PSC: Novel disease associations providing pathogenetic clues?
Authors: Hanno Ehlken, Christoph Schramm
Journal: Journal of Hepatology (2014)

Risk of diabetes and cardiovascular disease in patients with primary sclerosing cholangitisJournal of HepatologyVol. 60Issue 4PreviewPrimary sclerosing cholangitis (PSC) is associated with increased mortality. Cardiovascular disease is a leading cause of death in the Western world. We examined the risk of cardiovascular disease and diabetes (type 1 and type 2) in patients with PSC and their first-degree relatives. Full-Text PDF Primary sclerosing cholangitis (PSC) mainly affects young adults and progresses to end-stage liver disease or cholangiocarcinoma within 15–20 years [1Boonstra K. Weersma R.K. van Erpecum K.J. Rauws E.A. Spanier B.W.M. Poen A.C. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (394) Google Scholar, 2European Association for the Study of the LiverEASL Clinical Practice Guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar]. For these reasons most studies on the course of PSC have concentrated upon the progression of liver disease and the risk of malignancy. The study by Ludvigsson presented in this issue of the Journal [[3]Ludvigsson J.F. Bergquist A. Montgomery S.M. Bahmanyar S. Risk of diabetes and cardiovascular disease in patients with primary sclerosing cholangitis.J Hepatol. 2014; 60: 802-808Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] is of interest, since the authors focused on associations with cardiovascular and other chronic diseases that may not only affect patient health on the long term but may also provide clues to a better understanding of the pathogenesis of PSC. The authors should be applauded for their efforts to dissect the hereditary component of associated diseases from the effects of the chronic disease itself by including around 3000 first-degree relatives in addition to controls obtained from the Swedish National Registry.The aetiology of PSC remains unknown. The risk of developing PSC in first-degree relatives is strongly elevated and the genetic associations of PSC have been extensively studied in recent years [4Melum E. Franke A. Schramm C. Weismüller T.J. Gotthardt D.N. Offner F.A. et al.Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.Nat Genet. 2011; 43: 17-19Crossref PubMed Scopus (194) Google Scholar, 5Karlsen T.H. Kaser A. Deciphering the genetic predisposition to primary sclerosing cholangitis.Semin Liver Dis. 2011; 31: 188-207Crossref PubMed Scopus (24) Google Scholar]. It is clear that the HLA locus harbours a large part of the genetic risk for PSC. Among the non-HLA genes associated with the disease there are many risk variants in immunologically relevant genes shared with several other autoimmune diseases [[5]Karlsen T.H. Kaser A. Deciphering the genetic predisposition to primary sclerosing cholangitis.Semin Liver Dis. 2011; 31: 188-207Crossref PubMed Scopus (24) Google Scholar]. It is therefore not surprising, that PSC is associated with other immune-mediated and autoimmune diseases such as sarcoidosis, thyroid disease, and rheumatoid arthritis. Also, the prevalence of type 1 diabetes (T1D) has been reported to be highly increased in patients with PSC [[6]Mells G.F. Kaser A. Karlsen T.H. Novel insights into autoimmune liver diseases provided by genome-wide association studies.J Autoimmun. 2013; 46: 41-54Crossref PubMed Scopus (85) Google Scholar]. The shared genetic predisposition to develop T1D is nicely confirmed in the present study, since the prevalence of T1D, but not of the other chronic diseases analysed, was increased in the first-degree relatives of patients with PSC.In order to assess novel disease associations with PSC, almost 700 PSC patients from several tertiary care centres in Sweden were compared to more than 6000 controls obtained from the Swedish National Registry. The authors found an increased risk of non-ischemic cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) in PSC patients.While the novel associations that Ludvigsson et al. point out in their study are interesting, several limitations of their multicentre cohort study must be considered when interpreting the results. The authors argue that they have evaluated a large proportion of all PSC patients from the respective regions since for this disease patients are usually referred to tertiary care centres. The controls from the general population were matched for age, sex, calendar year, and county. Importantly though, it would appear likely that in expert centres for a rare disease other entities will be diagnosed with higher sensitivity when compared to the general population with patients seen in primary or secondary care units. Therefore, selection bias may have significantly influenced the results. The authors present the associations of diseases that they have identified in groups as they are listed in the ICD-code, and not as specific diseases. This makes it difficult to delineate possible pathophysiological concepts behind the data especially since numerous ICD-entities within these groups are expected to be associated with advanced liver disease in general.What can we learn from an association of PSC with cardiovascular disease and type 2 diabetes and how could these findings be incorporated into novel pathogenetic concepts? From the clinical point of view, we may not have screened our patients enough for these diseases since the described associations have not come up in single center analyses. From the scientific point of view, these results could fuel novel pathophysiological concepts that may help to better understand PSC pathogenesis. The association of PSC with atherosclerosis might reflect the increased inflammatory burden of an individual with a chronic inflammatory condition. Some autoimmune rheumatic diseases have been associated with premature atherosclerosis [[7]Hollan I. Meroni P.L. Ahearn J.M. Cohen Tervaert J.W. Curran S. Goodyear C.S. et al.Cardiovascular disease in autoimmune rheumatic diseases.Autoimmun Rev. 2013; 12: 1004-1015Crossref PubMed Scopus (192) Google Scholar]. Still, the pathomechanism underlying this association is unknown. What could be the possible underlying pathophysiology of PSC and atherosclerosis, two diseases that come along with sclerosis, dyslipidemia and evidence of endothelial dysfunction [[8]Sinakos E. Abbas G. Jorgensen R.A. Lindor K.D. Serum lipids in primary sclerosing cholangitis.Dig Liver Dis. 2012; 44: 44-48Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]? One of the links between chronic inflammation of the liver and atherosclerosis could be provided by the effects of bile salts and their receptors as they are now recognized as important mediators of inflammation, endocrine function, and energy metabolism [[9]Hageman J. Herrema H. Groen A.K. Kuipers F. A role of the bile salt receptor FXR in atherosclerosis.Arterioscler Thromb Vasc Biol. 2010; 30: 1519-1528Crossref PubMed Scopus (77) Google Scholar]. For example, polymorphisms for the gene encoding the G-protein coupled bile acid receptor TGR5 were associated with PSC and ulcerative colitis [[10]Karlsen T.H. Franke A. Melum E. Kaser A. Hov J.R. Balschun T. et al.Genome-wide association analysis in primary sclerosing cholangitis.Gastroenterology. 2010; 138: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar] and mutations found within the TGR5 gene in PSC were demonstrated to reduce TGR5 signalling capacity [[11]Hov J.R. Keitel V. Laerdahl J.K. Spomer L. Ellinghaus E. ElSharawy A. et al.Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis.PLoS One. 2010; 5: e12403Crossref PubMed Scopus (107) Google Scholar]. Among others, TGR5 is expressed by cholangiocytes, liver sinusoidal endothelial cells and macrophages [[12]Keitel V. Reinehr R. Gatsios P. Rupprecht C. Görg B. Selbach O. et al.The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells.Hepatology. 2007; 45: 695-704Crossref PubMed Scopus (249) Google Scholar]. In Kupffer cells, bile acid induced TGR5 activation reduced LPS mediated cytokine secretion [[13]Keitel V. Donner M. Winandy S. Kubitz R. Häussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells.Biochem Biophys Res Commun. 2008; 372: 78-84Crossref PubMed Scopus (313) Google Scholar]. In a mouse model the activation of this receptor in macrophages inhibited the production of pro-inflammatory cytokines and attenuated atherosclerosis [[14]Pols T.W.H. Nomura M. Harach T. Sasso Lo G. Oosterveer M.H. Thomas C. et al.TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading.Cell Metab. 2011; 14: 747-757Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar]. These results suggest that an altered function of TGR5 could represent a link between cardiovascular risk and bile duct pathology in patients with PSC.The incidence of inflammatory bowel diseases (IBD) and also PSC is increasing in many countries [[15]Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar]. There is now accumulating evidence that dietary factors may contribute to the rising incidence of IBD [[16]Albenberg L.G. Lewis J.D. Wu G.D. Food and the gut microbiota in inflammatory bowel diseases: a critical connection.Curr Opin Gastroenterol. 2012; 28: 314-320Crossref PubMed Scopus (80) Google Scholar]. In IBD, there is also growing support for the concept that the normal intestinal microbiota is dysbalanced. Devkota et al. have recently demonstrated in a mouse model how dietary fats could promote a change in bile acid composition and as a result could lead to chronic intestinal inflammation in a susceptible host [17Devkota S. Wang Y. Musch M.W. Leone V. Fehlner-Peach H. Nadimpalli A. et al.Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice.Nature. 2012; 487: 104-108PubMed Google Scholar, 18Trauner M. Fickert P. Tilg H. Bile acids as modulators of gut microbiota linking dietary habits and inflammatory bowel disease: a potentially dangerous liaison.Gastroenterology. 2013; 144: 844-846Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Atherosclerosis was also linked to the intestinal microbiota in another mouse model: Wang et al. showed that dietary phosphatidylcholine was metabolized by a gut flora dependent process resulting in the promotion of atherosclerosis [[19]Wang Z. Klipfell E. Bennett B.J. Koeth R. Levison B.S. Dugar B. et al.Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011; 472: 57-63Crossref PubMed Scopus (3322) Google Scholar]. For PSC, being closely linked to IBD, one could therefore speculate that an altered bile acid composition or bacterial dysbalance might affect disease pathogenesis. The obvious questions now are: What is the microbiome of PSC and how does it relate to the bile acid composition in ductular bile, in the intestine and the blood? Can we find a microbial dysbiosis or even pathobionts that trigger complications such as inflammation, cancer or atherosclerosis?Should this study impact on how we evaluate our PSC patients? Should we look for T2D and atherosclerosis more extensively? For us the results of this study were surprising since it is not our clinical experience that vascular disease or T2D are relevant problems in the PSC population. Generally, we observe health behaviour in our patients that should protect these individuals against T2D or atherosclerosis (non-smoking, normal BMI, healthy diet). Would this imply that the patients reported here would have been at an even higher risk for these diseases if they behaved like the average individual? Before these novel findings alter the clinical management of our patients the results should clearly be confirmed in other large patient cohorts.In summary, the associations described here by Ludvigsson et al. give stimulating input to develop ideas on the aetiology and pathogenesis of PSC. Is PSC the atherosclerosis of the biliary tree, as has been suggested by Fickert and colleagues [[20]Fickert P. Moustafa T. Trauner M. Primary sclerosing cholangitis – the arteriosclerosis of the bile duct?.Lipids Health Dis. 2007; 6: 3Crossref PubMed Scopus (27) Google Scholar]? The time has come to bring together experts from the fields of metabolic diseases, immunology as well as hepatology in order to decipher the pathogenesis of PSC.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Primary sclerosing cholangitis (PSC) mainly affects young adults and progresses to end-stage liver disease or cholangiocarcinoma within 15–20 years [1Boonstra K. Weersma R.K. van Erpecum K.J. Rauws E.A. Spanier B.W.M. Poen A.C. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (394) Google Scholar, 2European Association for the Study of the LiverEASL Clinical Practice Guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar]. For these reasons most studies on the course of PSC have concentrated upon the progression of liver disease and the risk of malignancy. The study by Ludvigsson presented in this issue of the Journal [[3]Ludvigsson J.F. Bergquist A. Montgomery S.M. Bahmanyar S. Risk of diabetes and cardiovascular disease in patients with primary sclerosing cholangitis.J Hepatol. 2014; 60: 802-808Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] is of interest, since the authors focused on associations with cardiovascular and other chronic diseases that may not only affect patient health on the long term but may also provide clues to a better understanding of the pathogenesis of PSC. The authors should be applauded for their efforts to dissect the hereditary component of associated diseases from the effects of the chronic disease itself by including around 3000 first-degree relatives in addition to controls obtained from the Swedish National Registry. The aetiology of PSC remains unknown. The risk of developing PSC in first-degree relatives is strongly elevated and the genetic associations of PSC have been extensively studied in recent years [4Melum E. Franke A. Schramm C. Weismüller T.J. Gotthardt D.N. Offner F.A. et al.Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.Nat Genet. 2011; 43: 17-19Crossref PubMed Scopus (194) Google Scholar, 5Karlsen T.H. Kaser A. Deciphering the genetic predisposition to primary sclerosing cholangitis.Semin Liver Dis. 2011; 31: 188-207Crossref PubMed Scopus (24) Google Scholar]. It is clear that the HLA locus harbours a large part of the genetic risk for PSC. Among the non-HLA genes associated with the disease there are many risk variants in immunologically relevant genes shared with several other autoimmune diseases [[5]Karlsen T.H. Kaser A. Deciphering the genetic predisposition to primary sclerosing cholangitis.Semin Liver Dis. 2011; 31: 188-207Crossref PubMed Scopus (24) Google Scholar]. It is therefore not surprising, that PSC is associated with other immune-mediated and autoimmune diseases such as sarcoidosis, thyroid disease, and rheumatoid arthritis. Also, the prevalence of type 1 diabetes (T1D) has been reported to be highly increased in patients with PSC [[6]Mells G.F. Kaser A. Karlsen T.H. Novel insights into autoimmune liver diseases provided by genome-wide association studies.J Autoimmun. 2013; 46: 41-54Crossref PubMed Scopus (85) Google Scholar]. The shared genetic predisposition to develop T1D is nicely confirmed in the present study, since the prevalence of T1D, but not of the other chronic diseases analysed, was increased in the first-degree relatives of patients with PSC. In order to assess novel disease associations with PSC, almost 700 PSC patients from several tertiary care centres in Sweden were compared to more than 6000 controls obtained from the Swedish National Registry. The authors found an increased risk of non-ischemic cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) in PSC patients. While the novel associations that Ludvigsson et al. point out in their study are interesting, several limitations of their multicentre cohort study must be considered when interpreting the results. The authors argue that they have evaluated a large proportion of all PSC patients from the respective regions since for this disease patients are usually referred to tertiary care centres. The controls from the general population were matched for age, sex, calendar year, and county. Importantly though, it would appear likely that in expert centres for a rare disease other entities will be diagnosed with higher sensitivity when compared to the general population with patients seen in primary or secondary care units. Therefore, selection bias may have significantly influenced the results. The authors present the associations of diseases that they have identified in groups as they are listed in the ICD-code, and not as specific diseases. This makes it difficult to delineate possible pathophysiological concepts behind the data especially since numerous ICD-entities within these groups are expected to be associated with advanced liver disease in general. What can we learn from an association of PSC with cardiovascular disease and type 2 diabetes and how could these findings be incorporated into novel pathogenetic concepts? From the clinical point of view, we may not have screened our patients enough for these diseases since the described associations have not come up in single center analyses. From the scientific point of view, these results could fuel novel pathophysiological concepts that may help to better understand PSC pathogenesis. The association of PSC with atherosclerosis might reflect the increased inflammatory burden of an individual with a chronic inflammatory condition. Some autoimmune rheumatic diseases have been associated with premature atherosclerosis [[7]Hollan I. Meroni P.L. Ahearn J.M. Cohen Tervaert J.W. Curran S. Goodyear C.S. et al.Cardiovascular disease in autoimmune rheumatic diseases.Autoimmun Rev. 2013; 12: 1004-1015Crossref PubMed Scopus (192) Google Scholar]. Still, the pathomechanism underlying this association is unknown. What could be the possible underlying pathophysiology of PSC and atherosclerosis, two diseases that come along with sclerosis, dyslipidemia and evidence of endothelial dysfunction [[8]Sinakos E. Abbas G. Jorgensen R.A. Lindor K.D. Serum lipids in primary sclerosing cholangitis.Dig Liver Dis. 2012; 44: 44-48Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]? One of the links between chronic inflammation of the liver and atherosclerosis could be provided by the effects of bile salts and their receptors as they are now recognized as important mediators of inflammation, endocrine function, and energy metabolism [[9]Hageman J. Herrema H. Groen A.K. Kuipers F. A role of the bile salt receptor FXR in atherosclerosis.Arterioscler Thromb Vasc Biol. 2010; 30: 1519-1528Crossref PubMed Scopus (77) Google Scholar]. For example, polymorphisms for the gene encoding the G-protein coupled bile acid receptor TGR5 were associated with PSC and ulcerative colitis [[10]Karlsen T.H. Franke A. Melum E. Kaser A. Hov J.R. Balschun T. et al.Genome-wide association analysis in primary sclerosing cholangitis.Gastroenterology. 2010; 138: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar] and mutations found within the TGR5 gene in PSC were demonstrated to reduce TGR5 signalling capacity [[11]Hov J.R. Keitel V. Laerdahl J.K. Spomer L. Ellinghaus E. ElSharawy A. et al.Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis.PLoS One. 2010; 5: e12403Crossref PubMed Scopus (107) Google Scholar]. Among others, TGR5 is expressed by cholangiocytes, liver sinusoidal endothelial cells and macrophages [[12]Keitel V. Reinehr R. Gatsios P. Rupprecht C. Görg B. Selbach O. et al.The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells.Hepatology. 2007; 45: 695-704Crossref PubMed Scopus (249) Google Scholar]. In Kupffer cells, bile acid induced TGR5 activation reduced LPS mediated cytokine secretion [[13]Keitel V. Donner M. Winandy S. Kubitz R. Häussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells.Biochem Biophys Res Commun. 2008; 372: 78-84Crossref PubMed Scopus (313) Google Scholar]. In a mouse model the activation of this receptor in macrophages inhibited the production of pro-inflammatory cytokines and attenuated atherosclerosis [[14]Pols T.W.H. Nomura M. Harach T. Sasso Lo G. Oosterveer M.H. Thomas C. et al.TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading.Cell Metab. 2011; 14: 747-757Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar]. These results suggest that an altered function of TGR5 could represent a link between cardiovascular risk and bile duct pathology in patients with PSC. The incidence of inflammatory bowel diseases (IBD) and also PSC is increasing in many countries [[15]Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar]. There is now accumulating evidence that dietary factors may contribute to the rising incidence of IBD [[16]Albenberg L.G. Lewis J.D. Wu G.D. Food and the gut microbiota in inflammatory bowel diseases: a critical connection.Curr Opin Gastroenterol. 2012; 28: 314-320Crossref PubMed Scopus (80) Google Scholar]. In IBD, there is also growing support for the concept that the normal intestinal microbiota is dysbalanced. Devkota et al. have recently demonstrated in a mouse model how dietary fats could promote a change in bile acid composition and as a result could lead to chronic intestinal inflammation in a susceptible host [17Devkota S. Wang Y. Musch M.W. Leone V. Fehlner-Peach H. Nadimpalli A. et al.Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice.Nature. 2012; 487: 104-108PubMed Google Scholar, 18Trauner M. Fickert P. Tilg H. Bile acids as modulators of gut microbiota linking dietary habits and inflammatory bowel disease: a potentially dangerous liaison.Gastroenterology. 2013; 144: 844-846Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Atherosclerosis was also linked to the intestinal microbiota in another mouse model: Wang et al. showed that dietary phosphatidylcholine was metabolized by a gut flora dependent process resulting in the promotion of atherosclerosis [[19]Wang Z. Klipfell E. Bennett B.J. Koeth R. Levison B.S. Dugar B. et al.Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011; 472: 57-63Crossref PubMed Scopus (3322) Google Scholar]. For PSC, being closely linked to IBD, one could therefore speculate that an altered bile acid composition or bacterial dysbalance might affect disease pathogenesis. The obvious questions now are: What is the microbiome of PSC and how does it relate to the bile acid composition in ductular bile, in the intestine and the blood? Can we find a microbial dysbiosis or even pathobionts that trigger complications such as inflammation, cancer or atherosclerosis? Should this study impact on how we evaluate our PSC patients? Should we look for T2D and atherosclerosis more extensively? For us the results of this study were surprising since it is not our clinical experience that vascular disease or T2D are relevant problems in the PSC population. Generally, we observe health behaviour in our patients that should protect these individuals against T2D or atherosclerosis (non-smoking, normal BMI, healthy diet). Would this imply that the patients reported here would have been at an even higher risk for these diseases if they behaved like the average individual? Before these novel findings alter the clinical management of our patients the results should clearly be confirmed in other large patient cohorts. In summary, the associations described here by Ludvigsson et al. give stimulating input to develop ideas on the aetiology and pathogenesis of PSC. Is PSC the atherosclerosis of the biliary tree, as has been suggested by Fickert and colleagues [[20]Fickert P. Moustafa T. Trauner M. Primary sclerosing cholangitis – the arteriosclerosis of the bile duct?.Lipids Health Dis. 2007; 6: 3Crossref PubMed Scopus (27) Google Scholar]? The time has come to bring together experts from the fields of metabolic diseases, immunology as well as hepatology in order to decipher the pathogenesis of PSC. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.