Long-term outcome in PSC/AIH “overlap syndrome”: Does immunosuppression also treat the PSC component?
Authors: Roman Zenouzi, Ansgar W. Lohse
Journal: Journal of Hepatology (2014)

Features of both primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) in the same patient were first described about 2 decades ago, including a small first case series published in the Journal of Hepatology in 1996 by Gohlke et al. [1Gohlke F. Lohse A.W. Dienes H.P. Lohr H. Marker-Hermann E. Gerken G. et al.Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis.J Hepatol. 1996; 24: 699-705Abstract Full Text PDF PubMed Scopus (163) Google Scholar, 2Rabinovitz M. Demetris A.J. Bou-Abboud C.F. Van Thiel D.H. Simultaneous occurrence of primary sclerosing cholangitis and autoimmune chronic active hepatitis in a patient with ulcerative colitis.Dig Dis Sci. 1992; 37: 1606-1611Crossref PubMed Scopus (87) Google Scholar]. Most notably, at first diagnosis all three patients from this early report fulfilled the criteria for a definite (patient 1 and 2) or probable (patient 3) AIH, according to the scoring system of the International Autoimmune Hepatitis Group (IAIHG) from 1993 [[3]Johnson P.J. McFarlane I.G. Meeting report: International Autoimmune Hepatitis Group.Hepatology. 1993; 18: 998-1005Crossref PubMed Scopus (1063) Google Scholar], but responded insufficiently to immunosuppression, particularly with respect to cholestatic biochemical parameters. Therefore, in all patients a retrograde endoscopic cholangiography was performed, showing a peripheral bile duct rarefication and multiple strictures and dilatations of the intra- (patients 1–3) and extrahepatic (patient 3) bile ducts. Additionally, early follow-up liver biopsy in two patients detected portal fibrosis with fibrous obliterative cholangitis and a reduction of bile ducts (patient 1) and a progression to liver cirrhosis with rarefication of bile ducts and partly onion-like periductular fibrosis (patient 3), respectively. The findings strongly suggested that from the beginning these patients were affected not only by AIH but also by cholangiopathy. Under the assumption of an "overlap syndrome" between PSC and AIH ursodeoxycholic acid (UDCA) was therefore added to the immunosuppressive regime and cholestatic biochemical parameters decreased. Since this early report, there has been an increasing awareness for patients with features of both conditions, often called "PSC/AIH overlap", and nowadays overlapping features are widely accepted to constitute a variant of the primary disorder, mostly PSC, rather than a separate disease entity. This, indeed, is a renunciation from the original term of the "overlap syndrome" and a consequence of a lack of specific diagnostic tests, evidence based treatment strategies and implications for prognosis [[4]Boberg K.M. Chapman R.W. Hirschfield G.M. Lohse A.W. Manns M.P. Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatol. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar]. In fact, despite some larger cohorts published on this issue in the last years [5Boberg K.M. Fausa O. Haaland T. Holter E. Mellbye O.J. Spurkland A. et al.Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis.Hepatology. 1996; 23: 1369-1376Crossref PubMed Google Scholar, 6Floreani A. Rizzotto E.R. Ferrara F. Carderi I. Caroli D. Blasone L. et al.Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.Am J Gastroenterol. 2005; 100: 1516-1522Crossref PubMed Scopus (178) Google Scholar, 7Luth S. Kanzler S. Frenzel C. Kasper H.U. Dienes H.P. Schramm C. et al.Characteristics and long-term prognosis of the autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.J Clin Gastroenterol. 2009; 43: 75-80Crossref PubMed Scopus (63) Google Scholar, 8van Buuren H.R. van Hoogstraten H.J.E. Terkivatan T. Schalm S.W. Vleggaar F.P. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis.J Hepatol. 2000; 33: 543-548Crossref PubMed Scopus (160) Google Scholar], data on PSC/AIH overlap patients are scarce and the long-term outcome is not well characterized, underlining that follow-up data focussing on this special patient cohort are required. Therefore, we here report the long-term follow-up of the three cases originally published by Gohlke et al. in 1996 [[1]Gohlke F. Lohse A.W. Dienes H.P. Lohr H. Marker-Hermann E. Gerken G. et al.Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis.J Hepatol. 1996; 24: 699-705Abstract Full Text PDF PubMed Scopus (163) Google Scholar]. The most important message is, that all patients (patients 1–3) are still alive 22, 27, and 25 years after first presentation – yet disease has been progressive in all three cases despite a combined regime of immunosuppression and UDCA (Table 1). In patient 1, the further clinical course was characterized by progressive bile duct destruction recently treated by balloon dilatation with partial success. The therapeutic regime with azathioprine and UDCA has been continued until today. Still, 20 years after the first presentation, follow-up liver biopsy demonstrated an incomplete biliary cirrhosis, while at the same time oesophageal varices were first diagnosed in this patient. Due to these findings and a progressive weight loss, the patient has now been listed for liver transplantation. In patient 2, bile duct interventions due to dominant strictures were required in the first years after diagnosis. While the patient's condition is clinically stable at the moment, as is his ulcerative colitis, a follow-up liver biopsy 17 years after the initial diagnosis showed beginning liver cirrhosis based on destructive cholangitis. Since portal hepatitis was mostly inactive, immunosuppressive treatment with azathioprine was stopped and the present treatment is limited to UDCA and mesalazine. As in patient 1, recent laboratory findings showed a distinct elevation of cholestatic biochemical parameters while aminotransferase levels were normal or only slightly elevated. Still, patient 2 has developed oesophageal varices and is listed for liver transplantation, as well. Until now, only in patient 3 liver transplantation has been performed – 22 years after the first diagnosis due to progressive bile duct destruction and liver cirrhosis. The examination of the explanted liver showed a complete cirrhosis with bile duct inflammation and fibrosis. The immunosuppressive regime, which included azathioprine until transplantation, now consists of tacrolimus and prednisolone. So far, there are no signs of recurrence of the original liver disease and the patient's physical condition is excellent. None of the three patients have developed malignancy until today, nor has an incidental tumour been observed in the explanted liver of patient 3.Table 1Long-term follow-up data of PSC/AIH overlap patients.Laboratory parameters (reference rage): ALP, alkaline phosphatase (40–129 U/l); ANA, antinuclear antibody (titre); ALT, alanine aminotransferase (10–50 U/l); AST, aspartate aminotransferase (10–50 U/l); GGT, gamma-glutamyl transpeptidase (0–65 U/l); Bilirubin (<1.2 mg/dl); IgG, immunoglobulin G (7–16 g/l); SMA, smooth muscle antibody (titre).IBD, inflammatory bowel disease; UC, ulcerative colitis.∗Before/1 year after start with immunosuppression with azathioprine (1–1.5 mg/kg) and prednisolone (1 mg/kg, initial dosis) in combination with ursodeoxycholic acid (UDCA). Open table in a new tab Laboratory parameters (reference rage): ALP, alkaline phosphatase (40–129 U/l); ANA, antinuclear antibody (titre); ALT, alanine aminotransferase (10–50 U/l); AST, aspartate aminotransferase (10–50 U/l); GGT, gamma-glutamyl transpeptidase (0–65 U/l); Bilirubin (<1.2 mg/dl); IgG, immunoglobulin G (7–16 g/l); SMA, smooth muscle antibody (titre). IBD, inflammatory bowel disease; UC, ulcerative colitis. ∗Before/1 year after start with immunosuppression with azathioprine (1–1.5 mg/kg) and prednisolone (1 mg/kg, initial dosis) in combination with ursodeoxycholic acid (UDCA). With up to 27 years, we here report the longest follow-up ever published on the PSC/AIH "overlap syndrome" so far. In all patients, the original diagnosis was AIH. However, all patients insufficiently responded to immunosuppressive therapy and eventually showed typical signs of a large duct PSC. The further course of the liver disease was primarily characterized by bile duct destruction rather than by hepatitis or decompensation of liver cirrhosis, underlining that PSC was the primary disorder. In inflammatory or aggressive PSC, as PSC/AIH overlap is now regarded, one would expect a poorer prognosis than in patients with straight forward PSC. However, the clinical course of these patients so far appears to be comparably benign with only one patient receiving liver transplantation after a relatively long observation period of 22 years and a transplant-free survival of 22 and 27 years of the other patients. Indeed, there is increasing evidence for a better outcome of PSC/AIH overlap compared to classical PSC patients, most notably demonstrated in a prospective case-control study by Floreani et al. where patients' survival was better when an overlap between both diseases was present [[6]Floreani A. Rizzotto E.R. Ferrara F. Carderi I. Caroli D. Blasone L. et al.Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.Am J Gastroenterol. 2005; 100: 1516-1522Crossref PubMed Scopus (178) Google Scholar]. What may be the reasons behind this proposed better outcome of the overlap patients? A major feature of both PSC/AIH overlap cohorts – the patients reported by Floreani et al. and our patients, separating them from classical PSC patients, is the use of immunosuppression, which for the vast majority of patients consisted of azathioprine and steroids. Most authors rate this regime as beneficial for the AIH component only [[4]Boberg K.M. Chapman R.W. Hirschfield G.M. Lohse A.W. Manns M.P. Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatol. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar]. This, in fact, would implicate a comparably poor outcome of PSC/AIH overlap and classical PSC patients. However, a better outcome of the overlap patients would indicate, that immunosuppression may benefit both conditions – the AIH and the PSC component, as well. In fact, even though data available on this issue are scarce and conflicting [[9]Cullen S.N. Chapman R.W. Review article: current management of primary sclerosing cholangitis.Aliment Pharmacol Ther. 2005; 21: 933-948Crossref PubMed Scopus (70) Google Scholar], there is evidence that a combined regime of azathioprine, steroids and UDCA positively effects disease progression in classical PSC also [[10]Schramm C. Schirmacher P. Helmreich-Becker I. Gerken G. zum Buschenfelde K.H. Lohse A.W. Combined therapy with azathioprine, prednisolone, and ursodiol in patients with primary sclerosing cholangitis. A case series.Ann Intern Med. 1999; 131: 943-946Crossref PubMed Scopus (101) Google Scholar]. This, indeed, would fit the concept of a putative autoimmune liver disease. Still, case numbers particularly of the series presented here are too small to draw any firm conclusions from the available data. Thus, the long-term outcome and the role of immunosuppression in patients with an overlap of both PSC and AIH need to be elucidated further. Summarized, the long-term follow-up of this very first case series suggests that the clinical course of patients with overlapping features between PSC and AIH seems to be better than in classical PSC, indicating that immunosuppression might have a positive effect on the progression of the PSC component. As particularly in classical PSC the prognosis is severe and treatment options are strongly needed, controlled trials with a combination of azathioprine, steroids and UDCA appear warranted. This work was supported by the Deutsche Forschungsgemeinschaft (SFB841). The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.