their INR was >1.5. As jaundice leads to vitamin K deficiency through lack of resorption of this fat-soluble vitamin, substitution of vitamin K is the first measure undertaken in any patient with jaundice and elevated INR, and only those patients remaining above a limit of 1.5 can truly be considered to suffer from liver failure. On the other hand, many patients with very severe acute AIH may still have sufficient hepatic reserve to provide adequate levels of coagulation factors despite severe hepatic inflammation
q
DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.05.021. Corresponding author. Address: 1st Dept. of Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Tel.: +49 40 7410 53910; fax: +49 40 7410 58531. E-mail address: [email protected] (A.W. Lohse). Abbreviation: AIH, autoimmune hepatitis. ⇑
and necroses. Thus, while INR (after vitamin K substitution) may be the best standard test for liver failure, it is not the best parameter to measure severity of AIH, for which the degree of necro-inflammation, measured by transaminase levels and/or measured by histological criteria is likely to better reflect the severity of the auto-aggressive condition [6]. The major challenge in acute severe AIH is to actually make the correct diagnosis and to differentiate this condition from other causes of acute liver disease. Diagnostic criteria of autoimmune hepatitis are largely based on the experience and data in patients presenting with milder disease [7,8], and it appears that both the more comprehensive 1999 revised diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) as well as the simplified diagnostic criteria (SDC) have limitations in particular in this group of acute severe disease. In the present study, the 1999 criteria were used as gold standard and only patients fulfilling these criteria were included – thus we are unable to judge if there might have been patients with acute severe AIH overlooked by these criteria. The ALF study group in 2011 took another approach [3]: all patients with ALF not explained by acetaminophen poisoning or viral hepatitis and in whom histology was available, were studied, and characteristic features of autoimmunity were looked at. This study showed convincingly that many of these patients have both histological and serological evidence of AIH, and the authors found a good correlation between histological criteria and the simplified diagnostic criteria. Comparison of the patients between the two studies shows that the King’s group has 91% women compared to 58% in the ALF study – a difference likely due to the inclusion criteria used: as female sex is included as one of the criteria in the 1999 IAIHG diagnostic criteria, men with AIH are more likely to be missed out. Both studies show that the most characteristic difference between acute severe AIH and other forms of AIH is the distribution of necro-inflammation in the liver lobule: while periportal inflammation with interface hepatitis is typical for most patients with AIH, acute severe AIH often shows predominantly and sometimes even exclusively centrilobular necrosis. This histological feature was traditionally considered a typical feature of druginduced toxic liver injury, but these studies as well as earlier reports clearly show that the same feature can be seen in very acute AIH [9,10]. This is a very important message, as pathologists and clinicians are likely to have overlooked many cases of acute severe AIH simply because centrilobular necrosis was
Journal of Hepatology 2014 vol. 61 j 727–729
Editorial erroneously interpreted as a clear evidence of toxic liver injury. Especially in older patients, who are likely to have had exposure to various drugs the diagnosis of acute severe AIH can thus be easily overlooked, and possibly beneficial immunosuppressive therapy is missed out. In older men, acute AIH is particularly likely to be misinterpreted, because treating physicians erroneously regard this disease as a disease of younger women. In addition to histomorphological criteria that appear to be clearly different in very acute AIH compared to more chronic AIH, serological and laboratory features are also somewhat different, and need to be better defined. While both autoantibodies and elevated IgG levels are very characteristic for AIH and present in more than 90% of all chronically affected patients [11], both features may be missing early in the course of patients with very acute presentation. This may simply be due to the kinetics of antibody production and clearance: in very acute disease, patients may not have had time to accumulate IgG and autoantibodies in their serum. Antibodies have a relatively long serum half-life, and thus changes tend to be slower, both upward and downward. The very wide range of normal IgG levels and the presence of low-level autoantibodies in healthy persons as well as other liver diseases make it difficult to really distinguish AIH from other causes of acute liver failure in patients with very recent disease onset. It is not uncommon that only as time goes on the more characteristic features become obvious, and their response to treatment confirms the diagnosis. What is the benefit of steroid treatment in these patients with acute severe AIH? Unfortunately, despite the careful analysis undertaken in this case series, we do not really know. Only 23 out of the 32 patients in this series received steroid therapy, and there were differences between these groups initially making the comparison almost impossible. Untreated patients showed significantly higher MELD scores, which might have been the main reason for not giving these patients steroid treatment. All untreated patients required liver transplantation, while of those given steroid treatment, 13 responded to treatment and recovered without liver transplantation. Of the 10 patients given steroids and showing treatment failure, all required and reached liver transplant. However, 4/10 died at various time-points post-transplant, as did 2/9 patients transplanted without prior steroid treatment. These results are too limited to justify treatment recommendations, but they hint towards early treatment, as a good response may make transplant unnecessary. Furthermore, prednisolone doses given in this study might have been too low, as none of the patients received more than 40 mg orally per day. In our experience 100 mg prednisolone intravenously is required in acute severe AIH, but we have to admit, there are no systematic data for this recommendation either. Nonetheless, in paediatric AIH, in which very acute presentation is observed more commonly, prednisolone doses are usually chosen at or above 1 mg/kg body weight [12]. Therefore, we need the data from other centres and need to compare the results of different treatment approaches. Discussion on the peculiar histological features of AIH may aid in making the diagnosis in future patients. This will be an important basis for the decision to biopsy early in acute liver failure. In particular in patients with impaired INR clinicians are often hesitant to perform a liver biopsy, even though it is not clear if changes in plasmatic coagulation parameters really increase the risk of post-biopsy bleeding. Anti-coagulant factors are similarly decreased in these patients as are the pro-coagulant factors
728
measured by INR. We lack studies, giving us clear guidance on the value of early liver biopsy in acute liver failure. Future studies addressing this issue, including the issue of safety and technique (percutaneous [13], transjugular [14] or mini-laparoscopic biopsy [15]), urgently need to be performed. The faster the diagnosis is made, the earlier potentially effective treatment can be started. It is likely that the benefit of steroid treatment in acute severe AIH might be decisively improved by earlier diagnosis and thus earlier start of therapy. The other issue in steroid treatment of acute severe AIH is the duration of high dose steroid therapy. In the present study, no patient was lost prior to transplantation, but that may have been due to early decisions to transplant. The same group of investigators have published in 2011 that failure of a response to steroids after 7 days should be the cut-off point to stop steroids and precede with transplantation [16]. Similar results have been reported by others, albeit all in very small case series [17]. In view of the significant mortality post-transplant and no mortality pre-transplant in the present report, we may have rushed in this critical patient population with our transplant decisions, and maybe more patients might achieve a steroid-induced remission with perhaps higher initial doses, as suggested above, and a little longer careful clinical observation. What are the lessons for the general hepatologist? First, AIH has to be considered early in any patient with very acute and severe liver failure. Secondly, liver biopsy in acute liver failure can be very helpful. However, features hitherto regarded as typical for drug-induced liver failure may also be seen in patients with very acute AIH, and therefore the diagnosis of AIH should not be discarded because of the presence of centrilobular necrosis. Thirdly, elevated IgG levels and autoantibodies can support the suspected diagnosis of AIH, but may also be absent or noncharacteristic in very acute AIH. Fourthly, a trial of steroid therapy in sufficiently high doses should be initiated very early, but the risk of infections in liver failure needs to be kept in mind. Finally, liver transplantation needs to be considered as an alternative, but nobody knows the best timing. In addition to these clinical lessons, the scientific community still has considerable homework to do, in order to define better the diagnostic criteria and the best treatment algorithms for patients with acute severe AIH. Due to the relative rarity of this condition, controlled trials will not be feasible. Instead, data need to be collected from various centres, and different approaches need to be compared. A mortality rate of 27% even in an expert centre as in this study shows that there is still plenty of room for improvement for these patients.
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
References [1] Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: contrasts and comparisons in children and adults – A comprehensive review. J Autoimmun 2013;46:7–16. [2] Schramm C, Kanzler S, Zum Buschenfelde KH, Galle PR, Lohse AW. Autoimmune hepatitis in the elderly. Am J Gastroenterol 2001;96: 1587–1591.
Journal of Hepatology 2014 vol. 61 j 727–729
JOURNAL OF HEPATOLOGY [3] Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, et al. Acute Liver Failure Study G: autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011;53:517–526. [4] Yeoman AD, Westbrook RH, Zen Y, Bernal W, Al-Chalabi T, Wendon JA, et al. Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome. J Hepatol 2014;61:876–882. [5] Lee WM, Squires Jr RH, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: summary of a workshop. Hepatology 2008;47:1401–1415. [6] Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–2213. [7] Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–938. [8] Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–176. [9] Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation. J Clin Pathol 2006;59:246–249. [10] Abe K, Kanno Y, Okai K, Katsushima F, Monoe K, Saito H, et al. Centrilobular necrosis in acute presentation of Japanese patients with type 1 autoimmune hepatitis. World J Hepatol 2012;4:262–267.
[11] Lohse AW, Mieli-Vergani G. Autoimmune hepatitis. J Hepatol 2011;55:171–182. [12] Mieli-Vergani G, Vergani D. Autoimmune liver diseases in children – what is different from adulthood? Best Pract Res Clin Gastroenterol 2011;25:783–795. [13] Menghini G. One-second needle biopsy of the liver. Gastroenterology 1958;35:190–199. [14] Behrens G, Ferral H. Transjugular liver biopsy. Semin Interv Radiol 2012;29:111–117. [15] Denzer U, Arnoldy A, Kanzler S, Galle PR, Dienes HP, Lohse AW. Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications. J Clin Gastroenterol 2007;41:103–110. [16] Yeoman AD, Westbrook RH, Zen Y, Maninchedda P, Portmann BC, Devlin J, et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 2011;53:926–934. [17] Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 2007;46:1138–1145.
Journal of Hepatology 2014 vol. 61 j 727–729
729
Acute autoimmune hepatitis: Many open questions Christina Weiler-Normann, Ansgar W. Lohse⇑ 1st Dept. of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
See Article, pages 876–882
Autoimmune hepatitis (AIH) is more variable than other liver diseases. Autoimmune hepatitis can present in young infants [1] and in octogenarians [2]. AIH can be a slowly progressive smouldering condition, or it can run an acute fluctuating course characterized by flares and spontaneous apparent remission, albeit usually associated with scarring and progressive fibrosis. AIH can present as a subclinical condition diagnosed on routine blood tests in an asymptomatic person, and it can present as acute liver failure [3]. It is the acute and hyper-acute presentation of AIH that remains the greatest challenge in this disease and at the same time has the least evidence basis to guide diagnosis and management. Key issues are the definition of diagnostic criteria, the need for prognostic parameters, and the therapeutic approach to acute AIH. The report by the King’s College group in this issue of the Journal [4] summarizing their experience in a series of 32 patients with acute severe AIH is thus an important attempt to answer some of these questions. This study only looks at patients with a severe impairment of liver function using an international normalized ratio (INR) of >1.5 as their cut-off, a limit also used as the cut-off for acute liver failure in the large American Acute Liver Failure (ALF) study group [5]. This definition is helpful to allow some comparison between the King’s data and the report of the ALF consortium looking at features of autoimmunity in patients presenting with cryptogenic acute liver failure, and it is the main reason why it was used in the study. This INR definition of liver failure does, however, have an important limitation: patients were included, if at ‘‘any time during the index presentation’’ their INR was >1.5. As jaundice leads to vitamin K deficiency through lack of resorption of this fat-soluble vitamin, substitution of vitamin K is the first measure undertaken in any patient with jaundice and elevated INR, and only those patients remaining above a limit of 1.5 can truly be considered to suffer from liver failure. On the other hand, many patients with very severe acute AIH may still have sufficient hepatic reserve to provide adequate levels of coagulation factors despite severe hepatic inflammation
q
DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.05.021. Corresponding author. Address: 1st Dept. of Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Tel.: +49 40 7410 53910; fax: +49 40 7410 58531. E-mail address: [email protected] (A.W. Lohse). Abbreviation: AIH, autoimmune hepatitis. ⇑
and necroses. Thus, while INR (after vitamin K substitution) may be the best standard test for liver failure, it is not the best parameter to measure severity of AIH, for which the degree of necro-inflammation, measured by transaminase levels and/or measured by histological criteria is likely to better reflect the severity of the auto-aggressive condition [6]. The major challenge in acute severe AIH is to actually make the correct diagnosis and to differentiate this condition from other causes of acute liver disease. Diagnostic criteria of autoimmune hepatitis are largely based on the experience and data in patients presenting with milder disease [7,8], and it appears that both the more comprehensive 1999 revised diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) as well as the simplified diagnostic criteria (SDC) have limitations in particular in this group of acute severe disease. In the present study, the 1999 criteria were used as gold standard and only patients fulfilling these criteria were included – thus we are unable to judge if there might have been patients with acute severe AIH overlooked by these criteria. The ALF study group in 2011 took another approach [3]: all patients with ALF not explained by acetaminophen poisoning or viral hepatitis and in whom histology was available, were studied, and characteristic features of autoimmunity were looked at. This study showed convincingly that many of these patients have both histological and serological evidence of AIH, and the authors found a good correlation between histological criteria and the simplified diagnostic criteria. Comparison of the patients between the two studies shows that the King’s group has 91% women compared to 58% in the ALF study – a difference likely due to the inclusion criteria used: as female sex is included as one of the criteria in the 1999 IAIHG diagnostic criteria, men with AIH are more likely to be missed out. Both studies show that the most characteristic difference between acute severe AIH and other forms of AIH is the distribution of necro-inflammation in the liver lobule: while periportal inflammation with interface hepatitis is typical for most patients with AIH, acute severe AIH often shows predominantly and sometimes even exclusively centrilobular necrosis. This histological feature was traditionally considered a typical feature of druginduced toxic liver injury, but these studies as well as earlier reports clearly show that the same feature can be seen in very acute AIH [9,10]. This is a very important message, as pathologists and clinicians are likely to have overlooked many cases of acute severe AIH simply because centrilobular necrosis was
Journal of Hepatology 2014 vol. 61 j 727–729
Editorial erroneously interpreted as a clear evidence of toxic liver injury. Especially in older patients, who are likely to have had exposure to various drugs the diagnosis of acute severe AIH can thus be easily overlooked, and possibly beneficial immunosuppressive therapy is missed out. In older men, acute AIH is particularly likely to be misinterpreted, because treating physicians erroneously regard this disease as a disease of younger women. In addition to histomorphological criteria that appear to be clearly different in very acute AIH compared to more chronic AIH, serological and laboratory features are also somewhat different, and need to be better defined. While both autoantibodies and elevated IgG levels are very characteristic for AIH and present in more than 90% of all chronically affected patients [11], both features may be missing early in the course of patients with very acute presentation. This may simply be due to the kinetics of antibody production and clearance: in very acute disease, patients may not have had time to accumulate IgG and autoantibodies in their serum. Antibodies have a relatively long serum half-life, and thus changes tend to be slower, both upward and downward. The very wide range of normal IgG levels and the presence of low-level autoantibodies in healthy persons as well as other liver diseases make it difficult to really distinguish AIH from other causes of acute liver failure in patients with very recent disease onset. It is not uncommon that only as time goes on the more characteristic features become obvious, and their response to treatment confirms the diagnosis. What is the benefit of steroid treatment in these patients with acute severe AIH? Unfortunately, despite the careful analysis undertaken in this case series, we do not really know. Only 23 out of the 32 patients in this series received steroid therapy, and there were differences between these groups initially making the comparison almost impossible. Untreated patients showed significantly higher MELD scores, which might have been the main reason for not giving these patients steroid treatment. All untreated patients required liver transplantation, while of those given steroid treatment, 13 responded to treatment and recovered without liver transplantation. Of the 10 patients given steroids and showing treatment failure, all required and reached liver transplant. However, 4/10 died at various time-points post-transplant, as did 2/9 patients transplanted without prior steroid treatment. These results are too limited to justify treatment recommendations, but they hint towards early treatment, as a good response may make transplant unnecessary. Furthermore, prednisolone doses given in this study might have been too low, as none of the patients received more than 40 mg orally per day. In our experience 100 mg prednisolone intravenously is required in acute severe AIH, but we have to admit, there are no systematic data for this recommendation either. Nonetheless, in paediatric AIH, in which very acute presentation is observed more commonly, prednisolone doses are usually chosen at or above 1 mg/kg body weight [12]. Therefore, we need the data from other centres and need to compare the results of different treatment approaches. Discussion on the peculiar histological features of AIH may aid in making the diagnosis in future patients. This will be an important basis for the decision to biopsy early in acute liver failure. In particular in patients with impaired INR clinicians are often hesitant to perform a liver biopsy, even though it is not clear if changes in plasmatic coagulation parameters really increase the risk of post-biopsy bleeding. Anti-coagulant factors are similarly decreased in these patients as are the pro-coagulant factors
728
measured by INR. We lack studies, giving us clear guidance on the value of early liver biopsy in acute liver failure. Future studies addressing this issue, including the issue of safety and technique (percutaneous [13], transjugular [14] or mini-laparoscopic biopsy [15]), urgently need to be performed. The faster the diagnosis is made, the earlier potentially effective treatment can be started. It is likely that the benefit of steroid treatment in acute severe AIH might be decisively improved by earlier diagnosis and thus earlier start of therapy. The other issue in steroid treatment of acute severe AIH is the duration of high dose steroid therapy. In the present study, no patient was lost prior to transplantation, but that may have been due to early decisions to transplant. The same group of investigators have published in 2011 that failure of a response to steroids after 7 days should be the cut-off point to stop steroids and precede with transplantation [16]. Similar results have been reported by others, albeit all in very small case series [17]. In view of the significant mortality post-transplant and no mortality pre-transplant in the present report, we may have rushed in this critical patient population with our transplant decisions, and maybe more patients might achieve a steroid-induced remission with perhaps higher initial doses, as suggested above, and a little longer careful clinical observation. What are the lessons for the general hepatologist? First, AIH has to be considered early in any patient with very acute and severe liver failure. Secondly, liver biopsy in acute liver failure can be very helpful. However, features hitherto regarded as typical for drug-induced liver failure may also be seen in patients with very acute AIH, and therefore the diagnosis of AIH should not be discarded because of the presence of centrilobular necrosis. Thirdly, elevated IgG levels and autoantibodies can support the suspected diagnosis of AIH, but may also be absent or noncharacteristic in very acute AIH. Fourthly, a trial of steroid therapy in sufficiently high doses should be initiated very early, but the risk of infections in liver failure needs to be kept in mind. Finally, liver transplantation needs to be considered as an alternative, but nobody knows the best timing. In addition to these clinical lessons, the scientific community still has considerable homework to do, in order to define better the diagnostic criteria and the best treatment algorithms for patients with acute severe AIH. Due to the relative rarity of this condition, controlled trials will not be feasible. Instead, data need to be collected from various centres, and different approaches need to be compared. A mortality rate of 27% even in an expert centre as in this study shows that there is still plenty of room for improvement for these patients.
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
References [1] Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: contrasts and comparisons in children and adults – A comprehensive review. J Autoimmun 2013;46:7–16. [2] Schramm C, Kanzler S, Zum Buschenfelde KH, Galle PR, Lohse AW. Autoimmune hepatitis in the elderly. Am J Gastroenterol 2001;96: 1587–1591.
Journal of Hepatology 2014 vol. 61 j 727–729
JOURNAL OF HEPATOLOGY [3] Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, et al. Acute Liver Failure Study G: autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011;53:517–526. [4] Yeoman AD, Westbrook RH, Zen Y, Bernal W, Al-Chalabi T, Wendon JA, et al. Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome. J Hepatol 2014;61:876–882. [5] Lee WM, Squires Jr RH, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: summary of a workshop. Hepatology 2008;47:1401–1415. [6] Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–2213. [7] Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–938. [8] Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–176. [9] Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation. J Clin Pathol 2006;59:246–249. [10] Abe K, Kanno Y, Okai K, Katsushima F, Monoe K, Saito H, et al. Centrilobular necrosis in acute presentation of Japanese patients with type 1 autoimmune hepatitis. World J Hepatol 2012;4:262–267.
[11] Lohse AW, Mieli-Vergani G. Autoimmune hepatitis. J Hepatol 2011;55:171–182. [12] Mieli-Vergani G, Vergani D. Autoimmune liver diseases in children – what is different from adulthood? Best Pract Res Clin Gastroenterol 2011;25:783–795. [13] Menghini G. One-second needle biopsy of the liver. Gastroenterology 1958;35:190–199. [14] Behrens G, Ferral H. Transjugular liver biopsy. Semin Interv Radiol 2012;29:111–117. [15] Denzer U, Arnoldy A, Kanzler S, Galle PR, Dienes HP, Lohse AW. Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications. J Clin Gastroenterol 2007;41:103–110. [16] Yeoman AD, Westbrook RH, Zen Y, Maninchedda P, Portmann BC, Devlin J, et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 2011;53:926–934. [17] Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 2007;46:1138–1145.
Journal of Hepatology 2014 vol. 61 j 727–729
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