Alimentary Pharmacology and Therapeutics Letter to the Editors
Letter: reversibility of hepatic fibrosis and immunosuppression withdrawal in patients with autoimmune hepatitis/ primary biliary cirrhosis overlap syndrome B. Yilmaz* & R. Dayanan† *Department of Gastroenterology, Bolu Izzet Baysal Education and Research Hospital, Bolu, Turkey. † Deparment of Internal Medicine, Batman State Hospital, Batman, Turkey. E-mail: [email protected] doi:10.1111/apt.13123
SIRS, In his recent articles,1, 2 Dr Czaja has evaluated the prevention of hepatic fibrosis and permanent immunosuppression withdrawal, which are very important issues in the management of autoimmune hepatitis (AIH). Patients with AIH may also present with features of primary biliary cirrhosis (PBC) or vice versa. The term of overlap or variant syndromes have been used to describe this clinical condition.3, 4 AIH/PBC is rare, but a real clinical entity that should be better diagnosed and treated. We would like to discuss these issues in patients with AIH/PBC overlap. In a recent large population-based study,5 the authors evaluated data from 88 AIH/PBC patients. Among them, control liver biopsy was performed in 23 biochemical responders. The fibrosis scores decreased or remained unchanged in 90% (21/23) of patients. Furthermore, immunosuppression was successfully withdrawn in 75% (15/20) of patients with AIH/PBC. In another study,6 fibrosis progression was prevented in 100% (6/6) of patients treated by immunosuppression, and relapses
Letter: reversibility of hepatic fibrosis and immunosuppression withdrawal in patients with autoimmune hepatitis/ primary biliary cirrhosis overlap syndrome – author’s reply A. J. Czaja Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA. E-mail: [email protected] doi:10.1111/apt.13126
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were not observed in 100% (4/4) of patients after immunosuppression withdrawal. Despite small cohort sizes, these results suggest that prevention of fibrosis progression and immunosuppression-free management is a realistic expectation for patients with AIH/PBC overlap. These studies also raise an old question as to whether AIH/PBC is a coexistence of two different autoimmune liver diseases, or a variant of AIH or PBC, with some overlapping features. Relapse-free rates after immunosuppression withdrawal are higher in AIH/PBC overlap than patients with pure AIH. Furthermore, prevention of fibrosis progression seems to be more common in overlap patients than those with pure AIH or PBC.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 1043–58. 2. Czaja AJ. Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 385–406. 3. Efe C, Wahlin S, Ozaslan E, et al. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol 2012; 24: 531–4. 4. Czaja AJ. Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 1430–8. 5. Ozaslan E, Efe C, Heurgue-Berlot A, et al. Factors associated with response to therapy and outcome of patients with primary biliary cirrhosis with features of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 863–9. 6. Chazouilleres O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 2006; 44: 400–6.
SIRS, The experience of Drs Yilmaz and Dayanan1 in patients with features of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) is similar to that in patients with classical AIH.2, 3 Liver inflammation is probably the principal driver of fibrosis in each of these clinical syndromes.4 As Drs Yilmaz and Dayanan suggest, the suppression of inflammation can be an effective anti-fibrotic strategy even when the inflammation is accompanied by features of PBC. Other studies of PBC support these observations.5, 6 The inflammatory features associated with AIH lack disease-specificity, and their occurrence in PBC has idenAliment Pharmacol Ther 2015; 41: 789–796 ª 2015 John Wiley & Sons Ltd
Letter to the Editors tified patients whose outcomes may be improved by management strategies that combine corticosteroids (with or without azathioprine) and ursodeoxycholic acid.7, 8 The experience of Drs Yilmaz and Dayanan suggests that immunosuppressive therapy alone may be effective as an anti-fibrotic regimen in some patients. Furthermore, outcomes may be better than in those with classical AIH or PBC. The overlap syndromes are clinical descriptions based largely on clinical judgments, and the AIH/PBC overlap syndrome described by Drs Yilmaz and Dayanan exists within a clinical spectrum that is bounded by patients with mainly AIH and weak manifestations of PBC and by patients with mainly PBC and inflammatory features reminiscent of AIH.8 Immunosuppressive therapy has a role across the spectrum, but outcomes may differ depending on the predominant component.8 The absence of relapse after drug withdrawal suggests that PBC may have been the predominant disease in this experience. The observations of Drs Yilmaz and Dayanan indicate that immunosuppressive therapy can have anti-fibrotic effects in immune-mediated liver diseases outside the classical phenotype of AIH. Future objectives must be to characterise those patients who are likely to respond, validate non-invasive methods to monitor fibrosis, and rigorously evaluate site-specific anti-fibrotic interventions that might supplement or replace current strategies.9
Letter: metabolic syndrome in patients with coeliac disease on a gluten-free diet G. Chiarioni*,†, S. De Marchi‡, M. Prior‡ & E. Arosio‡ *Division of Gastroenterology, University of Verona, Verona, Italy. † Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ‡ Division of Vascular Rehabilitation of the University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy. E-mail: [email protected] doi:10.1111/apt.13125
SIRS, We appreciated reading the study by Tortora et al. on potential metabolic risk of gluten-free diet (GFD) in coeliac disease (CD).1 The authors reported in an observational study that GFD in CD might facilitate de novo metabolic syndrome, questioning the potential full benefit of a dietetic intervention in this immune disease. For the first time, such impressive data are provided in a large-sized sample. Aliment Pharmacol Ther 2015; 41: 789–796 ª 2015 John Wiley & Sons Ltd
ACKNOWLEDGEMENT The author’s declarations of personal and financial interests are unchanged from those in the original article.9 REFERENCES 1. Yilmaz B, Dayanan R. Letter: reversibility of hepatic fibrosis and immunosuppression withdrawal in patients with autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Aliment Pharmacol Ther 2015; 41: 794. 2. Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 2004; 40: 646–52. 3. Mohamadnejad M, Malekzadeh R, Nasseri-Moghaddam S, et al. Impact of immunosuppressive treatment on liver fibrosis in autoimmune hepatitis. Dig Dis Sci 2005; 50: 547–51. 4. Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20: 2515–32. 5. Leuschner M, Guldutuna S, You T, et al. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol 1996; 25: 49–57. 6. Chazouilleres O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 2006; 44: 400–6. 7. Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54: 374–85. 8. Czaja AJ. Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 1430–8. 9. Czaja AJ. Review article: prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 385–406.
However, these data are at variance with the existing literature, and our own experience, where plasma triglycerides and LDL cholesterol were substantially unaffected by GFD.2, 3 On the contrary, in our sample of young CD patients, a number of blood and instrumental parameters of cardiovascular risk, including HDL cholesterol, were benefitted by GFD.3 In addition, our data are consistent with the low-grade inflammatory aetiology hypothesis of the metabolic syndrome, potentially improved by the treatment of a comorbid immune condition (i.e. CD).2 However, we would like to highlight some potential pitfalls of the valuable paper by Tortora et al. The authors apparently grouped a mixed population sample in their report. Potential CD is commonly not considered a mandatory indication for dietetic intervention.4 We feel that including potential CD patients in the data analysis might have biased the results, provided the percentage was relevant. In addition, the Marsh 2 histology grade used in the paper to diagnose classical CD may 795
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Letter: reversibility of hepatic fibrosis and immunosuppression withdrawal in patients with autoimmune hepatitis/ primary biliary cirrhosis overlap syndrome B. Yilmaz* & R. Dayanan† *Department of Gastroenterology, Bolu Izzet Baysal Education and Research Hospital, Bolu, Turkey. † Deparment of Internal Medicine, Batman State Hospital, Batman, Turkey. E-mail: [email protected] doi:10.1111/apt.13123
SIRS, In his recent articles,1, 2 Dr Czaja has evaluated the prevention of hepatic fibrosis and permanent immunosuppression withdrawal, which are very important issues in the management of autoimmune hepatitis (AIH). Patients with AIH may also present with features of primary biliary cirrhosis (PBC) or vice versa. The term of overlap or variant syndromes have been used to describe this clinical condition.3, 4 AIH/PBC is rare, but a real clinical entity that should be better diagnosed and treated. We would like to discuss these issues in patients with AIH/PBC overlap. In a recent large population-based study,5 the authors evaluated data from 88 AIH/PBC patients. Among them, control liver biopsy was performed in 23 biochemical responders. The fibrosis scores decreased or remained unchanged in 90% (21/23) of patients. Furthermore, immunosuppression was successfully withdrawn in 75% (15/20) of patients with AIH/PBC. In another study,6 fibrosis progression was prevented in 100% (6/6) of patients treated by immunosuppression, and relapses
Letter: reversibility of hepatic fibrosis and immunosuppression withdrawal in patients with autoimmune hepatitis/ primary biliary cirrhosis overlap syndrome – author’s reply A. J. Czaja Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA. E-mail: [email protected] doi:10.1111/apt.13126
794
were not observed in 100% (4/4) of patients after immunosuppression withdrawal. Despite small cohort sizes, these results suggest that prevention of fibrosis progression and immunosuppression-free management is a realistic expectation for patients with AIH/PBC overlap. These studies also raise an old question as to whether AIH/PBC is a coexistence of two different autoimmune liver diseases, or a variant of AIH or PBC, with some overlapping features. Relapse-free rates after immunosuppression withdrawal are higher in AIH/PBC overlap than patients with pure AIH. Furthermore, prevention of fibrosis progression seems to be more common in overlap patients than those with pure AIH or PBC.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 1043–58. 2. Czaja AJ. Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 385–406. 3. Efe C, Wahlin S, Ozaslan E, et al. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol 2012; 24: 531–4. 4. Czaja AJ. Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 1430–8. 5. Ozaslan E, Efe C, Heurgue-Berlot A, et al. Factors associated with response to therapy and outcome of patients with primary biliary cirrhosis with features of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 863–9. 6. Chazouilleres O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 2006; 44: 400–6.
SIRS, The experience of Drs Yilmaz and Dayanan1 in patients with features of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) is similar to that in patients with classical AIH.2, 3 Liver inflammation is probably the principal driver of fibrosis in each of these clinical syndromes.4 As Drs Yilmaz and Dayanan suggest, the suppression of inflammation can be an effective anti-fibrotic strategy even when the inflammation is accompanied by features of PBC. Other studies of PBC support these observations.5, 6 The inflammatory features associated with AIH lack disease-specificity, and their occurrence in PBC has idenAliment Pharmacol Ther 2015; 41: 789–796 ª 2015 John Wiley & Sons Ltd
Letter to the Editors tified patients whose outcomes may be improved by management strategies that combine corticosteroids (with or without azathioprine) and ursodeoxycholic acid.7, 8 The experience of Drs Yilmaz and Dayanan suggests that immunosuppressive therapy alone may be effective as an anti-fibrotic regimen in some patients. Furthermore, outcomes may be better than in those with classical AIH or PBC. The overlap syndromes are clinical descriptions based largely on clinical judgments, and the AIH/PBC overlap syndrome described by Drs Yilmaz and Dayanan exists within a clinical spectrum that is bounded by patients with mainly AIH and weak manifestations of PBC and by patients with mainly PBC and inflammatory features reminiscent of AIH.8 Immunosuppressive therapy has a role across the spectrum, but outcomes may differ depending on the predominant component.8 The absence of relapse after drug withdrawal suggests that PBC may have been the predominant disease in this experience. The observations of Drs Yilmaz and Dayanan indicate that immunosuppressive therapy can have anti-fibrotic effects in immune-mediated liver diseases outside the classical phenotype of AIH. Future objectives must be to characterise those patients who are likely to respond, validate non-invasive methods to monitor fibrosis, and rigorously evaluate site-specific anti-fibrotic interventions that might supplement or replace current strategies.9
Letter: metabolic syndrome in patients with coeliac disease on a gluten-free diet G. Chiarioni*,†, S. De Marchi‡, M. Prior‡ & E. Arosio‡ *Division of Gastroenterology, University of Verona, Verona, Italy. † Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ‡ Division of Vascular Rehabilitation of the University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy. E-mail: [email protected] doi:10.1111/apt.13125
SIRS, We appreciated reading the study by Tortora et al. on potential metabolic risk of gluten-free diet (GFD) in coeliac disease (CD).1 The authors reported in an observational study that GFD in CD might facilitate de novo metabolic syndrome, questioning the potential full benefit of a dietetic intervention in this immune disease. For the first time, such impressive data are provided in a large-sized sample. Aliment Pharmacol Ther 2015; 41: 789–796 ª 2015 John Wiley & Sons Ltd
ACKNOWLEDGEMENT The author’s declarations of personal and financial interests are unchanged from those in the original article.9 REFERENCES 1. Yilmaz B, Dayanan R. Letter: reversibility of hepatic fibrosis and immunosuppression withdrawal in patients with autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Aliment Pharmacol Ther 2015; 41: 794. 2. Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 2004; 40: 646–52. 3. Mohamadnejad M, Malekzadeh R, Nasseri-Moghaddam S, et al. Impact of immunosuppressive treatment on liver fibrosis in autoimmune hepatitis. Dig Dis Sci 2005; 50: 547–51. 4. Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20: 2515–32. 5. Leuschner M, Guldutuna S, You T, et al. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol 1996; 25: 49–57. 6. Chazouilleres O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 2006; 44: 400–6. 7. Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54: 374–85. 8. Czaja AJ. Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 1430–8. 9. Czaja AJ. Review article: prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 385–406.
However, these data are at variance with the existing literature, and our own experience, where plasma triglycerides and LDL cholesterol were substantially unaffected by GFD.2, 3 On the contrary, in our sample of young CD patients, a number of blood and instrumental parameters of cardiovascular risk, including HDL cholesterol, were benefitted by GFD.3 In addition, our data are consistent with the low-grade inflammatory aetiology hypothesis of the metabolic syndrome, potentially improved by the treatment of a comorbid immune condition (i.e. CD).2 However, we would like to highlight some potential pitfalls of the valuable paper by Tortora et al. The authors apparently grouped a mixed population sample in their report. Potential CD is commonly not considered a mandatory indication for dietetic intervention.4 We feel that including potential CD patients in the data analysis might have biased the results, provided the percentage was relevant. In addition, the Marsh 2 histology grade used in the paper to diagnose classical CD may 795
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
